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A comparative study of central cardiovascular dynamics in vertebrates Langille, Brian Lowell 1975

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A COMPARATIVE STUDY OF CENTRAL CARDIOVASCULAR DYNAMICS IN VERTEBRATES by BRIAN LOWELL LANGILLE B.Sc, University of B r i t i s h Columbia, 1969 M.Sc, University of B r i t i s h Columbia,. 1970 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE i REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in the Department of ZOOLOGY e accept t h i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA September, 1975 In presenting th i s thes is in pa r t i a l fu l f i lment of the requirements for an advanced degree at the Un ivers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make it f ree ly ava i l ab le for reference and study. I fur ther agree that permission for extensive copying of th is thes is for scho lar ly purposes may be granted by the Head of my Department or by his representat ives. It is understood that copying or pub l i ca t ion of th is thes is for f i nanc ia l gain sha l l not be allowed without my writ ten permission. The Univers i ty of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date Oct' 2.1 . Department of Abstract The dynamic properties of blood flow through the heart and a r t e r i a l systems have been examined i n representative species of f i s h , amphibia, b i r d s and mammals. In the amphibian examined, the b u l l f r o g Rana catesbeiana. the conus a r t e r i o s i s was found to perform no active valving function and hence was not responsible for shunting blood to, or away from, the lungs i n response to lung v e n t i l a t i o n or apnoea. Conus volume changes generated a small f r a c t i o n of cardiac stroke volume although a low impedance of the pulmocutaneous vasculature resulted i n a p r e f e r e n t i a l d i s t r i b u t i o n of t h i s blood to the gas exchanger c i r c u l a t i o n s . The pressure pulse took a n e g l i g i b l e f r a c t i o n of the cardiac cycle to traverse the a r t e r i a l tree and p e r i p h e r a l l y recorded pressures were si m i l a r i n p r o f i l e to c e n t r a l pressures, these r e s u l t s i n d i c a t i n g that wave transmission e f f e c t s were small. Impedance analysis of pressure and flow data suggested that a two element lumped parameter (windkessel) model accu-r a t e l y describes a r t e r i a l pressure-flow r e l a t i o n s h i p s i n the b u l l f r o g . A r t e r i a l haemodynamics i n the cod, Gadus morhua was examined i n terms of a hydraulic model of the ' i n s e r i e s ' g i l l and systemic c i r c u l a t i o n s . Results indicate that the dorsal aorta i s not a r i g i d conduit and the compliance of t h i s vessel has a marked e f f e c t on the p u l s a t i l i t y of blood flow through i i the g i l l s . i n the duck. Anas platyrhynchos pressure and flow pro-f i l e s have been mapped throughout the c e n t r a l c i r c u l a t i o n . Mean systemic a r t e r i a l pressure (143 +_ 2 mm Hg) and cardiac output (219 +_ 7 ml/min per kg) were high compared with mammals of s i m i l a r size although pulmonary pressures were not high, perhaps because of the unique structure of the avian lung. 75% of t o t a l systemic flow was d i s t r i b u t e d to wing, f l i g h t muscles and head by the brachiocephalic a r t e r i e s . Unlike the s i t u a t i o n i n the b u l l f r o g wave transmission phenomena had a pronounced e f f e c t on a r t e r i a l pressure and flow signals and impedance data were characterised by features commonly ascribed to the e f f e c t s of wave r e f l e c t i o n . Therefore i t i s concluded that the wind-kessel i s not a r e a l i s t i c model of the avian a r t e r i a l system. Pressures generated i n both v e n t r i c l e s of the rabbit heart were influenced by contraction of the opposite v e n t r i c l e although the influence of r i g h t v e n t r i c u l a r contraction on l e f t v e n t r i c u l a r pressure was n e g l i g i b l e during normal cardiac function and only became marked when the r i g h t v e n t r i c u l a r volumes were large or l e f t v e n t r i c u l a r volumes were small. Comparison of the e f f e c t s of vasomotion and a r t i f i c i a l l y induced di s c r e t e r e f l e c t i o n s confirmed that pulse wave transmission e f f e c t s i n mammalian a r t e r i e s are dominated by r e f l e c t i o n s from the a r t e r i o l a r beds. Although studies of a hydraulic model i i i confirmed the v i a b i l i t y of transmission l i n e theories on the e f f e c t s of s p a t i a l v a r i a t i o n s i n a r t e r i a l wall e l a s t i c i t y , close examination suggests that t h i s ' e l a s t i c taper' does not have a dominant e f f e c t on wave propagation. i i v i TABLE OF CONTENTS General Introduction 1 Section I. Central Blood Flow in the Bullfrog, Rana Catesbeiana Introduction 18 Methods 24 Results 29 Discussion 53 Section II. The Single Circulation in the Cod, Gadus morhua Introduction 60 Methods 64 Results 68 Discussion 76 Section III.Central Cardiovascular Dynamics of Ducks Introduction 81 Methods 83 Results 93 Discussion 103 Section IV. The Effects of 'Elastic Taper* and Reflections on Wave Propagation in Mammalian Arteries Introduction 109 Methods 113 Results 123 V Discussion Section V.. Mechanic Interaction Between of the Mammalian Heart Introduction Methods Results Discussion General Discussion Summary Bibliography Appendix Bibliography 133 the V e n t r i c l e s 140 143 147 156 160 163 166 182 185 VI Figure 1. Figure 2. Figure 3. Figure 1-1, Figure 1-2, Figure 1-3. Figure 1-4. Figure 1-5, Figure 1-6. Figure 1-7. Figure 1-8, ' L I S T OF P I G U A Z S Blood -flow pathways in vertebrates. 3 Central and peripheral a r t e r i a l pressure profiles from the rabbit, 9 Impedance curves, for v/indkessel models - ; i t h different time constants. 12 Intraventricular cavity of the frog heart. 30 The conus arteriosis and. spiral valve of the frog heart. 31 Frozen sections of the conus arteriosis and spiral valve. 33 Blood pressures in the v e n t r i c l e , conus a r t e r i o s i s and a r t e r i a l arches of the b u l l f r o g . 35 Blood pressures in the systemic arch, pulmo-cutaneous arch and V e n t r i c l e of the b u l l f r o g . 3 5 Arch pressures in the b u l l f r o g during synchronous contraction of the ventricle and conus arteriosis. 39 3ffeet of prolonged coronary ligation on central pressures in the bullfrog. 41 Test of valve competency in the r e l a x e d frog heart. 42 v i i Figure 1-9. Systemic and pulmocutaneous arch pressures and flows i n the b u l l f r o g . Figure 1-10. Arch pressures and flows before and during apnoea. Figure 1-11. Input impedance of the systemic c i r c u l a t i o n of the frog. Figure 1-12. Input impedance of the pulmocutaneous c i r c u l a t i o n i n the b u l l f r o g during lung v e n t i l a t i o n and during apnoea. Figure 1-13. Central and peripheral a r t e r i a l pressures i n the b u l l f r o g . Figure 2-1. Ventral and dorsal a o r t i c blood flows i n the cod. Figure 2-2. Dorsal a o r t i c pressure and flow i n the cod. Figure 2-3. E f f e c t of 'dorsal a o r t i c ' compliance on pressures and flows i n a hydraulic model of the f i s h c i r c u l a t i 6 n . Figure 2-4. G i l l and systemic flow r e l a t i o n s h i p s predicted by an e l e c t r i c a l analogue of the f i s h c i r c u l a t i o n . Figure 3-1. Technique for measuring a r t e r i a l pulse wave v e l o c i t y i n the duck. V l l l Figure 3-2. Pressures and flows in the ce n t r a l Figure 3-3. c i r c u l a t i o n of the duck. Overlap diagram of pressures and flows recorded i n the duck. Figure 3-5, Figure 3-6, Figure 4-1, Figure 4-2, Figure 4-3, Figure 4—4, Figure 4-5, 94 95 Figure 3-4. Central and peripheral a r t e r i a l pressures i n the duck. 97 E f f e c t of adrenaline on the pulmonary a r t e r i a l flow p r o f i l e i n the duck. 100 Input impedances to the systemic and pulmonary c i r c u l a t i o n s of the duck. 101 Apparatus for measuring e l a s t i c i t y . 114 E l a s t i c modulus vs. p o s i t i o n i n a hydraulic model. 124 Pressure wave ampl i f i c a t i o n i n an e l a s t i c a l l y tapered tube. 125 Transfer function for the pressure wave propagated along an e l a s t i c a l l y tapered tube. 127 Central and peripheral pressures recorded i n the rabbit aorta. The e f f e c t of vasoactive drugs. 129 Figure 4-6. The e f f e c t s of vasoactive drugs on the transfer function of a r t e r i a l pressure wave propagation. 131 i x Figure 5 - 1 . V e n t r i c u l a r pressures and rates of change of pressures i n the rabbit during a o r t i c occlusion. Figure 5 - 2 . V e n t r i c u l a r pressures during sinusoidal infusion of saline into the l e f t v e n t r i c l e Figure 5 - 3 . The e f f e c t of pulmonary outflow occlusion on v e n t r i c u l a r pressures and rates of change of pressures. Figure 5 - 4 . Inter-ventricular pressure transference i n the excised heart i n r i g o r mortis. Figure A - 1 . Manometer frequency response determined by the Fourier transform technique. X LIST OF TABLES Table 1. Values for cardiovascular parameters measured i n cod. xi ACKNOWLEDGEMENTS I wish to thank Dr. D.R. Jones f o r h i s e n t h u s i a s t i c s u p e r v i s i o n of t h i s research and p a r t i c u l a r l y f o r h i s e f f o r t s i n a c q u a i n t i n g me xvith experimental techniques of c a r d i o -v a s c u l a r b i o p h y s i c s . I am al s o g r a t e f u l to C o l i n Parkinson and Daphne Hards f o r t h e i r t e c h n i c a l a s s i s t a n c e and to Mr. E r i c Minch f o r as s i s t a n c e w i t h the computer a n a l y s i s of data In S e c t i o n IV. B i l l Milsom and N i g e l West c o n t r i b u t e d a number of help-f u l suggestions on the p r e s e n t a t i o n of my r e s u l t s . F i n a l l y I am most g r a t e f u l to L o r r a i n e L a n g i l l e f o r proof-reading and t y p i n g the t h e s i s and f o r her support and encouragement throughout the course of t h i s study. A l l i n vivo experiments on the cod i n S e c t i o n I I were performed by D.R. Jones, D.J. Randall and G. Shelton although these workers do not n e c e s s a r i l y agree w i t h the conclusions I have drawn from t h e i r r e s u l t s . Uany of the experiments in Sections I and III were performed jointly with D.R. Jones although D.R. Jones does not necessarily agree with my interpretation of the results of these experiments„ 1 GENERAL INTRODUCTION In a l l but the smallest, most p r i m i t i v e organisms d i f -fusion alone i s inadequate for the supply of oxygen and nutrients to, and the removal of metabolic wastes from,the tissues; there-fore most animals u t i l i z e some sort of convective transport system. In almost a l l vertebrates t h i s system consists of a cent r a l pump, the heart, which drives a l i q u i d transport medium, the blood, continuously around a closed vascular system. The vascular system d i s t r i b u t e s blood to s p e c i a l i z e d exchangers (e.g. g i l l s , lungs, gut), where l o c a l d i f f u s i o n supplies nutrients and oxygen to the blood, and to the tissues where these nutrients are absorbed. Metabolic wastes transferred to the blood from the tissues are removed by again passing the blood through exchanger systems (e.g. kidney). Transfer at the tissues takes place across a fin e network of microscopic c a p i l l a r y vessels, an arrangement that d i s t r i b u t e s blood supply to the deepest regions of the tissues and permits f i n e control of blood flow d i s t r i b u t i o n i n the in t e r e s t s of maintaining homeostasis. Thus an understanding of cardiovascular function requires a knowledge of the transport properties of the blood (e.g. blood-gas association, d i s s o c i a t i o n c h a r a c t e r i s t i c s ) , the mechanism of transfer across c a p i l l a r y walls, the regulation of the functions of the cardiovascular system and the mechanical 2 aspects of pumping blood through a complex network of blood vessels. It is with the last of factors that the present study i s concerned. A major d i f f i c u l t y of a comparative study of haemodynamics in vertebrates is the marked v a r i a b i l i t y in cardiovascular form and function which has accompanied vertebrate phylogenetic development. Such variations are intimately related to the different environments which vertebrate species inhabit and in this respect adaptions to different modes of respiratory gas exchange.are particularly important. Fig. 1 illustrates a schematic view of the manner in which blood is distributed to the gas exchanger and tissue circulation in vertebrates. The arrangement in fishes of a direct, 'in series* connection be-tween the g i l l and systemic circulations with no intervening pump poses unique questions about the dynamic interaction between these two systems and although Satchell (1971) has outlined some of the associated problems no experimental in-vestigations have been published. Instead experimental studies deal mainly with net cardiac output (Murdaugh et a l . , 1965; Mott, 1957) and comparisons of art e r i a l blood pressures proximal and di s t a l to the g i l l s (Stevens and Randall, 1967). While such measurements supply valuable information on cardiovascular adjustments to exercise (Stevens and Randall, 1967 a and b) and changing environmental factors (Holeton and Randall, 1967) they Figure 1. Blood flow pathways i n f i s h , amphibia, mammals (and birds) and r e p t i l e s . fishes gills tissues hearf skin lungs amphibia vent. nL.A. ^ - 1 tissues lungs mammals R.V UR.A. ^ —... 1 •« L V . N L . A . tissues crocodilia .-- • lungs — — . 4 " i R.V U R . A . „ + L L V . n L - A -tissues p . 1 non-crocodilian reptiles • ^ lungs T* . 1 UR.A . ^ 1 •< fetal — tissues > 1 provide l i m i t e d information on the dynamics of blood flow. The temptation to apply p r i n c i p l e s of blood flow i n single vascular beds to the combined g i l l and systemic c i r c u l a t i o n s of the f i s h i s dangerous and has led to erroneous arguments on the nature of the pressure gradient across the g i l l s (Holeton and Randall, 1967). In amphibia blood i n the single v e n t r i c l e t r a v e l s to either the gas exchanger (lungs, skin) or the tissue c i r c u l a t i o n s rather than sequentially through both, an arrangement which allows shunting of blood to or away from the lungs i n response to changes i n oxygen a v a i l a b i l i t y (Shelton, 1970; Emilio and Shelton, 1972). In bir d s and mammals blood flow again passes sequentially through the tissues and the lungs although i n t h i s case a second pump, the r i g h t v e n t r i c l e , drives blood around the lung c i r c u l a t i o n . The existence of two completely divided c i r c u l a t i o n s requires that the output of the two pumps be. equal i f volume loading of one c i r c u l a t i o n i s to be avoided and no shunting to or from the lungs i s possible. The s i t u a t i o n i n the non-crocodilian r e p t i l e s (Chelonia and Squamata) i s some-what intermediate between that of amphibia and mammals with the v e n t r i c l e being p a r t i a l l y divided. I t may be that, l i k e amphibia, these r e p t i l e s shunt blood to or from the lungs i n response to changing conditions but White (1968) fe e l s that, at l e a s t when these animals are re s t i n g and breathing a i r , there 5 is effective separation of cardiac cavities and the situation approaches that of mammals. In crocodilian reptiles the two ventricles are completely divided and although the l e f t aorta arises from the right ventricle i t anastomoses with the right aorta via the foramen Pinizzae and normally high systemic pressures transmitted through the foramen prevent right ven-tricular ejection into this vessel. Nonetheless the po s s i b i l i t y of blood shunting remains i f under certain circumstances right ventricular pressures reach those of the l e f t ventricle. Obviously an analysis of cardiovascular dynamics in any vertebrate species must involve consideration of the pumping characteristics of the heart, the dynamic properties of the vascular beds and the interaction between these two factors. Examinations of cardiac function in lower vertebrates have traditionally been based on purely anatomical studies (the study of Sabatier, 1873 is a classic examination of anatomy of vertebrate hearts whereas that of Sharma, 1957 is a modern application of the same approach). However the advancement of sophisticated techniques for measuring blood pressures, flow rates and flow patterns in the past two decades has resulted in many studies of both anatomy and physiology which, in some cases, have disproven theories based on purely anatomical investigations (for example see de Graff, 1957). In fishes this approach has established that the conus arteriosis of elasmobranchs (sharks and skates), a contractile chamber be-tween the ventricle and the ventral aorta, serves a type of active valving function (Satchell and Jones, 1967) while the similarly situated bulbus arteriosis of teleost fishes, is a simple elastic chamber which serves to depulsate ventricular ejection (Johansen, 1962; Randall, 1968). The complex nature of blood flow through the p a r t i a l l y divided amphibian and reptilian hearts has been elucidated by correlating the cy c l i c a l volume changes of the cardiac chambers with pressure recordings (Shelton and Jones, 1965(b)) and by following dye streams (Simons, 1957) and radio-opaque madia (Johansen 1971, White, 1968) through the heart. Despite such advances many problems remain. Even the mechanics of the mammalian heart, although widely studied, is in many ways poorly established and some of the problems encountered in analyzing the function of this pair of interconnected, asymmetrical, muscular pumps which contract in a complex fashion may be technically insurmountable at the present time. The complex nature of cardiac contraction in most vert-ebrate means that attempts to assess many aspects of blood flow through the cardiac chambers are limited to qualitative descriptions. On the other hand the nearly one-dimensional flow of blood in cyl i n d r i c a l l y symmetrical vessels of the art e r i a l tree makes a more quantitative approach feasible and 7 two such approaches have been applied to the study of blood flow i n mammalian a r t e r i e s . According to the f i r s t approach the high pressures produced by cardiac ejection (systole) cause a synchronous expansion of the a r t e r i a l tree and thus the a r t e r i e s hold an increased volume of blood during t h i s phase of the cycle. During d i a s t o l e passive contraction of these vessels drives t h i s stored blood through the terminal c a p i l l a r y beds to maintain peripheral flow between cardiac ejections; thus the a r t e r i a l c i r c u l a t i o n i s viewed as an e l a s t i c r e s e r v o i r connected to outflow resistance vessels. Otto Frank (1899) proposed the f i r s t quantitative analysis of t h i s model which i s now univer-s a l l y referred to as the ' e l a s t i c resevoir' or •windkessel' model. According to Frank the dynamics of the blood flow i n a r t e r i e s could be defined completely by the compliance of the a r t e r i a l system, K, and the resistance of the peripheral beds, R. (K i s the change i n volume of the a r t e r i a l e l a s t i c resevoir divided by the increment i n pressure which caused t h i s change and R i s the r a t i o of pressure to volume flow rate produced when a s t a t i c pressure i s applied to the system). Analysis of t h i s model led to the r e l a t i o n (1) Q = P / R + K f y -where Q = volume flow rate of blood into the system P = a r t e r i a l pressure = rate of change of a r t e r i a l pressure . 8 This equation s p e c i f i e s the r e l a t i o n s h i p between a r t e r i a l pressure and flow and was of immediate i n t e r e s t to c a r d i -ologists, since i t implies that cardiac output could be calculated from routine a r t e r i a l pressure measurements provided the physical parameters, K and R, could be determined. However attempts to apply t h i s analysis to the mammalian c i r c u l a t i o n were not h i g h l y productive and i t was recognized that a major l i m i t a t i o n of t h i s theory was the i m p l i c i t assumption that the pressure changes generated by cardiac ejection occur simultaneously throughout the system (McDonald, 1974). In r e a l i t y each heart beat sends out a pulse wave which t r a v e l s through the a r t e r i a l system and a r r i v e s at d i f f e r e n t s i t e s at d i f f e r e n t times and consequently instantaneous flow rate predicted by equation (1) would depend on the s i t e at which a r t e r i a l pressure was recorded. In addi-t i o n , a number of other features of a r t e r i a l haemodynamics could not be reconciled with the windkessel model. Not only does the pressure pulse a r r i v e l a t e r at s i t e s more d i s t a l to the heart but i t exhibits marked changes i n waveform as pulse pressure increases considerably (up to 100%) and secondary waves appear i n the d i a s t o l i c portion of the pulse (Fig. 2). Furthermore pressure-flow re l a t i o n s h i p s at the input to the system could not be predicted from a windkessel approach. A major advantage of the windkessel model was that the mathematical analysis was r e l a t i v e l y simple and a l l of the 9 Figure 2 . Pressures recorded i n the root of the aorta (smaller p r o f i l e ) and the d i s t a l abdominal aorta (larger p r o f i l e ) of the rabbit. OF) 9a E E lO 10 complex elastic and geometric properties of the ar t e r i a l system were lumped into two parameters, the compliance of the major arteries and the resistance of the peripheral beds. However analysis of wave propagation through the system requires a more complex approach. F i r s t l y , the analysis of wave phenomena i s only mathematically tractable i f sinusoidal waves are involved and consequently complex (non-sinusoidal) art e r i a l pressure and flow waves must be represented by Fourier series. According to Fourier's theorem any complex waveform of constant frequency can be represented by i t s mean value plus a sum of sinusoidal waves of various amplitudes osci l l a t i n g at the frequency of the complex wave and at multiples of this frequency. Thus i f heart rate is 1 beat per second then the art e r i a l pressure or flow wave can be expressed as the mean pressure or flow plus a sum of sinu-soidal waves of frequencies of 1,2,3,... cycles per second. These sinusoidal waves are referred to as the 1st, 2nd, 3rd,... harmonics of the complex wave and under certain assumptions which are generally considered acceptable in the cardiovascular system (Attinger et a l . , 1965; McDonald, 1974) each harmonic of pressure is related only to the corresponding harmonic of flow and vice versa. Generally, no more than the f i r s t five to ten harmonics make measurable contributions to ar t e r i a l pressure and flow waves. The advantage of the Fourier analysis approach is that by analyzing the response of the art e r i a l system to s i n u s o i d a l d r i v i n g p r e s s u r e s t h e r e s p o n s e t o an a r b i t r a r y o s c i l l a t i o n i n p r e s s u r e can be d e r i v e d . A f u r t h e r i m p l i c a t i o n o f F o u r i e r ' s t h e o r y i s t h a t when a system i s d r i v e n by a complex o s c i l l a t i o n i t i s n e c e s s a r y t o u n d e r s t a n d t h e r e s p o n s e o f t h e system b o t h a t t h e f r e q u e n c y o f t h e d r i v i n g f o r c e and a t t h e f r e q u e n c i e s o f t h e h i g h e r h a r m o n i c s . The dependence o f s i n u s o i d a l p r e s s u r e - f l o w r e l a t i o n s h i p s on f r e q u e n c y i s most s u c c i n c t l y e x p r e s s e d i n terras o f v a s c u l a r impedance c u r v e s . Impedance modulus i s t h e r a t i o o f t h e a m p l i t u d e o f t h e p r e s s u r e wave t o t h a t o f t h e f l o w wave and impedance phase d e s c r i b e s t h e degree t o w h i c h t h e p r e s s u r e o s c i l l a t i o n l e a d s t h e f l o w o s c i l l a t i o n ( i n s i m p l e terms, the amount by w h i c h c r e s t s (and t r o u g h s ) o f t h e two waves a r e o u t o f s y n c h r o n y ) . Because th e v i s c o u s and i n e r t i a l p r o p e r t i e s o f t h e b l o o d and the c o m p l i a n c e o f the a r t e r i a l w a l l e f f e c t b l o o d f l o w t o a d i f f e r e n t degree a t d i f f e r e n t f r e q u e n c i e s impedance i s h i g h l y dependent on f r e q u e n c y . F i g . 3 i l l u s t r a t e s a s e t o f impedance c u r v e s a p p l y i n g t o w i n d k e s s e l models o f d i f f e r e n t t i me c o n s t a n t s , (The time c o n s t a n t o f a w i n d k e s s e l , the p r o d u c t o f r e s i s t a n c e and c o m p l i a n c e , i s a measure o f how l o n g i t t a k e t h e a r t e r i a l e l a s t i c r e s e v o i r t o d i s c h a r g e t h r o u g h the p e r i -p h e r a l r e s i s t a n c e i f f u r t h e r c a r d i a c e j e c t i o n i s p r e v e n t e d . ) A l s o i n c l u d e d i n F i g . 3 i s a sample o f the t y p e o f impedance c u r v e commonly r e c o r d e d i n the a o r t i c r o o t o f mammals. 12 Figure 3. Impedance curves for windkessel systems ( s o l i d curves) of various time constants (T) as well as for the systemic c i r c u l a t i o n of the dog (dashed p r o f i l e - a f t e r O'Rourke and Taylor, 1967). IMPEDANCE PHASE (radians) IMPEDANCE MODULUS 13 The Fourier series approach was employed by Womersley (1958) who performed a sophisticated mathematical analysis of wave propagation through a viscous f l u i d contained i n a v i s c o - e l a s t i c tube. The analysis involved simultaneous solution of the momentum equations for the f l u i d and the membrane equa-tions of the tube and experimental studies by McDonald (1955, 1974) demonstrated that Womersley's r e s u l t s were applicable to short, uniform lengths of a r t e r i e s . Although a quantitative synthesis of wave propagation throughout the a r t e r i a l tree was not possible a number of generalizations could be made. Womersley predicted that branch s i t e s and other d i s c o n t i n u i t i e s i n the a r t e r i a l tree would give r i s e to r e f l e c t e d waves which are directed back towards the heart. More recent theories (Taylor, 1964, 1965(a)) suggest that the increase i n wall s t i f f n e s s with distance from the heart (Bergel, 1961; Learoyd and Taylor, 1966) produce e f f e c t s which may augment those of r e f l e c t i o n s although experimental v e r i f i c a t i o n of t h i s theory has not yet been presented. Thus the picture which emerges i s one of wave propagation through an interconnected system of tubes of spatia-l l y varying properties with r e f l e c t e d waves being sent back towards the heart from r e f l e c t i o n s i t e s scattered throughout the system. The pattern of pressure signals recorded at d i f -ferent s i t e s i n the a r t e r i a l tree of mammals i s well predicted by a wave transmission model and can be a t t r i b u t e d l a r g e l y to 14 interference between outgoing and r e f l e c t e d waves (O'Rourke, 1967; McDonald, 1974). The pattern of vascular impedance both at the input to the systemic c i r c u l a t i o n (Fig. 3) and at more peripheral beds i s also compatible with t h i s model (McDonald, 1974). The above considerations indicate why most investigators f e e l that windkessel models have ou t l i v e d t h e i r usefulness i n studies of mammalian c i r c u l a t i o n s , however there may be good reason to suspect that such models may be applicable to some non-mammalian systems. Taylor (1964) measured a r t e r i a l pressure at d i f f e r e n t s i t e s within the aortae of turkeys and finding no evidence of wave transmission e f f e c t s he speculated that a windkessel model may apply to the c i r c u l a t i o n s of b i r d s . In addition, many small poikilotherms e x h i b i t lower heart rates than s i m i l a r l y sized mammals and unless major a r t e r i e s are long, which w i l l not be the case i n smaller species, or a r t e r i a l pulse wave v e l o c i t i e s are low, the t r a n s i t time of the pulse through the a r t e r i a l system may be n e g l i g i b l e compared with the cardiac cycle. I f t h i s i s the case then wave transmission e f f e c t s w i l l be minor and simpler models may be applied. On the other hand an 'a p r i o r i ' assumption that pulse wave v e l o c i t i e s and hence a r t e r i a l compliances, i n these species are within the mammalian range seems questionable. I t has been suggested (Taylor, 1964) that a r t e r i a l systems exhi b i t an optimal compliance which 15 r e p r e s e n t s a b a l a n c e between r e d u c i n g b l o o d f l o w p u l s a t i l i t y and d e c r e a s i n g the ti m e r e q u i r e d t c a c c o m p l i s h r e g u l a t o r y changes i n p r e s s u r e , ( O b v i o u s l y i n a h i g h l y c o m p l i a n t system more b l o o d must be s h i f t e d from t h e venous t o . a r t e r i a l c i r c u -l a t i o n i n o r d e r t o e l e v a t e p r e s s u r e . ) The l o w e r h e a r t r a t e s p r o l o n g t h e time o v e r w h i c h t h e a r t e r i e s r e c o i l and d i s c h a r g e and hence f l o w p u l s a t i l i t y may be h i g h i f v e s s e l s a r e n o t h i g h l y d i s t e n s i b l e . I n a d d i t i o n t h e l e s s a c t i v e l i f e - s t y l e o f many p o i k i l o t h e r m s , compared w i t h most mammals o f s i m i l a r s i z e , may i n d i c a t e t h a t r a p i d b l o o d p r e s s u r e r e g u l a t i o n i s o f a l o w e r p r i o r i t y . I n t h e p r e s e n t s t u d y t h e dynamics o f b l o o d f l o w t h r o u g h t h e h e a r t s and a r t e r i a l systems o f a number o f v e r t e b r a t e s has been i n v e s t i g a t e d w i t h s p e c i a l emphasis p l a c e d on the i n t e r -p r e t a t i o n o f s p e c i e s d i f f e r e n c e s i n terms o f haemodynamic models. I n the f i r s t s e c t i o n t h e c i r c u l a t i o n o f t h e amp h i b i a n , Rana c a t e s b e i a n a , i s examined i n o r d e r t o d e s c r i b e t h e f u n c t i o n o f t h e p a r t i a l l y d i v i d e d c a r d i a c chambers and t o e s t a b l i s h t h e dynamic p r o p e r t i e s o f the a r t e r i a l systems t h a t t h e s e chambers s u p p l y . S i n c e a m p h i b i a o f t e n e x p e r i e n c e r a p i d s h i f t s from a t e r r e s t r i a l t o an a q u a t i c environment pronounced c a r d i o v a s c u l a r a d j u s t m e n t s t o d i f f e r e n t modes o f r e s p i r a t i o n must be made. C o n s e q u e n t l y the e f f e c t o f l u n g v e n t i l a t i o n on the dynamic p r o p e r t i e s o f the a r t e r i a l c i r c u l a t i o n has a l s o been examined. 16 In the second s e c t i o n t h e i m p l i c a t i o n s o f the ' i n s e r i e s ' g i l l and t i s s u e c i r c u l a t i o n s o f the f i s h have been a n a l y z e d i n terras o f t h e o r e t i c a l and h y d r a u l i c models i n an a t t e m p t t o c l a r i f y t h e p h y s i c a l i n t e r a c t i o n between t h e s e two systems. Model p r e d i c -t i o n s a r e a s s e s s e d i n terms o f p r e s s u r e and f l o w d a t a from i n v i v o i n v e s t i g a t i o n s o f the c i r c u l a t i o n o f the cod, Gadus morhua. A marked p a u c i t y o f i n f o r m a t i o n on haemodynamics i n b i r d s prompted the d e t a i l e d e x a m i n a t i o n o f c e n t r a l c a r d i o v a s c u l a r dynamics o f t h e duck, Anas p l a t y r h y n c h o s , i n S e c t i o n I I I . P r e s s u r e and f l o w p r o f i l e s have been mapped t h r o u g h o u t the c e n t r a l c i r c u l a t i o n and t h e r e l a t i o n s h i p s between p r e s s u r e and f l o w have been examined i n terms o f p r o p o s e d w i n d l c e s s e l ( T a y l o r , 1964) and wave t r a n s m i s s i o n models. S e c t i o n IV i n c l u d e s a t e s t o f t h e o r i e s o f t h e e f f e c t s o f s p a t i a l v a r i a t i o n s i n a r t e r i a l w a l l e l a s t i c i t y ( e l a s t i c t a p e r ) as w e l l as an e v a l u a t i o n o f t h e i m p o r t a n c e t h e s e e f f e c t s i n t h e mammalian s y s t e m i c c i r c u l a -t i o n compared w i t h t h o s e o f d i s c r e t e wave r e f l e c t i o n s . A l t h o u g h th e mammalian h e a r t i s c o m p l e t e l y d i v i d e d and t h e r e i s t o t a l s e p a r a t i o n o f f l o w t o t h e l u n g and s y s t e m i c c i r c u l a t i o n s i t cannot be i n f e r r e d t h a t t h e n a t u r e o f e j e c t i o n from each v e n t r i c l e i s i n d e p e n d e n t o f the f u n c t i o n o f t h e o p p o s i t e v e n t r i c l e . I n t h e f i n a l s e c t i o n t h e mammalian h e a r t i s examined f o r m e c h a n i c a l i n t e r a c t i o n between the two v e n t r i c l e s d u r i n g c a r d i a c c o n t r a c t i o n . In a d d i t i o n t o e x a m i n i n g .?.ucjc. e s t i o n s 17 that l e f t v e n t r i c u l a r contraction influences pressures generated by the r i g h t v e n t r i c l e evidence i s presented that, i n some circumstances, r i g h t v e n t r i c u l a r contraction s i g n i f i c a n t l y influences l e f t v e n t r i c u l a r pressure. t I -SECTION I Central Blood Flow i n the B u l l f r o g , Rana Catesbeiana Introduction In terms of gross morphological structure the central c i r c u l a t i o n of the frog i s intermediate between that of fishes and higher vertebrates. The frog heart r e t a i n s the four basic chambers found i n the f i s h heart; the sinus venosus, a u r i c l e , v e n t r i c l e and conus a r t e r i o s i s , ( o r bulbus, i n t e l e o s t f i s h e s ) , whereas, the d i s t r i b u t i n g a r t e r i e s more c l o s e l y follow the pattern of higher vertebrates with the t h i r d , fourth and s i x t h a o r t i c arches p e r s i s t i n g as the c a r o t i d , systemic and pulmonary (pulmocutaneous) a r t e r i e s . The pulmocutaneous c i r c u l a t i o n i s completely separated from the systemic c i r c u i t s and the lungs return oxygenated blood to the l e f t side of a completely divided a u r i c l e although t h i s separation of oxygenated and oxygen-poor blood i s l o s t i n the v e n t r i c l e , which, l i k e the v e n t r i c l e of fishes, i s undivided. Here the term 'oxygen-poor' i s used since r i g h t a t r i a l blood includes blood returning from the skin gas exhanger and thus the term 'venous blood* or •de-oxygenated blood' would seem inappropriate. Nonetheless, i n anura lung v e n t i l a t i o n predominates (Hutchison, et a l , 1968; Jones 1972(b)) and marked P0 2 gradiants between the two a t r i a are observed (DeLong, 1962, Johansen and D i t a d i , 1966). The absence o f a t o t a l l y d i v i d e d h e a r t o b v i a t e s t h e n e c e s s i t y e n c o u n t e r e d by h i g h e r v e r t e b r a t e s o f an e q u a l d i s t r i b u t i o n o f b l o o d t o t h e l u n g and body c i r c u l a t i o n s and t h u s a l l o w s amphibians t o shunt b l o o d t o o r from the l u n g s i n r e s p o n s e t o t h e wide rang e s o f O2 a v a i l a b i l i t y w h i c h t h e y e n c o u n t e r ( S h e l t o n , 1970; E m i l i o and S h e l t o n , 1972). A drawback t o t h i s a r r a n g e -ment i s t h a t t h e r e i s no p h y s i c a l s e p a r a t i o n o f oxygenated and oxygen-poor b l o o d w i t h i n t h e h e a r t and i f m i x i n g o f t h e s e two b l o o d - s t r e a m s o c c u r s t h e n oxygen d e l i v e r y t o the t i s s u e s i s compromised. The degree o f m i x i n g o f b l o o d w i t h i n t h e amphib-i a n h e a r t has been t h e s u b j e c t o f a number o f s t u d i e s (DeLong, 1962; H a b e r i c h , 1965; Johansen and D i t a d i , 1956; Toews e t a l . , 1971) and i t i s g e n e r a l l y f e l t t h a t a t l e a s t p a r t i a l s e p a r a t i o n i s m a i n t a i n e d . The amphibian v e n t r i c l e i s a h i g h l y t r a b e c u l a t e s t r u c t u r e and i t i s b e l i e v e d t h a t a t r i a l c o n t r a c t i o n d r i v e s b l o o d d i r e c t l y i n t o the f i n e c h a n n e l s i n t h e v e n t r i c u l a r w a l l and t h u s g r o s s s t i r r i n g i s p r e v e n t e d . The p a t t e r n o f b l o o d f l o w d u r i n g e j e c t i o n , p a r t i c u l a r l y d u r i n g p assage t h r o u g h t h e conus a r t e r i o s i s , i s more c o n t r o v e r s i a l . The conus a r t e r i o s i s i s a s e p a r a t e c o n t r a c t i l e chamber o f t h e h e a r t w h i c h b e a t s a t the c a r d i a c f r e q u e n c y , a l t h o u g h c o n t r a c t i o n i s d e l a y e d u n t i l l a t e i n v e n t r i c u l a r s y s t o l e (Brady, 1964) and l a s t s u n t i l l a t e i n d i a s t o l e ( S h e l t o n and J o n e s , 1963). I t i s d i v i d e d i n t o two c h a n n e l s , the cavum a o r t i c u m and the cavum pulmocutaneum, by 20 a s p i r a l l i n g c e n t r a l w a l l , t h e s p i r a l v a l v e , w h i c h s e p a r a t e s s y s t e m i c and pulmocutaneous o u t f l o w s . However, the v a l v e i s a t t a c h e d t o t h e conus w a l l o n l y a l o n g one edge and i t s f u n c t i o n and the degree o f f l o w s e p a r a t i o n i t a f f o r d s has been the sub-j e c t o f c o n t r o v e r s y (Noble, 1925; V a n d e r v a e l , 1933; Foxon, 1947; Simons, 1959). E a r l y a n a t o m i c a l s t u d i e s (Brucke, 1352; S a b a t i e r , 1373) l e d t o t h e ' c l a s s i c a l t h e o r y * a c c o r d i n g t o w h i c h ' t h e v e n t r i c l e f i r s t e j e c t s b l o o d i n t o a low p r e s s u r e pulmocu-taneous a r c h then, as v e n t r i c u l a r p r e s s u r e exceeds the h i g h e r s y s t e m i c p r e s s u r e , d e f l e c t i o n o f t h e s p i r a l v a l v e o c c l u d e s pulmocutaneous o u t f l o w and t h e v e n t r i c l e e j e c t s t h e r e m a i n d e r o f the s t r o k e volume i n t o t h e s y s t e m i c and c a r o t i d a r c h e s . I n t h e l a s t two decades, however, i t has been w e l l e s t a b l i s h e d t h a t p r e s s u r e s i n b o t h t h e s y s t e m i c and pulmocutaneous c i r c u i t s c l o s e l y f o l l o w v e n t r i c u l a r p r e s s u r e t h r o u g h o u t v e n t r i c u l a r e j e c t i o n and hence no s e q u e n t i a l d i s t r i b u t i o n . o f b l o o d c o u l d be o c c u r r i n g . O r i g i n a l l y i t was a l s o h e l d t h a t conus c o n t r a c -t i o n s e r v e d t o e x t e n d c a r d i a c e j e c t i o n u n t i l l a t e i n d i a s t o l e and thus d e p u l s a t e i n f l o v ; i n t o the a r t e r i a l c i r c u l a t i o n s (Johansen, 1963). However, d i r e c t measurement o f r e l a t i v e volume changes o f the conus and v e n t r i c l e t h r o u g h o u t the c a r d i a c c y c l e i n d i c a t e t h a t the conus c o n t r i b u t i o n t o c a r d i a c o u t p u t i s q u i t e s m a l l ( S h e l t o n and J o n e s , 1965). Thus the f u n c t i o n a l s i g n i f i c a n c e o f conus c o n t r a c t i o n remains o b s c u r e . 21 Despite the demise of the c l a s s i c a l theory the view that rapid deflections of the s p i r a l valve within the conus play an important r o l e i n central blood d i s t r i b u t i o n has per s i s t e d . Although pulmocutaneous arch pressure f a l l s to a s i g n i f i c a n t l y lower l e v e l than systemic pressure and hence should be exceeded e a r l i e r by the r i s i n g front of the v e n t r i c u l a r pressure pulse, Shelton and Jones (1965 (b)) were unable to detect a time d i f -ference between the onset of pressure r i s e i n the two arches. Consequently they concluded that the s p i r a l valve occluded the cavum pulmocutaneum u n t i l systemic e j e c t i o n started. Morris (1974) proposed that contraction of the conus a c t i v e l y d i s -placed the s p i r a l valve to i n i t i a t e t h i s occlusion during l a t e v e n t r i c u l a r e j e c t i o n . He argued that the timing of t h i s event was regulated by the pH of the coronary blood supply, pulmo-cutaneous outflow occlusion occurring e a r l i e r when blood pH (and presumably 0 2 a v a i l a b i l i t y ) was low and l a t e r when pH was high and thus the conus acted as a central 'variable shunt* to regulate blood flow d i s t r i b u t i o n during periods of apnoea, presumably i n addition to the controls afforded by regulated v a s o - a c t i v i t y i n peripheral vascular beds (Shelton, 1970; Emilio and Shelton, 1972). That the coronary c i r c u l a t i o n has persisted only i n the conus a r t e r i o s i s of the frog heart suggests an important functional s i g n i f i c a n c e and since Jones and Shelton (1965 (b)) f a i l e d to observe obvious detrimental e f f e c t s of acute 22 7 • j • • l i g a t i o n of the coronary supply of frogs under con t r o l l e d conditions the suggestion that i t plays, a r o l e i n regulatory adjustments to changing environments merits further i n v e s t i -gation. Oi- the other hand the absence of marked pressure '<• gradients between the v e n t r i c l e and pulmocutaneous arch during l a t e systole argues against Morris' theory. Since an under-standing of the mechanics of the conus a r t e r i o s i s i s e s s e n t i a l not only to an accurate description of cardiac function but also to the explanation of the c h a r a c t e r i s t i c s of blood pressure and flow within the a r t e r i a l beds supplied by the heart the present study includes an attempt to present a coherent picture of conus function. P a r t i c u l a r attention has been paid to the sig n i f i c a n c e of conus contraction and i t s timing with respect to other cardiac events, the function of the s p i r a l valve and the role of the coronary c i r c u l a t i o n . Although the nature of blood flow through the frog heart has attracted considerable attention few studies have i n v e s t i -gated the dynamics of blood flow within the a r t e r i a l systems supplied by t h i s pump and attempts to analyze a r t e r i a l pressure-flow r e l a t i o n s h i p i n amphibia have, to date, been based upon r e l a t i v e l y simple cardiovascular models such as the windkessel (Jones and Shelton, 1972) i n which haemodynamic relationships can be defined completely i n terms of the peripheral resistance of the terminal beds and a lumped compliance for the a r t e r i a l system. As discussed i n the "General Introduction" such models cannot account for the wave transmission phenomena associated with mammalian haemodynamics but may be suitable for examination of blood flow i n some lower vertebrates, p a r t i c u l a r l y small poikilotherms such as the frog. In the present study an assessment i s made of wave transmission e f f e c t s and the a p p l i c a b i l i t y of cardiovascular models to the amphibian a r t e r i a l systems. The cardiovascular responses to lung v e n t i l a t i o n are also examined i n terms of these models. 24 METHODS Pressure and flow recordings Experiments were performed on 26 bullfrogs (Rana  catesbeiana) weighing from 200 to 550 g. The frogs were anaesthetized by immersion in Sandoz MS 222 anaesthesia (1-2 g/L) and restrained on their backs and the heart and art e r i a l arches were exposed by a midline incision through the sternum. The lungs were cannulated through an incision in the l e f t abdominal wall which was subsequently sutured around the cannula and the animal was ventilated with a Harvard 670 positive pressure respirator, although some animals breathed sponta-neously when the pump was shut off. The frogs were allowed to recover to a more l i g h t l y anaesthetized state which was main-tained by frequently wetting the skin with the anaesthetic solution. Physiological Studies Pressures were recorded in the ventricle, conus arteriosis and right systemic and l e f t pulmocutaneous arches with Bio-tec BT-70 and Hewlett-Packard 267 BC pressure transducers connected to the blood vessels with 10 cm lengths of PE 50 tubing. Dynamic calibration of the manometers and recording systems was performed by applying a step change in pressure to the tips of the manometer cannulae and recording the free vibrations of the system. Since the natural frequency of the system always exceeded 50 Hz, far in excess of the frequency of the physio-logical signals recorded, no correction for manometer distortion was required. Blood flows were recorded in the l e f t systemic and right pulmocutaneous arches with Biotronix BL 610 electromagnetic flowmeters u t i l i z i n g cuff-type extra-corporeal flow probes. Flow probes were calibrated by excising a portion of the artery to which they were attached and perfusing this vessel under pressure with physiological saline. The saline was collected in a calibrated cylinder and the time taken for a given volume to pass through the vessel was recorded with a stopwatch. The volume flow rate thus determined was compared with the out-put voltage of the flowmeter. Flowmeter outputs during isotonic saline perfusion d i f f e r from outputs during blood perfusion by at most 2% (Pierce e_t a l . , 1964; Greenfield et a l . , 1966). Care was taken to site pressure and flow probes the same distance from the conus in both the systemic and pulmocutaneous arches and in a l l cases this distance was from 0.5 to 1.5 cm. In some experiments a stimulator attached to the conus via two fine copper wires sewn into conus wall was triggered by the QRS wave of the ECG so that the ventricle and conus contracted simultaneously. Normally conus contraction is not initiated u n t i l late in ventricular systole (Brady, 1964) and i t was 26 hoped that these experiments would provide i n s i g h t into the importance of t h i s delay. Data was recorded on a Techni-Rite TR888 chart recorder writing on r e c t i l i n e a r co-ordinates and i n most cases was i simultaneously recorded on an Akai 280DSS four channel tape recorder. F.M. adaptors (A.R. Vetter and Co.) frequency modulated the data for storage on the audio recorder and demodulated the output when the recorder was i n the playback mode. Vascular impedance at the input to both the systemic and pulmocutaneous c i r c u l a t i o n s was determined by playing tape recorded pressure and flow signals into an A-D converter i n t e r -faced with a LAB 8/E computer ( D i g i t a l Equipment) which per-formed a Fourier analysis of the pressure and flow signals and printed out the r a t i o of pressure to flow (impedance modulus) and the phase d i f f e r e n c e between pressure and flow (impedance phase) for each of the f i r s t ten harmonics. These experimentally determined impedance curves were compared with curves calculated from a windkessel model according to the equations where R i s the vascular resistance (mean a r t e r i a l pressure divided by mean flow), f i s frequency and T i s the time constant of the windkessel which i s determined from the d i a s t o l i c impedance phase = -arctan (2flf T) 27 i •J portion of the pressure p r o f i l e according to the equation T = t/ ln(P 0 /P(t)) where t i s the duration of d i a s t o l e , P(t) i s pressure at the end of d i a s t o l e and P0 i s pressure at thebeginning of d i a s t o l e . Pressures alone were recorded from the v e n t r i c l e , conus and both a r t e r i a l arches i n four frogs i n order to p r e c i s e l y determine the time r e l a t i o n s h i p s between events of the cardiac cycle. In a further two animals pressure was recorded i n a systemic arch and the s c i a t i c artery i n order to examine the t r a n s i t time and d i s t o r t i o n of the pressure pulse as i t t r a v e l l e d through the a r t e r i a l system. In four frogs the sternum was opened with a small i n c i s i o n d i r e c t l y v e ntral to the a t r i o - v e n t r i c u l a r junction and a l i g a t u r e was placed around the coronary artery. The wound was then closed and the frog l e f t to recover for one week. At t h i s time the chest was reopened and arch, v e n t r i c u l a r and conus pressures recorded to assess the e f f e c t s of long term coronary occlusion on conus performance. Anatomical Studies The conus was opened with a ventral midline i n c i s i o n and the cut edges were drawn back and trimmed to permit d i r e c t observation of the s p i r a l valve, the inflow and outflow regions of the conus and the cavum aorticum and cavum pulmo-cutaneura. In addition s e r i a l sections of the conus were 28 prepared. The v e n t r i c l e and conus were qui c k l y dissected from three frogs, washed i n sal i n e and fixed i n Bouin's s o l u t i o n . The hearts were set i n wax and s e r i a l sections made (5 u/ section). The procedure was not wholly successful as f i x a t i o n caused marked shrinkage of the s p i r a l valve however, the sections d i d allow close examination of the s i t e of attachment of the s p i r a l valve to the conus wall as a function of p o s i t i o n along the conus and also provided confirmation of some obser-vations made during d i s s e c t i o n . The shrinkage problem was avoided i n l a t e r preparations by having frozen sections of fresh conus preparations prepared by the department h i s t o l o g i s t (12 u/ section). 29 Results Anatomical Studies Detailed descriptions, of the functional anatomy of the frog heart are availa b l e i n the l i t e r a t u r e (Brucke, 1852; Sabatier, 1873; de Graaf, 1957; Sharma, 1957; Sharma, 1961) and with a few exceptions the present studies confirmed that these descriptions apply to R. catesbeiana. B r i e f l y , blood i s pumped into the v e n t r i c l e from the two a t r i a and passes imme-d i a t e l y into many deep trabeculae i n the sponge-like v e n t r i c u l a r wall (Fig. 1-1). During ejection blood directed ventral to the s p i r a l valve flows to the l e f t dorsal opening of the pulmo-cutaneous c i r c u l a t i o n at the anterior end of the conus (Fig. 1-2). Systemic outflow passes dorsal to the posterior end of the s p i r a l valve and exit s through the systemic opening at the l e f t v e n tral aspect of the anterior conus. Any def l e c t i o n s of the s p i r a l valve must serve to compress or close o f f one of these two outflow t r a c t s . The two branches of the truncus a r t e r i o s i s into which the conus empties each contain two in t e r n a l walls which keep separate flows to the caro t i d , systemic and pulmocutaneous arches. The a t r i o - v e n t r i c u l a r junction i s guarded by two si m i l a r valves and by smaller l e f t and r i g h t l a t e r a l pocket valves. Both conus outflow t r a c t s are guarded by watch-pocket valves. 30 Figure 1-1. View of the i n t r a - v e n t r i c u l a r c a v i t y exposed by a l a t e r a l i n c i s i o n from apex to base. 31 Figure 1-2. Ventral view of the heart of the b u l l f r o g before (A) and a f t e r (B) cutting away the ventral conus wall to expose the s p i r a l valve, V, v e n t r i c l e ; C.A., conus a r t e r i o s i s ; T.A., Truncus a r t e r i o s i s ; Sp. V., s p i r a l valve. V 31a 32 The most s i g n i f i c a n t contrast between the present study and previous work l i e s i n defining the properties of the s p i r a l valve. Previously the valve has been described as having a very t h i n attachment to the conus wall and a wide head (de Graaf, 1957; Sharma, 1957). The functional implications of such a structure are best stated by Sharma (1957), "The shape of the s p i r a l valve, i t s h i n g - l i k e attachment and d i s p o s i t i o n , a s l i g h t curvature i n form, i t s hammer-headed top-heavy head... a l l indicate that the s p i r a l , v a l v e moves...". Similar r e s u l t s were obtained i n the present i n v e s t i g a t i o n when standard h i s t o l o g i c a l preparations were employed. It was obvious, however when comparing the r e s u l t i n g s l i d e s with the s p i r a l valve i n fresh preparations, that marked shrinkage had occurred during preparation of the sections. When frozen section techniques were employed a d i f f e r e n t p icture arose. Although the s p i r a l valve resembles the above des c r i p t i o n i n the posterior region of the conus i t i s a much sturdier structure i n the anterior region of the conus and an obverse cross section of the valve i s not observed here (Fig. 1-3). Thus any displacement of t h i s s p i r a l valve would appear to r e s u l t from a bending of the valve rather than a flapping movement from a hinge-like attachment. 33 Figure 1-3. L a t e r a l cross-sections of the conus a r t e r i o s i s prepared using frozen section techniques. Slides are equally spaced samples chosen from 12u s e r i a l sections. Sections d i s p l a y the valve as seen from an upstream viewpoint at s i t e s which move progressively downstream from sections A to E. pd.v, pad-like valve; p.o.v., pulmocutaneous out-flow valves; sp.v, s p i r a l valve. The pad-like valve i s not a true valve but i s just a protruber-ance from the proximal, r i g h t dorsal conus w a l l . Magnification i s 30x. 33a 34 Blood pressures from v e n t r i c l e , conus and a r t e r i a l arches The pressure pulses recorded i n the central c i r c u l a t i o n of Rana catesbeiana (Fig. 1-4 and 1-5) confirmed the general shape of pulses reported for other amphibia. (Shelton and Jones, 1968). Pressure i n the v e n t r i c l e displayed an i n i t i a l sharp r i s e followed by a more gradual r i s e to peak pressure. Vent r i c u l a r contraction lasted approximately h a l f the cardiac cycle before being terminated by a rapid return to near-zero pressures. Often, v e n t r i c u l a r d i a s t o l i c pressure did not show a d i s t i n c t hump in d i c a t i n g a uricular contraction as has been recorded i n other amphibia (Shelton and Jones, 1968). Pressure i n the conus a r t e r i o s i s followed v e n t r i c u l a r pressure u n t i l l a t e systole but when v e n t r i c u l a r pressure dropped r a p i d l y conus pressure exhibited an i n f l e x i o n and conus contraction maintained pressure at a r t e r i a l l e v e l s , c l e a r l y i n d i c a t i n g closure of the p y l a n g i a l valves (between the v e n t r i c l e and conus)/ Late i n the cardiac cycle the conus relaxed and pressure f e l l but at normal heart rates never dropped to v e n t r i c u l a r pressure before the next contraction. During the phase when v e n t r i c u l a r pressure was r i s i n g d i a s t o l i c pressure i n the pulmocutaneous arches was exceeded before systemic pressure and pulmocutaneous pressure showed an i n i t i a l sharp r i s e (Fig. 1-5). Some 50 msec l a t e r v e n t r i c u l a r pressure exceeded systemic pressure and,as the synangial valves between the conus and systemic channels of the truncus opened 35 Figure 1-4. Blood pressures (mm Hg) i n the v e n t r i c l e , conus a r t e r i o s i s , pulmocutaneous arch and systemic arch. 25 -J 1 sec pulmocutaneous 5 0 arch — 2 5 -E E i 5 0 -conus A A A D 5 0 - i ventricle n ^ n n nnn r\ n mm u u ii U 36 Figure 1-5. Blood pressures recorded i n the systemic arch, pulmocutaneous arch and v e n t r i c l e . V e r t i c a l l i n e s l i n k co-incident events at the onset of e j e c t i o n into the pulmocutaneous and systemic c i r c u l a t i o n s . Arrows indicate spontaneous breathing movements and concomitant changes i n pressures. a) vo to systemic arch pressure 25 pulmocutaneous £ arch pressure 25 ventricular pressure 50 15 i 1 20 sec I . and systemic pressure started to rise, a marked inflexion in the pressure profiles in the ventricle, conus and pulmo-cutaneous arches was observed and subsequent pressure rises were more gradual (Fig. 1-4 and 1-5). Throughout the remainder of ventricular ejection a l l pressures followed ventricular pressure. The effect of conus contraction on arch pressures is slight because of the small ejection volume of this chamber and i s most often evident only as a small notch signalling conus relaxation. In the present study this conus component was observed in both arches although during, .lung ventilation i t frequently did not appear in the systemic arch pressure trace, a response attributed to marked lung vasodilation which may decrease outflow resistance to the lung-skin c i r c u i t to the extent that the conus is no longer capable of reaching systemic pressures. Although there must be a resultant elevation in conus ejection to the pulmocutaneous system, pressure in the pulmocutaneous arch often showed a reduced conus component and this is attributed to the marked f a l l in pulmocutaneous vascular impedance during lung ventilation (discussed later) which reduces pressure increments produced by a given inflow. The observation of a conus component on the pressure profile in both systemic and pulmocutaneous arches, is in agreement with the earlier report of de Graaf (1957) but at variance with the 3 0 f i n d i n g s o f S h e l t o n and J c n e s (1965 (a)) who r a r e l y o b s e r v e d any e v i d e n c e o f a conus c o n t r i b u t i o n t o pulmocutaneous o u t f l o w . D i a s t o l i c d e c l i n e o f pulmocutaneous p r e s s u r e was more r a p i d t h a n t h a t o f s y s t e m i c p r e s s u r e a l t h o u g h when b o t h p r e s s u r e s d i s p l a y e d a conus component t h i s more r a p i d d e c l i n e was r e s -t r i c t e d t o l a t e d i a s t o l e . C o n s e q u e n t l y p u l s e p r e s s u r e s were always g r e a t e r i n t h e pulmocutaneous c i r c u l a t i o n a l t h o u g h , as p r e v i o u s l y r e p o r t e d (Jones and S h e l t o n , 1 9 7 2 ) , t h i s d i f f e r -ence was d i m i n i s h e d d u r i n g apnoea. F i g . 1 - 5 a l s o i l l u s t r a t e s t h e immediate e f f e c t s o f l u n g v e n t i l a t i o n on c e n t r a l p r e s s u r e s . Spontaneous b r e a t h i n g movements (see arrows) i n f r o g s not a r t i f i c a l l y v e n t i l a t e d r e s u l t e d i n e l e v a t e d v e n t r i c u l a r p r e s s u r e s w h i c h caused an i n c r e a s e i n mean s y s t e m i c p r e s s u r e w i t h l i t t l e change i n p u l s e p r e s s u r e whereas i n the pulmocutaneous a r c h e s b o t h mean and p u l s e p r e s s u r e i n c r e a s e d d i s t i n c t l y . T h i s i n c r e a s e i n pulmocutaneous p u l s e p r e s s u r e had p r e v i o u s l y been i n v e s -t i g a t e d in Xenopus l a e y i s ( S h e l t o n , 1970) and found t o r e s u l t from l u n g v a s o d i l a t i o n w h i c h causes a drop i n t h e time c o n s t a n t o f t h e pulmocutaneous c i r c u l a t i o n , i . e . an i n c r e a s e i n the r a t e o f d e c l i n e o f d i a s t o l i c p r e s s u r e . E l i m i n a t i o n o f t h e v e n t r i c l e t o conus c o n d u c t i o n d e l a y by s t i m u l a t i n g the conus i n phase w i t h v e n t r i c u l a r d e p o l a r -i z a t i o n had a marked e f f e c t on a r c h p r e s s u r e p r o f i l e s ( F i g . 1 - 6 ) . In p a r t i c u l a r t h e r e i s a sharp decrement i n peak pulmo-3 9 Figure 1-6. Result of stimulating the conus contraction i n time with v e n t r i c u l a r contraction (stimulator triggered from QRS wave of the ECG). The decre-ment i n pulmocutaneous arch pressure during systole and co-incident r i s e i n systemic pressure c l e a r l y indicate occlusion of the pulmocutanious outflow. 'w 5 stimulus o ^ 0 40 pulmocutaneous arch pressure ^ £ 15 E E ~ 40 systemic arch pressure 15 time (sec) 40 cutanous arch pressures despite a r i s e i n systemic pressure and these r e s u l t s c l e a r l y indicate that the conus i s c l o s i n g o f f the pulmocutaneous outflow. Apparently the normal conduc-t i o n delay i s necessary to allow the v e n t r i c l e to f u l l y distend f the conus before conus contraction and when the delay i s elim-inated the u n f i l l e d conus closes down on the s p i r a l valve and occludes the cavum pulmocutaneu. These findings confirm s i m i l a r experiments by Morris (1974) although he interpreted the r e s u l t s as evidence that normal conus contraction occludes pulmocutaneous outflow. Pressures recorded i n the conus a r t e r i o s i s a f t e r l i g a t i o n of the coronary artery for one week indicated a complete loss of conus c o n t r a c t i l i t y . Conus pressures f e l l quickly to d i a s t o l i c l e v e l s following v e n t r i c u l a r r e l a x a t i o n and aside from a s l i g h t l y slower e l a s t i c r e c o i l during r e l a x a t i o n pressure followed that within the v e n t r i c l e (Fig. 1-7). The normal pattern, i n which pressures are maintained at a r t e r i a l l e v e l s u n t i l l a t e d i a s t o l e , was l o s t completely i n d i c a t i n g that, while the conus may survive short term coronary occlusion (Jones Shelton, 1965 (b)), coronary v a s c u l a r i z a t i o n i s required for adequate oxygen supply. Although there was a complete loss of conus contraction, pulmocutaneous arch pressure s t i l l exhibited a sharp i n i t i a l r i s e to systemic pressure c l e a r l y i n d i c a t i n g that the appearance of t h i s pressure r i s e i n normal animals d i d 41 Figure 1-7. A. Pressure recorded i n the conus a r t e r i o s i s of a 'normal' b u l l f r o g . B. Simultaneous pressures recorded i n the conus, v e n t r i c l e and the two arches of a frog following one week of coronary l i g a t i o n . I I A 50 conus pressure mm Hg 0 B conus 50-pressure mm Hg n . ventricular50 pressure ] mm Hg pulmocutaneous 'ch press (mm Hg) 0 _ ar ure 5 0 " syslemic a r c h 5 0 -pressure (mm Hg) 0 42 f ; • not signal the removal of an active conus occlusion of pulmo-cutaneous outflow. One f i n a l aspect of conus function has been investigated. In the conus of elasmobranch fishes there are three tiers of watch-pocket valves (no spiral valve) and contraction of the conus i s required to bring opposing valves in each t i e r s u f f i -ciently close together to permit competency (Satchell and Jones, 1967), a situation permitting smaller valves which require less backflow to close them. In the present experiments the frog conus was examined for a similar function. Frogs were deeply anaesthetized, the sternum opened as described above, and a stout ligature was tied around the sino-atrial junction which stopped the heart beating. Remaining venous return to the atria, and a l l a r t e r i a l arches except one systemic arch, were ligated and two pressure reservoirs were then connected via stopcocks and cannulae to the remaining systemic arch and the ventricle. Ventricular pressure was set at 10 mm Hg to f i l l the cardiac chambers and systemic pressure was raised in steps while recording pressure in the ventricle and conus. Competency of the conus valves consistently broke down, as indicated by a sudden jump in conus and ventricular pressures to resevoir levels, at reservoir pressures of 50 - 80 mm Hg (Fig. 1-8A), I • i.e. at high physiological pressures. Fig. 1-8B illustrates an experiment in an animal which exhibited persistent a t r i a l 43 Figure 1-8. A. Pressures recorded i n the v e n t r i c l e and conus i n a fresh, post-mortem preparation when pressure to the systemic arch i s increased i n a step-wise fashion. When a c r i t i c a l pressure i s exceeded there i s a sudden breakdown i n the conus valves and both chambers suddenly f i l l , as indicated by a sudden jump i n pressures (upward arrow). At the downward arrow the systemic arch pressure resevoir i s returned to 0 mm Hg. B. Same experiment as i n A except that i n t h i s preparation a t r i a l contraction p e r s i s t e d through-out the experiment. Since a t r i a l contractions were immediately superimposed on v e n t r i c u l a r and conus pressures i t follows that a t r i o - v e n t r i c u l a r valves are not competent i n the f i l l e d v e n t r i c l e when i t i s relaxed. 751 ventricular pressure E 0 § 75-conus pressure j time (sec) c o n t r a c t i o n s . I m m e d i a t e l y upon breakdown o f t h e conus v a l v e s a t r i a l p r e s s u r e waves were superimposed on conus and v e n t r i c u l a r p r e s s u r e s , s u g g e s t i n g t h a t v e n t r i c u l a r c o n t r a c t i o n p l a y s a r o l e i n c l o s i n g t h e a t r i o - v e n t r i c u l a r v a l v e s as w e l l . The s u r v i v a l o f f r o g s w i t h conus d y s f u n c t i o n i n d u c e d by c o r o n a r y l i g a t i o n appeared c o n t r a r y t o the above f i n d i n g s however when t h e s e e x p e r i m e n t s were r e p e a t e d on such a n i m a l s no l o s s i n v a l v e f u n c t i o n was o b s e r v e d u n t i l s y s t e m i c a r c h p r e s s u r e exceeded 100 mm Hg. A p p a r e n t l y a r e d u c e d m y o c a r d i a l c o m p l i a n c e a s s o c -i a t e d w i t h i n f a r c t i o n p r e v e n t e d t h e normal d i s t e n s i o n o f t h e conus w h i c h draws a p a r t t h e p o c k e t v a l v e s . A r t e r i a l f l o w and p r e s s u r e - f l o w r e l a t i o n s F lows i n t h e a r t e r i a l a r c h e s o f t h e b u l l f r o g r e s e m b le t h o s e r e p o r t e d f o r o t h e r a m p h i b i a ( S h e l t o n , 1970, E m i l i o and S h e l t o n , 1972). The s y s t e m i c f l o w p u l s e i s c o n c e n t r a t e d m a i n l y i n v e n t r i c u l a r s y s t o l e ( F i g . 1-9) and 'resembles t h e f l o w p u l s e r e c o r d e d i n t h e mammalian a o r t a (McDonald, 1960; O'Rourke, 1967). V e n t r i c u l a r s y s t o l e i s t e r m i n a t e d by a r e v e r s a l o f s y s t e m i c flow w h i c h s e r v e s t o c l o s e t h e p y l a n g i a l v a l v e s and p o s s i b l y causes the s y n a n g i a l v a l v e s between t h e conus and s y s t e m i c t r u n c u s t o c l o s e b r i e f l y . T h i s b a c k f l o w i s g e n e r a l l y f o l l o w e d by a p e r i o d o f p o s i t i v e f l o w due to conus c o n t r a c t i o n . The o n s e t o f e j e c t i o n i n t o t h e pulmocutaneous a r c h e s was synchronous w i t h t h e i n i t i a t i o n o f t h e p r e s s u r e pui;:.e c.nd 45 Figure 1-9. Pressures and flows recorded i n the systemic and pulmocutaneous arches. The v e r t i c a l l i n e indicates onset of pulmocutaneous outflow. pulmocutaneous 25 arch flow (ml/min) . : • pulmocutaneous 35 arch pressure (mm Hg) 20 syslemic arch flow 2 ^ (ml/min) 0 syslemic arch pressure (mm Hg) 35 20 46 c o n s e q u e n t l y p r e c e d e d e j e c t i o n i n t o t h e s y s t e m i c a r c h e s . Marl red d i a s t o l i c f l o w s were o b s e r v e d ( F i g . 1-9) w h i c h t y p i c a l l y c o n t -r i b u t e d 35-40% o f s t r o k e f l o w d u r i n g l u n g v e n t i l a t i o n and up t o 50% d u r i n g apnoea. A t t h e end o f d i a s t o l e t h e s t e a d y d e c l i n e i n s y s t e m i c p r e s s u r e was i n t e r r u p t e d a t t h e p o i n t when pulmocutaneous o u t f l o w s t a r t e d and p r e s s u r e l e v e l l e d o f f o r r o s e s l i g h t l y b e f o r e s y s t e m i c e j e c t i o n and a t t h e same ti m e a s l i g h t p o s i t i v e f l o w was r e c o r d e d i n t h e s y s t e m i c a r c h ( F i g . 1-9). V e n t r i c u l a r p r e s s u r e was s t i l l c l e a r l y b e l o w s y s t e m i c p r e s s u r e a t t h i s p o i n t . T h i s s m a l l d i s t u r b a n c e i n t h e s y s t e m i c system i s a t t r i b u t e d t o d e f l e c t i o n o f t h e septum between the s y s t e m i c and pulmocutaneous c h a n n e l s o f t h e t r u n c u s as pulmocutaneous p r e s s u r e r i s e s and a l t h o u g h p r o b a b l y o f l i t t l e f u n c t i o n a l ' s i g n i f i c a n c e t h i s phen-omena a g a i n r e f l e c t s t h e ti m e d i f f e r e n c e between e j e c t i o n i n t o t h e two c i r c u l a t i o n s . F i g . 1-10 i l l u s t r a t e s t h e e f f e c t s o f apnoea on p r e s s u r e s and f l o w s i n t h e a r t e r i a l a r c h e s . Apnoea caused a sh a r p drop i n pulmocutaneous f l o w whereas s y s t e m i c f l o w was r e l a t i v e l y u n a l t e r e d i n t h e s h o r t term. I n v e n t i l a t e d a n i m a l s pulmo-cutaneous f l o w exceeded s y s t e m i c f l o w by up t o 50% whereas d u r i n g apnoea pulmocutaneous f l o w f e l l t o l e s s t h a n h a l f s y s t e m i c f l o w d e s p i t e a r i s e i n mean pulmocutaneous p r e s s u r e . A l t h o u g h s y s t e m i c f l o w s were n o t i m m e d i a t e l y i n f l u e n c e d by l u n g v e n t -47 Figure 1-10. Arch pressures and flows before (A) and a f t e r 10 min apnoea. CO c- time (sec) pulmocutaneous 35-, arch pressure (mm Hg) 15 J A pulmocutaneous arch flow (ml/min) 0 J syslemic arch pressure (mm Hg) 43 i l a t i o n long-term apnoea caused a marked r e d u c t i o n i i n systemic f low ; with flow d e c l i n i n g gradually by some 40% over 10 minutes apnoea. The r e l a t i o n s h i p s between a r t e r i a l pressures and flows are most conveniently expressed i n terms of vascular impedance which indicates the r e l a t i v e s i z e and phase r e l a t i o n s h i p s between corresponding pressure and flow harmonics. F i g . 1-11 shows systemic impedances calculated f o r three frogs. Impedance modulus, normalized by d i v i d i n g by peripheral resistance (zero frequency impedance) to.allow comparison of r e s u l t s from d i f -ferent frogs, displayed a sharp i n i t i a l f a l l followed by a more gradual but steady decline towards zero at higher frequencies. Impedance phase was between 1 and 1.57 radians (57 and 90°) at a l l p u l s a t i l e harmonics examined. Only three harmonics are used to compute these curves because higher harmonics of pressure were co n s i s t e n t l y below 1 mm Hg i n amplitude and therefore could not be used accurately for impedance determination. The s o l i d curves i n F i g . 1-11 are t h e o r e t i c a l impedance curves for one frog (triangles) calculated from a windkessel model 0 F i g . 1-12 i l l u s t r a t e s the e f f e c t s of apnoea on impedance of the pulmocutaneous vascular beds. Apnoea caused an increase i n impedance modulus which i s most s i g n i f i c a n t at the zero frequency l i m i t and a consistent drop i n impedance phase was observed. 49 Figure 1 - 1 1 . Input impedance modulus (Z) and phase (d» of the systemic c i r c u l a t i o n i n 3 b u l l f r o g s . The s o l i d curves i l l u s t r a t e t h e o r e t i c a l l y predicted (windkessel) impedances for one of the frogs ( t r i a n g l e s ) . Impedance modulus i s normalized by d i v i d i n g by peripheral resistance (R ) to allow comparison of d i f f e r e n t i n d i v i d u a l s . 49a 50 Figure 1-12. input impedance to the pulmocutaneous c i r c u l a t i o n during a r t i f i c a l lung v e n t i l a t i o n and during apnoea. 50a - 10 8 control apnoea I 2 3 FREQUENCY (HZ) -1-5 51 Pressure wave propagation i n the systemic c i r c u l a t i o n F i g . 1-13 i l l u s t r a t e s systemic a r t e r i a l pressures recorded i n the proximal systemic arch and the s c i a t i c a r t e r y 14 cm away. The pressure pulse i s unchanged d u r i n g propagation between the r e c o r d i n g s i t e s , a s i d e from s l i g h t damping, and, i n t h i s i n d i v i d u a l , a r r i v e s a t the d i s t a l s i t e some 45 msec (3.7% of the c a r d i a c c y c l e ) a f t e r i t passes the proximal transducer, thus t r a v e l l i n g w i t h a mean pulse wave v e l o c i t y of 3.1 m/sec. 52 Figure 1-13. Near i n d e n t i c a l pressures recorded i n the systemic arch (SAP) and s c i a t i c artery (SP) of the b u l l -frog. Distance between the recording s i t e s i s 14 cm (recorded at the l e v e l of the heart and midway along the thigh ) . Mean pressure at the two s i t e s i s the same and p r o f i l e s have been s h i f t e d apart for c l a r i t y . 5 3 D i s c u s s i o n F u n c t i o n o f t h e conus a r t e r i o s i s R e s u l t s o f the p r e s e n t s t u d y c o n t r a d i c t r e c e n t t h e o r i e s on the f u n c t i o n o f t h e anuran conus a r t e r i o s i s s i n c e i t has been e s t a b l i s h e d t h a t no a c t i v e o c c l u s i o n o f t h e pulmocutaneous o u t f l o w o c c u r s e a r l y i n d i a s t o l e i n t h e b u l l f r o g . Among t h e s t r o n g e s t e v i d e n c e o f t h i s i s t h e marked d i a s t o l i c f l o w s r e c o r d e d i n t h e pulmocutaneous a r c h e s , f o r w h i c h t h e o n l y p o t e n t i a l s o u r c e s a r e d i a s t o l i c r e c o i l o f the t r u n c u s a r t e r i o s i s and/or conus e j e c t i o n , the l a t t e r c l e a r l y r e q u i r i n g a p a t e n t pulmocutaneous o u t f l o w . S h e l t o n and Jones (1955(b)) have measured volume changes i n t h e v e n t r i c l e , conus a r t e r i o s i s and t r u n c u s a r t e r i o s i s o f Rana p i p i e n s t h r o u g h o u t t h e c a r d i a c c y c l e and found t h a t t r u n c u s volume changes a r e v e r y s m a l l . I f s i m i l a r ( p e r c e n t a g e ) changes a p p l y t o Rana c a t e s b e i a n a t h e n even l i b e r a l e s t i m a t e s o f t r u n c u s volumes i n d i c a t e t h a t t r u n c u s r e c o i l g e n e r a t e s a s m a l l f r a c t i o n o f pulmocutaneous d i a s t o l i c f l o w (20% a t most) even i f a l l t r u n c u s r u n - o f f were d i r e c t e d down t h e pulmocutaneous c i r c u l a t i o n . On t h e o t h e r hand t h e volume o f t h e conus i s h a l v e d d u r i n g c o n t r a c t i o n and the r e s u l t a n t o u t f l o w s a r e i n t h e range o f pulmocutaneous d i a s t o l i c f l o w . The appearance o f a conus wave on t h e pulmocutaneous p r e s s u r e p r o f i l e ( F i g . 1-4 and 1-5) s u p p o r t s t h i s i n t e r p r e t a t i o n . 54 Previous conclusions to the contrary, i . e . that pulmocutaneous outflow i s occluded (Shelton and Jones 1965(a),,1972; Morris, 1974) are based l a r g e l y on the absence of a detectable time difference between the s y s t o l i c r i s e i n pressure i n the systemic and pulmocutaneous arches. C e r t a i n l y the r i s i n g portion of the pulmocutaneous arch pressure (Fig. 1-5), which exhibits a sharp i n i t i a l r i s e followed by a slower r i s e to peak pressure, i s suggestive of the sudden removal of an occlusion, however i n the present study a time difference was observed and both arch pressures followed v e n t r i c u l a r pressure throughout systole. In addition there i s an i n f l e x i o n i n the r i s i n g front of v e n t r i c u l a r pressure co-incident with that i n the pulmocutaneous arch pressure (Fig. 1-5). It appears that t h i s i n f l e x i o n i n pressure r i s e i s due to the sudden release of systemic outflow rather than the removal of a pulmocutaneous occlusion (occasionally v e n t r i c u l a r pressure exhibited a s i m i l a r break co-incident with the s t a r t of pulmocutaneous outflow (Fig. 1-4)). It may be that the reason I was able to detect a time difference between r i s e i n the two arches, whereas previous workers were not, i s that v e n t r i c u l a r pressure r i s e s more slowly i n Rana catesbeiana than i n other species. The duration of the sharply r i s i n g phase of pulmocutaneous pressure i s some 50 msec whereas pre-liminary experiments with Rana pipiens indicate that times of le s s than 20 msec are more t y p i c a l . A l t e r n a t i v e l y i t i s p o s s i b l e t h a t t h e mechanisms o f conus f u n c t i o n a r e d i f f e r e n t i n t h e two s p e c i e s however s i m i l a r i t i e s i n t h e anatomy and p h y s i o l o g y o f the two systems argue a g a i n s t t h i s c o n c l u s i o n . F i n a l l y t h e p e r s i s t e n c e o f t h i s s h a r p l y r i s i n g component o f pulmocutaneous p r e s s u r e f o l l o w i n g c o r o n a r y l i g a t i o n v e r i f i e d ' t h a t i t d i d n o t r e s u l t from conus o c c l u s i o n o f pulmocutaneous o u t f l o w . Thus, a c c o r d i n g t o present, f i n d i n g s , t h e conus i s p i c t u r e d as a c o n t r a c t i l e chamber b e a t i n g w i t h a t i m e d e l a y w i t h r e s p e c t t o t h e v e n t r i c l e , t h i s t i m e d e l a y s e r v i n g t o a l l o w t h e chambers t o work i n harmony w i t h o u t d i s r u p t i n g f l o w t o any v a s c u l a r bed. The pumping a c t i o n o f t h e conus d r i v e s a s m a l l f r a c t i o n o f t o t a l c a r d i a c s t r o k e volume however d u r i n g l u n g v e n t i l a t i o n t h i s f l o w i s d i s t r i b u t e d p r e f e r e n t i a l l y t o t h e pulmocutaneous c i r c u l a t i o n (conus p r e s s u r e o c c a s i o n a l l y b e i n g i n s u f f i c i e n t to open s y s t e m i c o u t f l o w v a l v e s ) and c o n t r i b u t e s a s i g n i f i c a n t f r a c t i o n o f t h i s f l o w . I n a d d i t i o n c o n t r a c t i o n o f t h e conus draws o p p o s i n g s y n a n g i a l ( o u t f l o w ) and p y l a n g i a l ( i n f l o w ) v a l v e s s u f f i c i e n t l y c l o s e t o g e t h e r t o e n s u r e competency and s i n c e t h e conus does n o t f i l l b e f o r e t h e n e x t v e n t r i c u l a r e j e c t i o n , conus p r e s s u r e e x c e e d i n g v e n t r i c u l a r p r e s s u r e t h r o u g h -out d i a s t o l e , t h e conus p r e s e n t s u n d i s t e n d e d v a l v e s t o b o t h t h e a x t e r i a l c i r c u l a t i o n and t h e f i l l i n g v e n t r i c l e , a s i t u a t i o n n o t p o s s i b l e i f t h i s chamber were m i s s i n g . The i n i t i a l surge o f 56 flow to the pulmocutaneous c i r c u l a t i o n may cause minor d e f l e c -t i o n s of the s p i r a l valve to widen the cavum pulmocutaneum and bring the free edge into closer proximity with the conus wall (Sharma, 1957, 1961) however, no major defl e c t i o n s of the s p i r a l valve are envisaged and no valving function appears to be served by t h i s structure. It i s tempting to speculate on the absence of a complete septum within the conus since homologous structures i n higher vertebrates, e.g. the f o e t a l bulbus cordis of mammals, are t o t a l l y divided. I t may be that during the course of normal a c t i v i t y when blood i s shunted from the lungs to the tissues or v i c e versa the s i t e of r e d i s t r i b u t i o n i s within the conus. Simons (1959) observed that dye streams injected into the r i g h t atrium would occasionally divide on entering the conus with part of the stream passing into the cavum aorticum. A reverse d i v i s i o n could, at times, be seen i n dye streams injected into the l e f t atrium.(In t h i s study no control over lung v e n t i l a t i o n was exercised.). I f shunting does occur within the conus t h i s would allow a variable d i s t r i b u t i o n of blood to the vascular beds without disrupting flow streams along the v e n t r i c u l a r outflow t r a c t where no physical separation e x i s t s . During pro-longed submergence, when flow to the lungs i s d r a s t i c a l l y reduced, such a mechanism might be d i f f i c u l t to maintain, and i n any event would convey no advantage since arch PC^'s are the same i n t h i s i n s t a n c e (Toews, 1969; S h e l t o n , u n p u b l i s h e d ) . F l r e d i s t r i b u t i o n w i t h i n t h e v e n t r i c l e Might be more l i k e l y i n t h i s s i t u a t i o n . Foxon (1946, 1955, 1954) has s u g g e s t e d t h a t t h e c o m p l e t e l y u n d i v i d e d v e n t r i c l e i n t h e f r o g i s an amphibian s p e c i a l i z a t i o n a s s o c i a t e d w i t h t h e s h i f t from a t e r r e s t r i a l t o amphibious environment (and c o n c o m i t a n t b l o o d s h u n t i n g r e q u i r e ' m e n t s ) . I t i s p o s s i b l e t h a t t h e p a r t i a l d i v i s i o n o f t h e conus i s a s i m i l a r s p e c i a l i z a t i o n and i n t h i s r e g a r d a m p h i b i a w h i c h have r e t u r n e d to a more a q u a t i c e n v i r o n m e n t , t h e u r o d e l e s , commonly e x h i b i t l e s s w e l l d e v e l o p e d s p i r a l v a l v e s than a n u r a . I n any e v e n t t h e s e c o n s i d e r a t i o n s s e r v e t o s t r e s s t h e important o f f i r m l y e s t a b l i s h i n g s t r e a m p a t t e r n s t h r o u g h t h e amphibian h e a r t and t h e i r r e l a t i o n s h i p t o r e s p i r c i t i o n . P r e s s u r e - f l o w r e l a t i o n s h i p s i n a r t e r i e s I t i s a p p a r e n t from t h e p r e s e n t s t u d y t h a t wave t r a n s -m i s s i o n phenomena a r e o f l i t t l e s i g n i f i c a n c e i n t h e a r t e r i a l s ystem o f t h e f r o g s i n c e p r e s s u r e s measured i n d i s t a l a r t e r i e s a r e v i r t u a l l y i d e n t i c a l t o t h o s e measured near the h e a r t and v a s c u l a r impedance shows no e v i d e n c e o f t h e o s c i l l a t i o n s w h i c h wave r e f l e c t i o n s produce i n mammals. Undoubtedly t h e c h i e f r e a s o n f o r t h i s i s t h e b r i e f t i m e talcen f o r t h e p u l s e t o t r a v e l from t h e h e a r t t o p e r i p h e r a l a r t e r i e s , a r e s u l t o f a s h o r t a r t e r i a l t r e e and a s u f f i c i e n t l y h i g h p u l s e wave v e l o c i t y ( a p p r o x i m a t e l y 3 m/scc). Wave t r a n s m i s s i o n e f f e c t s , o f which 58 / . • • - ' ' . -r e f l e c t i o n phenomena are most s i g n i f i c a n t , become manifest when pressure (and flow) o s c i l l a t i o n s are appreciably out of phase at d i f f e r e n t s i t e s within the a r t e r i a l tree and i n t h i s regard the absence of higher harmonics of the pressure wave contributes to the lack of wave transmission e f f e c t s since a given time lag between the a r r i v a l of pressure waves at two d i f f e r e n t s i t e s represents a greater phase difference for higher frequen-c i e s . Other wave transmission phenomena, dispersion e f f e c t s for example, are s i m i l a r l y of less s i g n i f i c a n c e when transmission time are low. I t i s widely believed that wave transmission e f f e c t s contribute to the mechanical e f f i c i e n c y of the mammalian c i r c u l a t i o n by reducing the energy expended on d r i v i n g the p u l s a t i l e component of a r t e r i a l blood flow (Milnor et a l . , 1965; O'Rourke, 1967; Taylor, 1973; McDonald, 1974) although apparently i n frogs the costs of higher heart-rates and very low pulse wave velocxties outweight these advantages. The absence of wave transmission e f f e c t s i n the frog c i r c u l a t i o n implies that simple 'lumped-parameter* models should apply and the findings of t h i s study indicate that the simpJest of these models, the two parameter (compliance and resistance) windkessel, y i e l d s a good estimate of pressure-flow r e l a t i o n s h i p s as measured by a r t e r i a l impedance. In addition the v a r i a t i o n s i n impedance associated with cessation o f lung v e n t i l a t i o n can be interpreted i n terms of a simple 59 change i n time constant of the system associated with peripheral vasoconstriction (see General Introduction F i g . 3 ) . Consequently the present study has established the v i a b i l i t y of a windkessel approach to modelling a r t e r i a l haemodynamics i n small p o i k i l -otherms. 60 SECTION II The Single C i r c u l a t i o n i n the Cod, Gadus Morhua Introduction In t e l e o s t fishes blood i s pumped from a single v e n t r i c l e through a large e l a s t i c chamber, the bulbus a r t e r i o s i s , into the v e n t r a l aorta.. The bulbus i s expanded during v e n t r i c u l a r systole and the subsequent passive contraction during d i a s t o l e generates a s i g n i f i c a n t d i a s t o l i c flow i n the v e n t r a l aorta, thus the bulbus performs a depulsating function (Johansen, 1962; Randall, 1968). The ventral aorta divides to form the g i l l a f f erent vessels which supply the g i l l c a p i l l a r y beds. The efferent vessels draining these beds ire-unite to form the dorsal aorta which runs the length of the v e r t e b r a l column po s t e r i o r to the g i l l s and supplies blood to the systemic c i r c u l a t i o n . Thus fishes possess a single c i r c u l a t i o n c o n s i s t i n g of two c a p i l l a r y beds joined ' i n s e r i e s ' by a major a r t e r i a l system. The i n t e r p o l a t i o n of the g i l l c a p i l l a r i e s between the heart and systemic c i r c u l a t i o n must be of fundamental importance to the blood flow dynamics of the a r t e r i a l system, p a r t i c u l a r l y , since the g i l l bed t y p i c a l l y represents about one-third of the t o t a l vascular resistance (Holeton and Randall, 1967). Despite t h i s unique arrangement few workers have investigated haemody-namics i n f i s h e s . Primarily blood pressures, heart rates and 61 flow rates have been recorded in order to gain insight into regulatory mechanisms associated with stress (hypoxia, exercise, etc.) but few attempts have been made to interpret these records in terms of the dynamics of the fi s h circulation (Holeton and Randall, 1967; Satchell, 1971). The aim of this investigation i s to examine present knowledge of haemodynamics in fishes in terms of a simple cardiovascular model in order to see i f the model provides physiological insight not apparent from direct inspection of data and to test the v i a b i l i t y of the model with respect to more rigorous analysis of cardiovascular dynamics in fishes. A simple windkessel model proposed by Satchell (1971) has been chosen since many fish circulations, like the circula-tory systems of frogs, are characterized by low heart rates and short art e r i a l vessels. Although there was no direct test of the v a l i d i t y of a windkessel approach measurements in fish paralleled this study allowing a direct assessment of model predictions. As described in Section I, Taylor's analysis of windkessel models (1964) indicates that a windkessel has an optimal time constant which represents a compromise between reducing blood flow p u l s a t i l i t y and decreasing the time required to accomplish regulatory changes in pressure. In a simple wind-kessel the time constant is the product of the total vascular compliance and the peripheral resistance and since peripheral 62 resistance must be governed by blood supply demands of the tissues one might expect evolutionary trends to e s t a b l i s h vessel compliances at the l e v e l which produces t h i s optimal time constant. Although the time constant concept i s not s t r i c t l y applicable to two vascular systems connected i n series i t i s apparent that a compromise between the depulsating e f f e c t of high vascular compliance and the rapid response c h a r a c t e r i s t i c s of a s t i f f system (in which only a small volume of venous blood must be s h i f t e d to the a r t e r i a l system to increase pressure) suggests that there i s an optimal t o t a l compliance. S a t c h e l l (1971) has argued that i n fishes the most advantagous arrange-ment r e s u l t s i f as much of t h i s optimal compliance as possible i s located proximal to the g i l l s , f or i f the dorsal aorta were highly compliant each systole would produce large surges i n flow through the g i l l s to distend t h i s vessel and thus smooth i r r i g a t i o n of the g i l l s would be compromised. Since the ventral aorta contains the highly e l a s t i c bulbus and the dorsal aorta tends to be r e l a t i v e l y s t i f f - w a l l e d (Lander, 1964) some weight must be given to Satchell's argument. Thus i n the present study pressure and flow patterns recorded i n the dorsal and vent r a l aortae of the cod were examined i n l i g h t of these concepts i n terms of simple hydraulic and e l e c t r i c a l models based on the morphology of the system. Iri vivo recordings from f i s h c i t e d i n t h i s study were recorded by D.R. Jones, Randall and G. Shelton. 64 Methods E x p e r i m e n t s on f i s h . In__viyc> E x p e r i m e n t s c i t e d i n t h i s s t u d y were p e r f o r m e d on 18 cod, Gadus morhua, w e i g h i n g between 2 and 3 k g . The f i s h were a n e s t h e t i z e d , i n 2% u r e t h a n e s o l u t i o n , and cannulae and f l o w probes were i n s e r t e d w i t h t h e f i s h s u p p o r t e d , i n a i r , on an o p e r a t i n g t a b l e . D u r i n g t h i s t i m e w a t e r c o n t a i n i n g the a n e s t h e t i c was pumped o v e r t h e g i l l s . The v e n t r a l a o r t a was exposed by a 4—cm i n c i s i o n i n t h e v e n t r a l m i d l i n e , j u s t a n t e r i o r t o t h e p e c t o r a l f i n s , a n d a f l o w probe was p l a c e d around t h e v e n t r a l a o r t a . The l e a d s were s u t u r e d t o t h e a d j a c e n t muscle mass and t h e i n c i s i o n was c l o s e d . The u n i o n of the e f f e r e n t b r a n c h i a l v e s s e l s t o form the d o r s a l a o r t a i s e x t r e m e l y v a r i a b l e i n f i s h e s . I n t h e cod t h e e f f e r e n t b r a n c h i a l s on each s i d e j o i n the l a t e r a l d o r s a l a o r t a s , w h i c h a r e l i n k e d a n t e r i o r l y and p o s t e r i o r l y , t o form t h e c i r c u l u s c e p h a l i c u s . P a r t o f t h e r i g h t d o r s a l a o r t a t o g e t h e r w i t h i t s a s s o c i a t e d e f f e r e n t b r a n c h i a l s was exposed-by an i n c i s i o n i n t h e s k i n f o r m i n g t h e p o s t e r i o r w a l l o f t h e o p e r c u l a r c a v i t y . The f o u r t h e f f e r e n t b r a n c h i a l a r t e r y was c a n n u l a t e d toward t h e d o r s a l a o r t a w i t h PE-90 t u b i n g t o r e c o r d d o r s a l a o r t i c p r e s s u r e . The g i l l s i d e o f t h e v e s s e l was t i e d . . o f f . A c u f f - t y p e f l o w probe was p l a c e d around t h e r i g h t d o r s a l a o r t a a d j a c e n t t o the f o u r t h e f f e r e n t b r a n c h i a l a r t e r y 65 / along with- a pneumatic flow occluder. The incision was closed and the cannula and probe leads were sutured to the body wall. Blood flows were determined by means of a Biotronix 610 electromagnetic flowmeter and pressures with Sanborn 267B pressure transducers. The signals were recorded on a Sanborn 966 six-channel pen recorder writing on rectilinear coordinates. Zero flow in the right dorsal aorta was achieved by inflating the pneumatic cuff and in the ventral aorta by injection of 5-10 g/kg acetylcholine which slowed the heart rate to such an extent that zero flow was well established in late diastole. After implantation of the cannulas and flow probes, fis h were placed, singly, in 50-gal polyethylene tanks containing seav/ater. Records were obtained from the unrestrained fis h in these tanks after recovery from the operation. Hydraulic Model The hydraulic model of the fish circulation was constructed as follows: To simulate the heart a constant pressure head was connected to a rotary valve which opened once per cycle for 50% of the total cycle period. The ventral aorta was simulated by using variable lengths of compliant rubber tubing (0.25 in dia.I to which extra compliance could be added by means of a side arm connected to further lengths of blind-ended rubber tubing. The •ventral aorta* was connected to the 'dorsal aorta' (made of s t i f f walled vinyl tubing of 0.5 cm. dia.) by a capillary tube 66 which represented the g i l l r esistance. A side arm from the v i n y l tubing connected a blind-ended length of compliant rubber tubing which, i n the condition of zero compliance i n the 'dorsal aorta*, was closed o f f at the side arm by a p a i r of haemostats. Removal of the haemostats effected an immediate and marked change i n 'dorsal a o r t i c ' compliance. The 'dorsal aorta* terminated i n a length of c a p i l l a r y tubing which represented the systemic resistance. Cannulating flow probes of 4-5 mm diameter were inserted i n both the 'ventral aorta* i n a p o s i t i o n where 80% of the compliance was upstream and the 'dorsal aorta' immediately a f t e r the ' g i l l resistance', proximal to the i n t r o -duced compliance. Positioning the v e n t r a l a o r t i c flow probe d i s t a l to the major portion of "ventral a o r t i c compliance" was intended to mimic, a p r i o r i , the raeording s i t e of iri vivo measurements, i . e . immediately d i s t a l to the bulbus a r t e r i o s i s . Pressures were measured i n the "ventral and dorsal aortae" of the model using Hewlett-Packard 267 pressure transducers, connected to 18G hypodermic needles which were forced through the walls of the tubes. Since flow through a pure resistance has the same p r o f i l e as pressure, dorsal a o r t i c pressure was also used as a measure of flow through the systemic resistance. The hydraulic model was f i l l e d with .9% NaCI to allow e x c i t a t i o n of the electromagnetic flow probes. Mathematical analysis of the model was based upon the e l e c t r i c a l analogue shown i n F i g . 2-4 (after S a t c h e l l , 1971). Unlike systems characterized by a single a r t e r i a l compliance and peripheral resistance t h i s model cannot be completely analyzed i n terms of simple time constants because of the i n t e r -play between the g i l l and systemic c i r c u l a t i o n s , thus the : approach taken was to examine the e f f e c t s of varying the physical parameters of the c i r c u l a t i o n . It was assumed that g i l l and systemic resistance were determined by gas exchange requirements and consequently the problem was reduced to examining the e f f e c t s of a l t e r i n g the r e l a t i v e s i z e of ve n t r a l and dorsal a o r t i c compliance. 68 / . • i / • . . Results Pressures and flows in the cod Flows measured just d i s t a l to the bulbus arteriosis (ventral acrtic blood flow, Fig. 2-1) in the cod confirmed the depulsating role of this chamber. No flow reversal was recorded and flow was significant throughout diastole, in some cases as high as one half peak systolic flow at end-diastole. Flow into the dorsal aorta was even less oscillatory than in the ventral aorta, as on average the amplitude of the oscillations in flow (peak minus minimum flow rate) during each cardiac cycle was 46 + 10% of the mean flow in the dorsal aorta (Table 1). The shape of the dorsal aortic flow profile was also markedly different from that in the ventral aorta. The blood velocity in the dorsal aorta increased slowly following ventricular systole and declined even more slowly, resulting in a flow profile that was very rounded in outline (Fig. 2-1 and 2-2). The p u l s a t i l i t y of the oscillations in dorsal aortic pressure (peak minus minimum pressure during each cardiac cycle expressed as a fraction of mean pressure) was 22 +_ 5% as com-pared with 46 +. 10% for the oscillations in flow (Fig. 2-2). In other words the oscillations in flow (as a per cent of mean) in the dorsal aorta were twice as large as the oscillations in • pressure. 69 Table 1. Values for cardiovascular parameters measured in cod. Heart rate, beats, min 31.5+5.5 (n = 11) Cardiac output, ml/min 52.0+8.0 (n=5) Dorsal aorta Systolic pressure, cmH 0 43.0 + 8.0 (n = 7) Pulse pressure, cmH 0 8.1 +_ 4.5 (n 7) Pulse: mean pressure 22 + 5% (n 6) Peak blood flow, ml/min 24.4 + 4.0 (n = 9) Pulse flow, ml/min 8.3 + 4.1 (n = 9) Pulse : mean flow 46 + 10% (n = 6) A l l values are means + SE. n = number of animals on which observations were made. Pulse pressure and flow refers to the difference between maximum and minimum pressure and flow during each cardiac cycle. 70 Figure 2-1. Blood flow i n the v e n t r a l (top trace) and dorsal (middle trace) aortae of the cod. Vent ra l A o r t i c B l o o d F l o w (ml / min) D o r s a l A o r t i c B l o o d F l o w ( m l / m i n ) 10 seconds J L 5 s e c o n d s T i m e 71 Figure 2-2. Dorsal a o r t i c blood pressure (top trace) and flow (bottom trace) i n the cod. Dorsa I Aort i c Pressure (mm Hg) 40 r 30 L Dorsal Aor t i c Flow (ml /min) 40 20 0 L J 5 seconds 50 seconds Ti me Pressure-flow relationships predicted by the model When a l l a r t e r i a l compliance was located proximal to the • g i l l resistance', i.e., when the 'dorsal aorta* was r i g i d , dorsal aortic pressure and flow were of similar wave-form and p u l s a t i l i t y (Fig. 2-3), a situation markedly different from that recorded in the fish (Fig. 2-2). However, when a compli-ance was introduced into the 'dorsal aorta* flow p u l s a t i l i t y increased whereas pressure p u l s a t i l i t y decreased and pressures and flows more closely resembled those recorded in vivo. Since outflow through the systemic resistance vessels is. proportional to dorsal aortic pressure, the decrease in pressure p u l s a t i l i t y implies that this outflow is also less pulsatile. This i s despite a more pulsatile flow through the g i l l s and therefore, in the compliant system, flow i s much less pulsatile at the peripheral end of the 'dorsal aorta' than at the ' g i l l ' end of the same vessel. Similarly the marked damping of the 'dorsal aortic' pressure pr o f i l e observed when a compliance i s introduced indicates that the flow pulse at the peripheral end of a compliant 'dorsal aorta' also has a much smoother profile than at the input ('gill') end. The origin of the damping effect is most clearly illustrated by a simple mathematical analysis of Satchell's (1971) el e c t r i c a l analogue (Fig. 2-4 (A)). The analysis indicates that, with constant input pressure o s c i l l a -73 Figure 2 - 3 . Pressures and flows before and a f t e r ' g i l l resistance* i n the hydraulic model. Traces (from top to bottom) - f i r s t : pressure i n the 'ventral aorta' (Pva). Second: flow i n the v e n t r a l aorta, a f t e r 4/5 of the ventral a o r t i c compliance (Qva). Third: flow into the dorsal aorta (Qda). Fourth: pressure i n the 'dorsal aorta* (Pda). At the arrow a compliance was introduced into the dorsal aorta. ^ 73a 74 Figure 2-4. An analysis of Satchell*s (1971) e l e c t r i c a l ana-logue (A) i l l u s t r a t i n g the dependence of pulsa-t i l i t y i n 'systemic* (B) and ' g i l l ' (C) r e s i s -tances. In deriving the curves, ' g i l l ' resistance was assumed to be 33% of 'systemic' resistance and •dorsal a o r t i c * capacitance was taken as the value which best predicted the dorsal a o r t i c pressure and flow patterns seen i n the animal. 75 tions i n the v e n t r a l aorta, larger current o s c i l l a t i o n s i n the • g i l l * resistance (Fig. 2-4 (C)) and smaller o s c i l l a t i o n s i n the •systemic* resistance (Fig. 2-4 (B)) are produced as frequency i s increased. Consequently the model predicts that the higher harmonics i n the complex waveform of flow seen i n the dorsal aorta w i l l be r e l a t i v e l y much smaller than the corresponding harmonics of v e n t r a l a o r t i c flow and therefore the flow p r o f i l e w i l l appear much smoother. To calcu l a t e the curves of F i g . 2-4 the values of resistance and compliance chosen for the analogue are those that best predicted the pressure and flow waveforms observed i n the animal, although the general shape of the curves i n F i g . 2-4 (B) and 2-4 (C) are s i m i l a r over a wide range of such values. A l t h o u g h v e n t r a l a o r t i c f l o w , r e c o r d e d j u s t d i s t a l t o the b u l b u s a r t e r i o s i s o f t h e c o d , was c o n t i n u o u s t h r o u g h o u t d i a s t o l e marked d e p u l s a t i o n o f f l o v ; i n t h e v e n t r a l aorta, a l s o o c c u r s d i s t a l t o the b u l b u s (compare t h e two f l o v ; s i g n a l s i n F i g . 2-1}. T h i s degree o f f l o w d e p u l s a t i o n between t h e two r e c o r d i n g s i t e s was n o t produ c e d i n the. model even though 20% o f t h e ' v e n t r a l a o r t i c ' c o m p l i a n c e r e s i d e d i n t h i s r e g i o n . O b v i o u s l y , t h e n , t h e c o m p l i a n c e o f t h e v e n t r a l a o r t a i s n o t t o t a l l y dominated by t h e b u l b u s a r t e r i o s i s , and a s i g n i f i c a n t compliance c h a r a c t e r i z e s the v e n t r a l a o r t a between t h e b u l b u s a r t e r i o s i s and the g i l l s . The r e s u l t s from t h e f i s h a l s o i n d i c a t e t h a t f l o w p u l s -a t i l i t y , i n t h e d o r s a l a o r t a was u s u a l l y d o u b l e p r e s s u r e p u l s -a t i l i t y . As the p r e s e n t model s t u d i e s d e m o n s t r a t e d , d i f f e r e n c e s between d o r s a l a o r t i c p r e s s u r e and f l o v / p r o f i l e s were d i m i n i s h e d as d o r s a l a o r t i c c o m p l i a n c e was reduced and i n a r i g i d system t h e two p r o f i l e s were i d e n t i c a l i n waveform and p u l s a t i l i t y . S i n c e t h i s s i t u a t i o n was n o t o b s e r v e d i n t h e f i s h measurements a s i g n i f i c a n t s y s t e m i c c o m p l i a n c e must r e s i d e d i s t a l t o t h e g i l l s . A l t h o u g h t h e r e have been no measurements o f a r t e r i a l c o m p l i a n c e i n t e l e o s t s d a t a on t h e e l a s t i c i t y o f t h e a o r t a e o f e l a s m o r b r a n c h s s u g g e s t s t h a t the w a l l o f t h e d o r s a l a o r t a i s some s i x t i m e s as s t i f f as t h a t o f t h e v e n t r a l a o r t a , 77 (Lander, 1969). However the dorsal aorta i s a much longer vessel and obviously i t s total compliance i s elevated propor-tionately. There i s some indication that fish may be capable of altering systemic compliance. Occasionally the cod would show a brief rise in blood pressure which was accompanied by an increase in pressure p u l s a t i l i t y and a f a l l in flow p u l s a t i l i t y . Elevated dorsal aortic pressure may result from either an increase in ventral aortic pressure or a f a l l in g i l l resistance. According to model predictions the simultaneous increase in pulse pressure and f a l l in pulse flow must reflect a drop in dorsal aortic compliance. It is possible that the same agent, norepinephrine for example, could cause both a f a l l in g i l l resistance and f a l l in systemic compliance. Certainly in mammals norepinephrine can induce increases in the moduli of el a s t i c i t y and viscosity of art e r i a l vessels (Peterson et a l . , 1960; Bergel, 1964; Gillespie and Rae, 1972) and in teleost fishes norepinephrine i s known to cause g i l l vasodilation (Keys and Bateman, 1932; Ostland and Fange, 1962). Similarly Stevens and Randall (1967) report that the response of a trout to exercise consisted of a marked increase in ventral aortic pulse pressure and a decrease in dorsal aortic pulse pressure accompanied by a small increase in both mean pressures although the ratio of g i l l to systemic resistance 73 changed v e r y l i t t l e , . A c c o r d i n g t o t h e e l e c t r i c a l analogue th e a m p l i t u d e o f t h e h a r m o n i c s o f d o r s a l a o r t i c p r e s s u r e (Pda) a r e r e l a t e d t o t h o s e o f v e n t r a l a o r t i c p r e s s u r e (Pva) by t h e e q u a t i o n where Rs and Rg a r e s y s t e m i c and g i l l v a s c u l a r r e s i s t a n c e s , f i s f r e q u e n c y and Cda i s d o r s a l a o r t i c c o m p l i a n c e . S i n c e Rs/Rg and h e a r t r a t e d i d n o t v a r y and Rs d e c r e a s e s d u r i n g e x c e r c i s e a marked d e c r e a s e i n Pda/Pva (at l e a s t 50%) must r e f l e c t an i n c r e a s e i n Cda. The model p r e d i c t s t h a t any d o r s a l a o r t i c c o m p l i a n c e w i l l r e s u l t i n an a m p l i f i c a t i o n o f t h e h i g h e r h a r m o n i c s o f g i l l f l o w c o u p l e d w i t h s e l e c t i v e d i s s i p a t i o n o f t h e s e h i g h e r h a r m o n i c s between the g i l l and c a p i l l a r y c i r c u l a t i o n s . S i m i l a r l y i t must be e x p e c t e d t h a t when h i g h e r f r e q u e n c i e s a r e g e n e r a t e d by e l e v a t e d h e a r t r a t e s , f o r example when the f i s h i s s t r e s s e d , even more pronounced d i f f e r e n c e s i n g i l l and s y s t e m i c f l o w p u l s a t i l i t y w i l l be o b s e r v e d . I t has been argued t h a t c i r c u l a t o r y systems i n g e n e r a l p e r f o r m o p t i m a l l y i n s t r e s s s i t u a t i o n s ( T a y l o r , 1964) and, i f t h i s i s t h e c a s e , t h e r e seems t o be some r e a s o n t o q u e s t i o n t h e advantages commonly a c c e p t e d f o r smooth f l o w o f b l o o d i n t h e g i l l s . O p t i m a l e f f i c i e n c y o f gas exchange r e q u i r e s t h a t minute 79 / • • ' ' • volume of water pumped across the g i l l s be in a specific ratio to blood flow through the g i l l s so that the P O 2 of blood closely approaches the P 0 2 of the inspired water at a minimal water transport. However; there seems to be l i t t l e reason to suspect that steady blood flow conveys an advantage over pulsatile flow in this respect. Obviously i f the volume of blood exposed to respiratory exchange ( g i l l blood volume) was smaller than' cardiac stroke volume then totally pulsatile flow would imply that some blood would be rushed completely through the g i l l s at each cardiac ejection with l i t t l e opportunity for gas exchange. However the rather limited available data suggests that this situation does not arise. Calculations based on Hughes' (1964) data suggest a g i l l blood volume of 1.3 ml/kg which i s double the stroke volumes (.65 ml/kg) measured in the present experiments. Since direct measurements of g i l l blood volume in the trout (Salmo trutta) by Stevens (1968) are well above those calculated from Hughes* data on Salmo gairdneri (3.8 ml/kg as opposed to 1 ml/kg) there i s reason to suspect that Hughes' data may lead to highly conservative estimates and consequently i t seems unlikely, even in exercising cod which may demonstrate marked increases in stroke volume, that stroke volume ever exceeds g i l l blood volume. Consequently the advan-tage of smooth blood flow through the g i l l s i s suspect and this may indicate why the fish foregoes this adaptation and d i s t r i b -1 80 i utes the t o t a l a r t e r i a l compliance throughout the a r t e r i a l system. 81 SECTION III Central Cardiovascular Dynamics of Ducks  Introduction The avian and mammalian stock have been phylogenetically separated for more than 150 million years and one might expect significant differences in cardiovascular function to have arisen during this period of evolution. It i s known, for example, that cardiac outputs and systemic blood pressure levels in birds are higher than those of most similarly sized mammals but, unfortunately, extensive studies on avian cardio-vascular dynamics which might allow an evaluation of the signfic-ance of such differences are lacking. This i s perhaps surprising; avain species are frequently used in studies of cardiovascular disease since they exhibit a propensity for naturally occurring and induced atherosclerosis (Katz and Stamler, 1953; Fox, 1933; Middleton, 1965; Pritchard, 1965) and i t might be hoped uiat birds could be used to study the pronouced haemodynamic effects of art e r i a l degenerative disease observed in humans (O'Rourke et a l . , 1968). However, sophisticated wave trans-mission models are required to describe pressure-flow relation-ships in mammalian arteries (Attinger et a l . , 1966; Taylor, 1964) whereas i t has been suggested that a simple 'windkessel* model might be applied to avian circulations (Taylor, 1964; 82 '/ • • ' • O'Rourke et a l . , 1968). Since the windkessel represents a lumped parameter system in which pressure and flow changes occur simultaneously throughout the system arte r i a l circulations described by this model cannot be used to study characteristics of wave transmission. The physical properties of the avian ar t e r i a l system, a distensible thoracic aorta distributing blood into stiff-walled peripheral vessels, lend credence to the windkessel model but experimental evidence supporting this approach is apparently limited to single investigation of pressure wave propagation in the turkey aorta (Taylor, 1964). On the other hand the low heart rates and short art e r i a l lengths which made a windkessel approach seem viable in amphibia and smaller fishes are not observed in birds. In the present investigation an attempt has been made to examine the relation-ships between pressures and flows in the circulation of ducks and to investigate the applicability of different cardio-vascular models to this system. 83 Methods The Experiments The experiments were performed on 72 white Pekin ducks l (Anas platyrhynchos) weighing from 1.75 to 3.40 kg (mean weight 2.2 +0.1 kg). The ducks were restrained on t h e i r backs and anaesthetized with 25% urethane solu t i o n i n saline (0.75 +_ 1.5 g/kg, I.M.). A f t e r c u t t i n g through the firculum, a midline thoracotomy was performed to expose the heart and major a r t e r i e s and an in f r a - r e d heat lamp was s i t e d over the duck to a s s i s t maintenance of body temperature. The animals breathed normally without assisted v e n t i l a t i o n . Blood flows i n the aorta (just d i s t a l to the branch point with the brachiocephalic a r t e r i e s ) , one pulmonary artery and both brachiocephalic a r t e r i e s were recorded with a Biotronix BL 610 pulsed-logic electromagnetic flowmeter. A wide s e l e c t i o n of cuff-type flow probes was on hand and a good probe f i t (less than 10% vessel c o n s t r i c t i o n during diastole) was always achieved. When necessary, zero flow was obtained by occluding the vessels d i s t a l to the recording s i t e with forceps or pneumatic flow occluders. Often, however, a constant flowmeter output was observed i n l a t e d i a s t o l e and repeated a p p l i c a t i o n of the above procedure con-firmed that t h i s output represented a r e l i a b l e measure of zero flow. 84 B l o o d p r e s s u r e was recorc.ec from t h e a o r t a , the- pulr . 'Onary-a r t e r y ana t h e v e n t r i c l e s u s i n g Stathava P23 Gb9 H e w l e t t - P a c k a r d 267 BC, B i o - t e c BT-70 and s i z e 3F and 4F 3 i o - t e c c a t h e t e r t i p manometers. A o r t i c p r e s s u r e was r e c o r d e d by c a n n u . l a t i n g the. l e f t , b r a c h i o c e p h a l i c a r t e r y and a d v a n c i n g t h e c a n n u l a t o t h e p o i n t where t h i s a r t e r y j o i n e d t h e a o r t a (about 3 cm from t h e h e a r t ) . The b r a c h i o c e p h a l i c a r t e r y was not p e r m a n e n t l y o c c l u d e d by t h i s p r o c e d u r e . In a few c a s e s t h e a o r t a was c a n n u l a t e d j u s t d i s t a l t o t h e a o r t i c f l o w p r o b e . Pulmonary a r t e r i a l • p r e s s u r e was r e c o r d e d by i n s e r t i n g a c a n n u l a i n t o t h e p r o x i m a l pulmonary a r t e r y and a d v a n c i n g t h e c a n n u l a u n t i l t h e t i p was so some 4-6 cm from t h e h e a r t . T h e o r e t i c a l l y p r e s s u r e s r e c o r d e d w i t h t h e c a n n u l a d i r e c t e d downstream d i f f e r from t r u e l a t e r a l p r e s s u r e s by a k i n e t i c e n e r g y component, 1/2 pv , where p i s t h e b l o o d d e n s i t y and v i s t h e b l o o d v e l o c i t y . F o r pulmonary a r t e r i a l p r e s s u r e s t h i s d i f f e r e n c e c o u l d amount t o 10% d u r i n g s y s t o l e . (The k i n e t i c energy component was e s t i m a t e d by assuming a f l a t v e l o c i t y p r o f i l e and t a k i n g v as t h e volume f l o w r a t e r e c o r d e d by t h e f l o w m e t e r d i v i d e d b y t h e c r o s s -s e c t i o n a l a r e a o f the f l o w m e t e r probe lumen. A b l o o d d e n s i t y o f 1.08 g/cm was assumed (McDonald, I 9 6 0 ) ) . C o n s e q u e n t l y , the t i p s o f t h e f l u i d - f i l l e d a r t e r i a l c a n n u l a s were trimmed t o a v e r y l o n g b e v e l so t h a t r e c o r d e d p r e s s u r e would c l o s e l y f o l l o w t r u e l a t e r a l p r e s s u r e . T h i s p r e c a u t i o n was a l s o t a k e n when 85 recording aortic pressure although kinetic energy effects in this vessel alter recorded blood pressures by at most 1%. Hepp et a l . , (1973) were in fact unable to detect a difference be-tween downstream and lateral pressures either in models or in vivo. They suggest that turbulence around the catheter t i p transmits true lateral pressure to the transducer. Ventricular pressures were recorded by direct ventricular puncture using cannulae tipped with short lengths of 18G hypo-dermic needles. Alternatively a catheter tip transducer was inserted half way through a hypodermic needle which was sub-sequently forced through the ventricular wall. Implanting the pressure probes rarely resulted in detectable changes in the blood flows recorded during the cannulation. In four ducks the four pressures and four flows were recorded simultaneously whereas in, seven other only flov/ in one brachiocephalic artery was not monitored. In twelve ducks single pairs of pressure and flow v?ere recorded from the same vessel for detailed pressure-flow analysis. In thirteen ducks aortic pressure was measured at several sites by advancing a cannula well down the aorta then withdrawing i t , in 3 cm steps, to the normal recording site. In five ducks pressures and rate of change of pressures (dP/dt) (computed by Biotronix B1620 and BL622 analogue computers) were recorded simultaneously in the aortic arch and at varying known positions in the aorta. 86 Fig. 3-1 illustrates a typical recording. Pulse wave velocity, as a function of position in the aorta, was determined by comparing the difference in transit time of peak dP/dt between the recording sites, marked as AT in Fig. 3-1, with the d i f -ference in position between the recording sites (usually 3 cm). This technique was found superior to the standard approach to measuring the transit time of the ascending limb of the pressure pulse between recording sites (McDonald, 1968) since changes in the pressure profile during propagation resulted in d i f f i c u l t y in identifying corresponding points on the two profiles whereas peak dP/dt was always well determined. In the remaining thirty-one animals different combinations of at least 3 pressures and/or flows were recorded. Recording systems and data analysis Some of the pressure and flow data were recorded directly on a Techni-Rite Tr 888 pen recorder writing on rectilinear co-ordinates. The pen recorder was tested using a sine wave generator and had a maximum frequency response of 120 Hz when the pen deflection was 5 mm peak to peak. At a pen deflection of 40 mm peak to peak the frequency response f e l l to 35 Hz. For this reason the pen recorder traces were only used to establish the temporal relationships between pressure and flow pulses whereas pressure and flow traces which were subjected to more rigorous analysis were converted to frequency modulated 87 Figure 3-1. Demonstration of the technique used to measure pulse wave v e l o c i t y . The top two traces are pres-sures (P) recorded at two s i t e s , separated by 3 cm, i n the duck aorta. The bottom two traces are the corresponding rates of change of pressure, dP/dt. Traces, from top to bottom; pressure recorded proximal to the heart; pressure recorded d i s t a l to the heart; rate of change of pressure recorded proximal to the heart; rate of change of pressure recorded d i s t a l to the heart. 8 7 a .2 SEC 88 signals by an FM adaptor (A.R. Vetter & Co., Pa., U.S.A.) and stored on magnetic tape on an Akai 2800 DSS four channel tape recorder. These signals were simultaneously displayed on a Hewlett-Packard 1201 A storage o s c i l l o s c o p e . The FM adaptor demodulated the taped signal when the recorder was i n the playback mode. The tape-recorder adaptor system was tested with an audio frequency generator and was found to produce less than 1% amplitude d i s t o r t i o n i n the range 0-100 Hz and a l i n e a r phase lag (0.25 /Hz) that was i d e n t i c a l on a l l recorder channels, therefore no c o r r e c t i o n for recorder d i s t o r t i o n was required. These pa i r s of a r t e r i a l pressures and flows were d i g i t i z e d and the r e s u l t i n g data subjected to Fourier analysis using a "fast Fourier transform" program (Cooley and Tukey, 1965) on an IBM 360 computer. The impedances (modulus and phase) of the a o r t i c c i r c u l a t i o n and the vascular bed supplied by one pulmonary artery were calculated from these computed pressure and flow components and appropriate corrections were made for flowmeter phase l a g . Mean blood pressures and flows were calculated by measur-ing areas under the respective pulses, either with a planimeter or by comparing the weight of the paper defining the area to be determined with the weight of a known area of the same paper and d i v i d i n g by the cycle length. Cardiac output was calculated as the sum of the flows i n the two brachiocephalic a r t e r i e s plus the aortic flow. Biotronix BL 620 and BL 622 analog computers were used to compute time derivatives of aortic pressure for the determination of aortic pulse wave velocity. Because of the high frequency" content of signals generally recorded in homeotherms rigorous static and dynamic calibration of manometric and flowmeter systems i s essential i f sophisti-cated methods of analysis are to be applied to data obtained using these systems. This constraint i s particularly important when attempting to record pressures from such sites as the l e f t ventricle where the higher harmonics make significant contribut-ions to the total signal. These higher harmonics often cause manometer resonance resulting in overshoot artefacts which in some cases have been attributed to a physiological origin (Spencer & Greiss, 1962). For such reasons the static and dynamic calibrations of the recording systems used in this series of experiments w i l l be discussed in detai l . A l l mano-metric systems, except the catheter tip manometers, were f i l l e d with de-aerated avian saline containing 40 i.u./ml of heparin, after f i r s t flushing the system with CO., gas. These manometers were connected to two s a l i n e - f i l l e d reservoirs (the surface of the saline was covered with paraffin o i l ) which could be moved independently to give the zero level (which, in the recording situation was at the opening of the catheter) and a known pressure head. Static calibration of the catheter tip manometers 90 was a c h i e v e d by submerging t h e manometer t o known d e p t h s i n a v e r t i c a l column o f w a t e r w h i c h was m a i n t a i n e d a t 3 8 - 4 0 ° C „ S h o r t p o l y t h e n e o r v i n y l c a n n u l a e o f v a r i o u s d i a m e t e r s were used t o make c o n n e c t i o n between t h e s a l i n e - f i l l e d manometers and the b l o o d v e s s e l s . Dynamic c a l i b r a t i o n o f a l l manometers was p e r f o r m e d b e f o r e o r a f t e r each e x p e r i m e n t b y a p p l y i n g a sudden p r e s s u r e change t o the t i p o f t h e c a t h e t e r s (Hansen ' p o p - t e s t ' ) and r e c o r d i n g t h e f r e e v i b r a t i o n s o f t h e raanometric system on t h e r e c o r d i n g system vised i n t h e e x p e r i m e n t . The f r e q u e n c y r e s p o n s e s o f t h e manometric systems w h i c h c o u l d be c o n s i s t e n t l y o b t a i n e d were as f o l l o w s : H e w l e t t - P a c k a r d 2 6 7 EC - 7 0 Hz at 0.1 r e l a t i v e damping; Statham P23 Gb - 90 Hz, a t 0.15 r e l a t i v e damping.; B i c - t e c BT-70 - 200 Hz a t 0.1 r e l a t i v e damping and t h e B i o - t e c c a t h e t e r t i p manometers - 330 Hz a t 0 . 0 5 r e l a t i v e damping. A l t h o u g h a l l t h e s e manometers were c a p a b l e o f a c c u r a t e l y r e p r o d u c i n g a r t e r i a l p r e s s u r e s t h i s was n o t t h e case w i t h v e n t r i c u l a r p r e s s u r e s . W i t h t h e l o w e r f r e q u e n c y manometers a pronounced ' o v e r s h o o t ' o c c u r r e d e a r l y i n s y s t o l e , t h e s i z e o f w h i c h was p r o g r e s s i v e l y r e d u c e d as the f r e q u e n c y r e s p o n s e o f t h e manometer used i n c r e a s e d . S t a t i c c a l i b r a t i o n o f t h e B i o t r o n i x BL 6 1 0 p u l s e d - l o g i c e l e c t r o m a g n e t i c f l o w m e t e r was perfomed a t t h e end o f an e x p e r i -ment. A t t h i s t i me a p o r t i o n o f the a r t e r y was e x c i s e d and, w i t h t h e t r a n s d u c e r i n p l a c e , s a l i n e o r b l o o d was p a s s e d t h r o u g h 91 the vessel from a r e s e r v o i r . The f l u i d passing through the transducer was c o l l e c t e d i n a graduated cyli n d e r and the. period fo r c o l l e c t i o n of 100 ml was timed by stopwatch. Saline and blood gave i d e n t i c a l c a l i b r a t i o n s when a single probe was tested with both. Other i n v e s t i g a t i o r s have found that saline c a l i b r a t i o n s d i f f e r from blood c a l i b r a t i o n s by 2% or les s when the blood haematocrit i s normal (Pierce e_t a l . , 1964; Greenfield et a l . , 1966). Flowmeter outputs were l i n e a r throughout the range tested (0-1000 ml/min ). Dynamic c a l i b r a t i o n of the flowmeter and recording systems (Techni-Rite TR 888 or Akai recorder and Hewlett-Packard 1201 A oscilloscope) was performed using a pump s i m i l a r to that described by Taylor (1959) or by applying a known a.c. signal to the input side of the flow transducer cable. The pump allowed assessment of the transducer phase lag and amplitude d i s t o r t i o n up to frequencies of 10 Hz whereas the el e c t r o n i c c a l i b r a t i o n could be applied over an unlimited range. When a step voltage was applied to the input connectors of the flow-meter the output response was i d e n t i c a l to that seen when a constant flov/ through the flow probe was suddenly occluded by a solenoid valve, thus v e r i f y i n g the v a l i d i t y of the ele c t r o n i c c a l i b r a t i o n , i . e . confirming that v i r t u a l l y a l l d i s t o r t i o n was produced i n the input amplifier of the flowmeter rather than i n the flow probe. Other investigators have previously established 92 the v a l i d i t y of t h i s type of e l e c t r o n i c c a l i b r a t i o n (Gessner and Bergel, 1964; Case et a l . . 1966). With both the pen recorder and the oscilloscope systems amplitude d i s t o r t i o n was n e g l i g i b l e over the frequency range 0 - 2 0 Hz\, (3cJb point was 50 Hz) however, phase lag was 1.8 /Hz when recording on the oscilloscope and 3 .2 to 3 .7 /Hz when using the pen-recorder. The larger and more variable phase lag with the pen recorder was related to the c h a r a c t e r i s t i c s of the pen galvanometer rather than the input amplifiers of the system. 93 . R e s u l t s P r e s s u r e s and f l o w s i n t h e C e n t r a l c i r c u l a t i o n P r essure' and f l o w p u l s e s r e c o r d e d from th e a o r t a , b o t h bra.chiocepha.lic a r t e r i e s , pulmonary a r t e r y and b o t h v e n t r i c l e s a r e shown i n F i g . 3-2. The e i g h t t r a c e s shown i n F i g . 3-2A were r e c o r d e d s i m u l t a n e o u s l y so t h a t tempora.1 r e l a t i o n s h i p s between e v e n t s o f t h e c a r d i a c c y c l e c o u l d be e s t a b l i s h e d . The o s c i l l o s c o p e t r a c e s i n F i g . 3 - 2 B were r e c o r d e d i n p a i r s so t h a t p a r t i c u l a r a t t e n t i o n c o u l d be p a i d t o t h e f i d e l i t y o f each r e c o r d e d s i g n a l t o a s s u r e an e x a c t r e p r e s e n t a t i o n o f a l l wave-forms . F o r p r e s e n t a t i o n p u r p o s e s t y p i c a l p u l s e s a r e s u p e r -imposed i i i F i g . 3 - 3 . The o n s e t o f c o n t r a c t i o n o c c u r r e d s y n -c h r o n o u s l y i n t h e two v e n t r i c l e s and t h e a o r t i c and p u l m o n i c v a l v e s opened s i m u l t a n e o u s l y . L e f t v e n t r i c u l a r s y s t o l e l a s t e d a p p r o x i m a t e l y 0 . 1 2 sec and v a r i e d l i t t l e w i t h changes i n h e a r t r a t e . A t t h e mean h e a r t r a t e o f 219+_ 4 b e a t s / m i n l e f t v e n t r i c u l a r s y s t o l e o c c u p i e d 44% o f t h e c a r d i a c c y c l e b u t t h e d u r a t i o n o f r i g h t v e n t r i c u l a r s y s t o l e exceeded l e f t by up t o 30% ( F i g . 3-2B and 3 0 3 ) . The c e n t r a l a o r t i c p r e s s u r e p u l s e was c h a r a c t e r i z e d by a sharp i n i t i a l r i s e w h i c h was u s u a l l y t e r m -i n a t e d i n a d i s t i n c t a n a c h r o t i c s h o u l d e r , f o l l o w e d by a s i owe it-r i s e t o peak p r e s s u r e ( F i g . 3-1, 3-2 and 3-3) . A t peak pressure-t h e r e was no d e t e c t a b l e p r e s s u r e d i f f e r e n c e between th e l e f t v e n t r i c l e (mean v a l u e 165 j _ 1.2 man Hg) zavl the a o r t a (mean v a l u e 94 Figure 3-2 A. Pressures (mm Hg) and flows (L/min.) recorded simultaneously i n the c e n t r a l a r t e r i a l system of the duck. Traces, from top to bottom; flow i n the r i g h t brachiocephalic artery, RBAF; flow i n the l e f t brachiocephalic artery LEAF; pulmonary a r t e r i a l flow, PAF; pulmonary a r t e r i a l pressure PAP; a o r t i c flow, AF; a o r t i c pressure, AP; r i g h t v e n t r i c u l a r pressure, RVP; l e f t v e n t r i c u l a r pressure, LVP. B. Oscilloscope records of c e n t r a l pressures and flows recorded i n p a i r s . Traces match those i n F i g . 2A, but were recorded, each p a i r , from a d i f f e r e n t animal. \ 94a 1 S E C 0.5 SEC 95 Figure 3-3. Overlap drawing of pressure ( ) and flow ( ) pulses i n the systemic (A) and pulmonary (E) c i r c u l a t i o n s of the duck. The v e r t i c a l l i n e s are separated by time i n t e r v a l s of 0.025 sec. LVP, l e f t v e n t r i c u l a r pressure; AP, a o r t i c pressure; AF, a o r t i c flow; RVP, r i g h t v e n t r i c u l a r pressure; PAP, pulmonary a r t e r i a l flow; PAF, pulmonary a r t e r i a l flov/. BLOOD PRESSURE [mm Hg] 9G 165+ 1.6 mm Kg}. *n i n c i s u r a marked c l o s u r e o f t h e a o r t i c v a l v e s and t h e d i a s t o l i c c l s c l i n a o" r. o r t i c p::e •";<".u r e rar^.'iy d i s p l a y e d a c i c h r c t i c wave. D u r i n g d i a c t o l o c o n t r o l a o r t i c p r e s s u r e d e c l i n e d t o a mean v a l u e o f 3.21 + 2 Ian I-g. However, d u r i n g t r a n s r a i s s i o n a l o n g t h e a o r t a t h e p r e s s u r e p u l s e chanced i n b o t h p u l s e a m p l i t u d e and c o n t o u r w i t h p u l s e p r e s s u r e i n -c r e a s i n g by an average o f 2S.1 +_ 3,1%. T h i s i n c r e a s e i n p u l s e p r e s s u r e ( p e a k i n g o f the p r e s s u r e wave) r e s u l t e d from a marked i n c r e a s e i n the a m p l i t u d e o f t h e s y s t o l i c p o r t i o n , o f t h e p r e s s u r e p u l s e w i t h l i t t l e change i n t h e d i a s t o l i c p o r t i o n ( F i g . 3-4). Ducks w h i c h d i s p l a y e d o n l y s l i g h t i n c r e a s e s i n p u l s e p r e s s u r e a l s o e x h i b i t e d l i t t l e change i n p u l s e c o n t o u r . The p u l s e wave v e l o c i t y a l s o i n c r e a s e d a l o n g t h e a o r t a r i s i n g from 4.4 +_ 0.8 m/sec i n t h e a o r t i c a r c h t o 11.7 +_ 1.2 m/sec i n t h e adbominal a o r t a . I n t h e m a j o r i t y o f a n i m a l s t h e i n c r e a s e i n p u l s e wave v e l o c i t y was e f f e c t e d i n t h e t h o r a c i c a o r t a . The t o t a l t r a n s i t , t i m e f o r t h e p u l s e t o r e a c h t h e d i s t a l end o f t h e n o r t s , a t r.-. mean b l o o d p r e s s u r e o f 143 + 2 mm Hg o b t a i n i n g i n t h e s e e x p e r i m e n t s , was a p p r o x i m a t e l y 20 m.sec, o r 5-10% o f t h e c a r d i a c c y c l e . A o r t i c b l o o d f l o w r o s e s h a r p l y a f t e r o p e n i n g o f t h e a o r t i c v a l v e and peak f l o w p r e c e d e d peak p r e s s u r e by about 25 msec. ( F i g . 3-2B and 3-3). A o r t i c f l o w r a t e f e l l s h a r p l y a t t h e end o f s y s t o l e b u t l i t t l e o r no b a c k f l o w was r e c o r d e d ( F i g . 3-2). 97 Figure 3-4. Pressure waves recorded i n the abdominal aorta ( l e f t trace) and the a o r t i c arch of the duck. Marked changes i n the amplitude and p r o f i l e of the wave are seen during propagation along the aorta. mm Hg o o in o 97a 98 Frequently a o r t i c flow displayed a double maximum. Flow traces were nearly i d e n t i c a l i n the two brachiocephalic a r t e r i e s (Fig. 3-2B; a narrow peak flow rate was observed whereas the f a l l i n g limb of the flow p r o f i l e was interrupted by a l e v e l l i n g o f f i n l a t e systole. This phase was co n s i s t e n t l y followed by a b r i e f period of backflow and l a t e r return to zero flow for the remainder of d i a s t o l e . Three-quarters of the t o t a l cardiac output (482 +_ 7 ml/ min) was d i s t r i b u t e d equally between the brachiocephalic a r t e r i e s which supply the wing, f l i g h t muscles, and head. The pulmonary a r t e r i a l pressure wave was s i m i l a r to that seen i n the aorta but pressure was more p u l s a t i l e , with the average d i a s t o l i c pressure of 9 +_ 0.2 mm Hg being l e s s than one-half the average peak s y s t o l i c pressure of 26 + 0.5 mm Hg (Fig. 3-3). The peak s y s t o l i c pressure i n the pulmonary artery-was, on average, some 2 mm Hg below the peak r i g h t v e n t r i c u l a r pressure although t h i s difference was not s i g n i f i c a n t . Blood flow i n the pulmonary artery was c o n s i s t e n t l y maintained during d i a s t o l e and at normal heart rates flow f e l l to zero only immediately before the onset of the next cardiac e j e c t i o n (Fig. 3-2 and 3-3). In t h i s regard the flow p r o f i l e c l o s e l y resembled that recorded i n the pulmocutaneous arches of amphibia (Section I; Fig.1-9; Shelton, 1972). However, the a p p l i c a t i o n of adrenalin (20 ug/ml) to the external wall of the pulmonary artery resulted 99 i n a marked change i n flow p r o f i l e (Fig. 3-5). Forward d i a s t o l i c flow was completely eliminated and a d i s t i n c t period of backflow following systole was observed. Pressure flow r e l a t i o n s h i p s Impedance versus frequency curves from i n d i v i d u a l ducks are presented because averaging procedures cannot be applied to impedance data from animals v/ith uncontrolled heart rates since each animal supplies impedance information at a d i f f e r e n t d i s t r i b u t i o n of frequencies. In any event when such data can be combined, f o r example when the heart i s a r t i f i c i a l l y paced, the averaging procedure tends to obscure d e t a i l s of impedance re l a t i o n s h i p s (O'Rourke and Taylor, 1966). The impedance curves presented are t y p i c a l of a l l experiments and although the high heart rates encountered necessitate considerable i n t e r p o l a t i o n of impedances at anharmonic frequencies, impedance curves from other ducks displayed no consistent features not i l l u s t r a t e d by the curves presented here. F i g . 3-6 i l l u s t r a t e s t y p i c a l impedance modulus and phase graphs determined at the input of the a o r t i c c i r c u l a t i o n (Fig. 3-6A) and the c i r c u l a t i o n of the l e f t pulmonary artery (Fig. 3-6B). A o r t i c impedance modulus f e l l sharply from i t s maximum at zero frequency (resistance to steady flow) to a minimum at 9-12 Hz before r i s i n g again. At higher frequencies the impedance modulus was less than o n e - t h i r t i e t h the d.c. resistance. A o r t i c impedance phase f e l l to -1 radian 100 Figure 3-5. Pulmonary a r t e r i a l flow recorded before (a) and a f t e r (b) a p p l i c a t i o n of adrenaline (20 ug/ml) to the external w a l l of the pulmonary artery. Positive d i a s t o l i c flow i n the control s i t u a t i o n (a) i s replaced by a period of backflow followed by a return to zero flow a f t e r a p p l i c a t i o n of adrenaline (b). 101 Figure 3-6. Input impedance modulus and phase versus frequency graphs for the a o r t i c (A) and pulmonary (B) c i r c u l a t i o n s of the duck. Impedance data from 6 ducks i s supplied, one p a i r of modulus and phase curves from each animal. Also shown i s the harmonic content of the pressure and flow waves i n the aorta and pulmonary artery. 101a 102 a t low f r e q u e n c i e s t h e n r o s e s h a r p l y t o about -M r a d i a n . Z e r o phase o c c u r r e d a t t h e f r e q u e n c y o f t h e minimum i n impedance modulus. Impedance o f t h e pulmonary a r t e r i a l bed showed much l e s s dependence on f r e q u e n c y t h a n a o r t i c impedance ( F i g . 3 - 6 ) . Impedance modulus f e l l t o s l i g h t l y l e s s t h a n h a l f i t s d.c. v a l u e t h e n remained i n d e p e n d e n t o f f r e q u e n c y w h i l e impedance phase was c l o s e t o z e r o t h r o u g h o u t t h e f r e q u e n c y range t e s t e d . T h i s r e l a t i v e independence o f impedance on f r e q u e n c y i m p l i e s t h a t c o r r e s p o n d i n g p r e s s u r e and f l o w harmonies were p r o p o r t i o n a t e l y r e l a t e d and i n phase, hence t h e s i m i l a r p r o f i l e s o f pulmonary a r t e r i a l p r e s s u r e and f l o w ( F i g . 3-3). F i g . 3-S a l s o i l l u s t r a t e s t h e harmonic c o n t e n t o f t h e p r e s s u r e and f l o w waves from one duck. A l t h o u g h t h e s i x t h harmonic o f f l o w i s s t i l l h i g h l y s i g n i f i c a n t i n t h e s y s t e m i c c i r c u l a t i o n t h e same harmonic o f p r e s s u r e i s v e r y s m a l l and h i g h e r h a r m o n i c s make no measureable c o n t r i b u t i o n t o t h e p r e s s u r e wave. 103 D i s c u s s i o n H i g h s y s t e m i c b l o o d p r e s s u r e s r e p o r t e d f o r o t h e r b i r d s ( S t u r k i e and V o g e l , 1957; Speckmann and R i n g e r , 1963) have been c o n f i r m e d i n t h e p r e s e n t e x p e r i m e n t s . T h i s h i g h b l o o d p r e s s u r e i s a r e f l e c t i o n o f an e l e v a t e d o u t p u t o f t h e c a r d i a c pump r a t h e r t h a n a h i g h f l o w r e s i s t a n c e s i n c e t o t a l p e r i p h e r a l r e s i s t a n c e (mean a r t e r i a l p r e s s u r e d i v i d e d by c a r d i a c o u t p u t ) f o r t h e s y s t e m i c c i r c u l a t i o n i s b e l o w t h a t r e p o r t e d f o r mammals o f s i m i l a r s i z e (e.g. c a t s , S p e c t o r , 1956). C a r d i a c o u t p u t i n t h e p r e s e n t a c u t e p r e p a r a t i o n s was l o w e r t h a n t h o s e d e t e r m i n e d i n ducks by t h e dye d i l u t i o n t e c h n i q u e ( S t u r k i e , 1966; Folkow e t a l . , 1967; Jones and H o l e t o n , 1972a), b u t was i n t h e same range as t h o s e r e c o r d e d c h r o n i c a l l y w i t h e l e c t r o m a g n e t i c f l o w -meters (Jones and H o l e t o n , 1972b). I t now appears o b v i o u s t h a t a major d i s c r e p a n c y e x i s t s between t h e s e t e c h n i q u e s w h i c h i s u n r e l a t e d t o whether the e x p e r i m e n t s were p e r f o r m e d on open o r c l o s e d c h e s t a n i m a l s . Mean pulmonary a r t e r i a l p r e s s u r e s (17 + 0 . 3 mm Hg), u n l i k e t h e mean s y s t e m i c a r t e r i a l p r e s s u r e s , were w i t h i n t h e mammalian range ( P a t e l e t a l . , 1963; B e r g e l and M i l n o r , 1965). E v i d e n t l y t h e v a s c u l a r arrangement i n t h e a v i a n l u n g accommodates h i g h pulmonary f l o w w i t h o u t e l e v a t e d p r e s s u r e s ; i n o t h e r words, th e r e s i s t a n c e o f the pulmonary v a s c u l a r bed i s e x t r e m e l y low. 104 Dynamically the avian c i r c u l a t i o n shares many properties with that of the mammal. The increase i n amplitude and v e l o c i t y of the pressure pulse during transmission through the aorta resembles the s i t u a t i o n observed i n mammals (McDonald, 1968; O'Rourke et a l . , 1968). On the other hand, the a o r t i c pulse r a r e l y displayed d i c h r o t i c waves which are frequently seen i n mammals (McDonald, 1960; Remington, 1960). The shape of the pressure and flow waves i n the cen t r a l c i r c u l a t i o n were s i m i l a r to those observed i n mammals (Bergel and Milnor, 1965; O'Rourke, 1967; Oboler et. a l . , 1973), with the marked exception of pulmonary a r t e r i a l flow. The appreciable pulmonary a r t e r i a l flow during d i a s t o l e may be attr i b u t e d , i n part, to s i t i n g the flow probe further from the heart than i n t y p i c a l experiments on dogs (in b i r d s the root of the pulmonary artery i s not e a s i l y a c c e s s i b l e ) . Nevertheless t h i s marked d i a s t o l i c flow must indicate a high d i s t e n s i b i l i t y of the proximal portion of the pulmonary artery. A highly d i s t e n s i b l e pulmonary artery may be necessary to depulsate pulmonary pressure and flow since the volume of the avian puomonary c i r c u l a t i o n i s small (Burton and Smith , 1968), and, as flow resistance i s low, s t i f f supply vessels would be unable to store s u f f i c i e n t blood during systole to maintain d i a s t o l i c pressure and flow. The extended duration of r i g h t v e n t r i c u l a r systole compared with l e f t , which decreases the d i a s t o l i c i n t e r v a l over which pressure and flow rate decline, 105 also contributes to the maintenance of flow throughout the cardiac cycle (Taylor, 1964), t h i s feature of the avian c i r c u l a -t i o n not being shared by mammals (Franklin e_t a l . , 1962; Oboler et a l . , 1973). The d i s t i n c t a l t e r a t i o n i n the flow p r o f i l e following external a p p l i c a t i o n of adrenalin to the a r t e r i a l wall indicates a decrease i n the time constant of the pulmonary vascular bed. Such an e f f e c t can only be the r e s u l t of a f a l l i n pulmonary compliance or resistance and,as pulmonary resistance rose following adrenalin a p p l i c a t i o n , t h i s decreased time constant i s interpreted as i n d i c a t i n g a marked s t i f f e n i n g of the a r t e r i a l -wall. The flow p r o f i l e r e s u l t i n g a f t e r adrenalin a p p l i c a t i o n c l o s e l y resembled that normally recorded i n the pulmonary artery of mammals (Bergel and Milnor, 1965; Pace, Cox, Alvarez-Vara and Karreman, 1972). Undoubtedly, the adrenalin was absorbed systemically and caused generalised c i r c u l a t o r y changes i n that heart rate and stroke volume f e l l but those e f f e c t s cannot provide an explanation for the observed changes i n the flow p r o f i l e . The need for sophisticated cardiovascular models to describe pressure-flow r e l a t i o n s h i p s i n mammalian a r t e r i e s can be attributed, for the most part, to the f i n i t e v e l o c i t y of the pulse wave generated by. the heart. Pressure (and flow) o s c i l -l a t i o n s at d i f f e r e n t s i t e s i n mammalian a r t e r i a l systems are s i g n i f i c a n t l y out of phase and pressure and flov/ waves may be 106 vr.ark'.'v-.Tly a l t e r e d by r c f. 1 '.-.<.•'*'.ion. ad i i i 1 - . ; : : L p a t i o n v. i T f ^ c t " «: r>.c b y s p a t i a l . v a r i a t i o n o f a r t e r i a l •.-.•all p r o p c r t l - u s , f a c t o r s w h i c h can o n l y be d e s c r i b e d i n ' ter:v\::; o f v:a*.*3 t:cr-..::.r- d c r i o n v..c£o.Is.-r . c f l e c t i o n -e f f e c t s . , f o r yrcr^vplc, a r e maximal vfnv.ii t h e t r a n s i t t i n e o f a p r e s s u r e wave betv/een t h e h e a r t anc r e f l e c t i n g . t - i t e s (the a r t e r i o l a r beds) i s 1/4 o f a c y c l e and c a n be n e g l e c t e d o n l y f o r much l o v e r • t r a n s i t t i m e s . S i n c e a t l e a s t t h e f i r s t f i v e h a r m o n i c s make s i g n i f i c a n t c o n t r i b u t i o n s t o t y p i c a l p r e s s u r e .waves ( P a t e l e t a l . . , 1963) t r a n s i t t i m e s must be b e l o w 5% o f t h e t o t a l c a r d i a c c y c l e i f r e f l e c t i o n effect;-:; a r t t o be i g n o r e d , a s i t u a t i o n n o t e n c o u n t e r e d i n mammals commonly s t u d i e d . C e r t a i n l y measurements- o f a o r t i c p u l s e wave v e l o c i t i e s i n ducks g i v e no i n d i c a t i o n t h a t a w i n d k e s s e l model can be. used t o c h a r a c t e r i s e the a v i a n s y s t e m i c c i r c u l c i t i c n . P u l s e wave v e l o c i t i e s a r e n o t s i g n i f i c a n t l y above t h o s e r e p o r t e d f o r t h e dog (I'.cDonald, 1968) and t h e t r a n s m i s s i o n t i m e o f t h e p u l s e wave a l o n g t h e a o r t a .is 5-10%. o f t h e c a r d i a c c y c l e and c o n s e q u e n t l y n o t even t h e f i r s t h a r m o n i c s - o f t h e pressure- and. f l o w waves w i l l be f r e e from wave ••ran^micsion phenoio.c=na. Ir, a d d i t i o n , the impedance c u r v e s o f t h e a o r t i c c i r c u l a t i o n d i s p l a y e d f e a t u r e s commonly o b s e r v e d i n s t u d i e s o f nsairaaalian c i r c u l a t i o n s ( P a t e l e t a l . , .1963; O'Rourke and T a y l o r 1967) e x c e p t t h a t i n the l a t t e r the. minimum i n impedr.ae • >odvi';;j o c c u r s a t a l o w e r frequency (2r6 Uz) l a r g o p o s i t i v e 107 phase a n g l e s a re n o t always o b s e r v e d . A minimum i n impedance modulus and t h e c o r r e s p o n d i n g p a t t e r n o f impedance phase a r e not p r e d i c t a b l e from a w i n d k e s s e l model and a r e n o r m a l l y a t t r i b u t e d t o the e f f e c t s o f wave r e f l e c t i o n . F u r t h e r e v i d e n c e t h a t wave t r a n s m i s s i o n e f f e c t s a re s i g n i f i c a n t i n t h e a o r t i c c i r c u l a t i o n was o b s e r v e d when p r e s s u r e s v e r s r e c o r d e d a t d i f f e r e n t s i t e s i n t h e a o r t a . Pronounced 'peaking' o r a m p l i f i c a t i o n o f the. p r e s s u r e p u l s e was o b s e r v e d w i t h p u l s e p r e s s u r e i n c r e a s i n g b y a p p r o x i m a t e l y 30% between t h e a o r t i c a r c h and t h e abdominal a o r t a . T h i s degree o f a m p l i f i c a t i o n i s s i m i l a r t o t h a t r e p o r t e d i n humans. O'Rourke e t a l (1968) found t h a t t h e p r e s s u r e p u l s e i n c r e a s e d i n a m p l i t u d e by an average o f 35% ( c a l c u l a t e d from t h e i r g r a p h i c a l d a t a ) d u r i n g t r a n s m i s s i o n a l o n g t h e a o r t a o f p a t i e n t s who d i s p l a y e d no e v i d e n c e o f v a s c u l a r l e s i o n s (20 p a t i e n t s , aged 6-70 y e a r s ) . The change i n shape o f t h e p r e s s u r e p u l s e d u r i n g p r o p a g a t i o n was a l s o q u i t e s i m i l a r t o t h a t r e p o r t e d by O'Rourke e t a l , , (1968). P e a k i n g o f the p r e s s u r e p u l s e has been a t t r i b u t e d t o b o t h r e f l e c t i o n e f f e c t s (McDonald, 1960) and the p r o g r e s s i v e s t i f f e n i n g o f t h e a r t e r i a l w a l l a t s i t e s more d i s t a l t o t h e h e a r t ( T a y l o r , 1964). In any event p e a k i n g i s a m a n i f e s t a t i o n o f wave t r a n s m i s s i o n and ca n n o t be p r e d i c t e d from a w i n d k e s s e l model. On t h e o t h e r hand, a l t h o u g h t h e major c h a r a c t e r i s t i c s o f pulmonary a r t e r i a l impedance, a moderate d e c l i n e i n modulus and n e a r - z e r o phase, a r e s i m i l a r t o tho s e 108 reported for the mammal (Caro and McDonald, 1961; Bergel and Milnor, 1965; Reuben et a l . , 1971; Pace et a l . , 1972) no o s c i l -lations in pulmonary impedance modulus and phase were observed in the duck. It may be that wave transmission effects are not of major importance in the avian pulmonary circulation or that terminations in the low -resistance pulmonary bed are well-matched with the characteristic impedance of the supply vessels in which case reflection effects would be minimized. However, since pulse wave velocities were not determined in pulmonary vessels this question cannot be settled at the moment. 109 SECTION IV The E f f e c t s of ' E l a s t i c Taper 1 and Reflections on Wave Propagation i n Mammalian A r t e r i e s  Introduction Theories describing the dynamic aspects of blood flow i n a r t e r i a l systems have developed almost e x c l u s i v e l y from studies on mammals, most notably the dog, cat and rabbit, and consequently far more i s known about haemodynamics i n these species than i n any others. Nonetheless a complete, quantitative analysis of pressure-flow r e l a t i o n s h i p s throughout a mammalian a r t e r i a l system i s s t i l l not possible and undoubtedly t h i s i s r e l a t e d to the myriad of factors which influence these r e l a t i o n s h i p s . Rapid gains i n t h i s d i r e c t i o n were made i n the 1950's following the r e a l i z a t i o n that lumped parameter models of mammalian a r t e r i a l systems, such as the windkessel, had to be abandoned i n favour of a wave transmission approach. Most notably the theories of Womersley (1958) appeared capable of incorporating most factors which influence pressure-flow r e l a t i o n s i n uniform segments of a r t e r i e s and c e r t a i n l y h i s approach was highly successful i n predicting l o c a l flow patterns from the pressure gradient along short lengths of vessel (McDonald, 1955, 1974). The hope was expressed that by d i v i d i n g the a r t e r i a l system into a multitude of such vessel segments and integrating the e f f e c t s of wave 110 transmission over these many segments that transmission through the complete a r t e r i a l tree could be synthesized. Unfortunately the most cursory attempts i n t h i s d i r e c t i o n were unsuccessful and i t soon became apparent that such an approach could not account for such factors as the continuous, gradual changes i n vessel properties, e.g. the progressive s t i f f e n i n g of the a r t e r i a l tree at s i t e s more d i s t a l to the heart, for r e f l e c t i o n of waves from d i s c o n t i n u i t i e s such as branch s i t e s or for the flow distrubances which these discontinuites produce. Perhaps the greatest obstacle to progress i n t h i s d i r e c t i o n , c e r t a i n l y the most extensively investigated, l i e s i n assessing the phenomenon of wave r e f l e c t i o n . Although i t i s now widely accepted that r e f l e c t i o n s occur t h e i r importance to a r t e r i a l dynamics i s s t i l l a point of dispute (McDonald, 1974). There are a number of reasons for t h i s controversy. F i r s t l y wave r e f l e c t i o n s i n a system of e l a s t i c tubes may occur wherever there i s a d i s c o n t i n u i t y i n the system and i n the highly arborized a r t e r i a l tree the near i n f i n i t e number of bends and branch points at many d i f f e r e n t distances from the heart w i l l send back numerous small r e f l e c t i o n s which summate i n a highly complex fashion. The approaches of t r e a t i n g the summed r e f l e c t e d wave as i f i t originated from an 'average' r e f l e c t i o n s i t e (McDonald, 1974) or lumping together a l l r e f l e c t i o n s from s p e c i f i c regions (O'Rourke, 1967) are useful but c l e a r l y limited,, I l l I t i s also not c l e a r which s i t e s makes the greatest contribution to wave r e f l e c t i o n s . O r i g i n a l l y i t was f e l t that major branch points such as the a o r t i c t r i f u r c a t i o n generated the greatest r e f l e c t i o n s (see Remington and 0*Brian, 1970) whereas i t i s now argued that the many smaller d i s c o n t i n u i t i e s i n the a r t e r i o l a r beds are of greater signifigance. The reason for the s h i f t i n opinion i s that impedance curves are said to show more evidence of r e f l e c t i o n s when peripheral beds are vasoconstricted and less during v a s o d i l a t i o n (O'Rourke and Taylor, 1966; Westerhof et a l . , 1973) although these differences i n impedance pattern appear, to t h i s worker, equivocal at best. In recent years a further d i f f i c u l t y i n assessing r e f l e c t i o n phenomena has been elucidated. Taylor (1964, 1965) has developed a theory based upon an e l e c t r i c a l transmission l i n e analogue which predicts that the progressive s t i f f e n i n g of a r t e r i a l vessels at s i t e s more d i s t a l to the heart, the so-called " e l a s t i c tapering" of a r t e r i e s , may produce e f f e c t s which mimic those of r e f l e c t i o n s . Both a m p l i f i c a t i o n of the pressure wave and o s c i l l a t i o n s i n impedance curve, the two most s t r i k i n g e f f e c t s of r e f l e c t i o n s , may be generated and thus d i s t i n q u i s h i n g r e f l e c t i o n e f f e c t s from those of e l a s t i c taper i s d i f f i c u l t . Although t h i s theory has prompted a number of related studies i n the l a s t decade (e.g. Barnard et a l . , 1966; F i c h et ajL,, 1966; Fich and Welkowitz, 1967; Attinger et a l . , 1968) there 112 has been no experimental v e r i f i c a t i o n that t h i s transmission l i n e theory i s meaningful i n a f l u i d mechanical system. Certainly, such tests would be d i f f i c u l t to perform i n i n vivo studies since so many factors a f f e c t the nature of pulse wave propagation. In the present i n v e s t i g a t i o n the e f f e c t s of e l a s t i c taper are studied i n a model * artery*, an e l a s t i c tube which has been chemically treated to produce a continuously varying wall s t i f f n e s s . The propagation c h a r a c t e r i s t i c s . o f pressure waves of varying frequency are examined by a new approach which may have widespread applications i n other areas of cardiovascular research. The p o s s i b i l i t y of t r e a t i n g e l a s t i c taper e f f e c t s as r e f l e c t i o n phenomena i s discussed. Further i n vivo experiments are aimed a t " i n v e s t i g a t i n g the e f f e c t s of drug-induced vasomotion on wave r e f l e c t i o n s by examining pressure wave propagation c h a r a c t e r i s t i c s as opposed to studying the e f f e c t s of such interventions on impedance curves. 113 Methods Hydraulic model of an artery with e l a s t i c taper The model was prepared by f i l l i n g a p o l y v i n y l tube (radius 0.8 cm, wall thickness 0.2 cm) with'"-a softening chemical (cyclohexanone) and draining the chemical at con t r o l l e d rate so that c e r t a i n regions of the tube were exposed for longer periods than others. In order to determine an appropriate drainage rate lengths of s i m i l a r tubing were f i r s t treated with the chemical for d i f f e r e n t time periods i n order to e s t a b l i s h an exposure time versus tube s t i f f n e s s r e l a t i o n s h i p . " S t i f f n e s s " (Youngs modulus, E, times wall thickness, h) was determined by stretching samples of the tubes i n the apparatus shown i n F i g 4-1. The extension, read o f f the micrometer scale, was compared with the force recorded by the s t r a i n gauge and s t i f -fness was calculated according to the equation E h = U A F ^ 2 n R • A L ( ' ' • ' where A F i s the force applied, A L i s the r e s u l t i n g extension, L 0 the r e s t i n g length and R the tube radius. Drainage rate of the actual model was then regulated to produce a tube v/hich was softened to the maximal extent possible for the f i r s t 30 cm of the inflow region with s t i f f n e s s then increasing l i n e a r l y to a maximum at 150 cm from the o r i g i n . Tube s t i f f n e s s was then 114 Figure 4-1. Apparatus for measuring e l a s t i c i t y of cyclone; xanone-treated p o l y v i n y l tube. Tube sample i s clamped to two plugs one of which i s attached to a s t r a i n gauge and the other i s mounted on a moveable stage which can be displaced known distances with a micro-meter recorder strain gauge 114a tube clamps moveable stage * i. H i micrometer 115 constant at t h i s maximum l e v e l throughout the r e s t of i t s length which was 7 m. At the end of experiments tube s t i f f n e s s as a function of p o s i t i o n was determined d i r e c t l y by c u t t i n g the model into short lengths and measuring the s t i f f n e s s of each segment. In preparing the model i t was necessary to pretreat the entire tube with cyclohexanone for 15 min. since shorter. . exposure times produced e r r a t i c r e s u l t s . In addition treatment times were li m i t e d to a maximum of 4 hours since longer exposures caused a complete breakdown of the tubing material as indicated by a l i q u i f y i n g and 'running' of the inner w a l l . The experimental set-up consisted of connecting the tube to inflow and outlfow resevoirs, the inflow resevoir being completely f i l l e d and closed so that re s t i n g pressure i n the tube was determined by the water l e v e l i n the outflow resevoir. This l e v e l was set to 100 cm I^O, a pressure s u f f i c i e n t to ensure that the cross-section of the tube, which was s l i g h t l y e l l i p t i c a l when unloaded, was c i r c u l a r . Transient pulse waves were driven through the model by r a p i d l y infusing 1 ml B^O into the inflow resevoir and the resultant pressure pulses were recorded at a reference s i t e , the d i s t a l end of the tapered section using two Bio-tec BT-70 pressure transducers which were coupled to the tube lumen with 24 gauge hypodermic needles forced through the tube wall (experiments repeated for each t e s t s i t e ) . The t e s t manometer was then moved d i s t a l l y i n 20 cm 116 i I steps and the procedure was repeated for each te s t p o s i t i o n . Data was stored on magnetic tape (Akai 2 8 0 D T S S recorder) using the FM conversion system described i n Section III and these pressure signals were l a t e r d i g i t i z e d at a rate of 2 0 0 ' samples/sec with an A-D converter ( D i g i t a l Equipment Corp.). The resultant data were fed into a Lab 8/E computer ( D i g i t a l Equipment Corp.) which computed the Fourier transforms of the transient pressure pulses by standard techniques. 'Aliasing' errors (see appendix) were avoided by e l e c t r o n i c a l l y f i l t e r i n g out a l l signals above 100 Hz. The Fourier transform of a transient s i g n a l expresses the amplitude d i s t r i b u t i o n of the frequencies which make up the signal (Tsien, 1959) and thus by comparing the transforms of pressures recorded at the r e f e r -ence and the various t e s t s i t e s the response of the system to a d i s t r i b u t i o n of input frequencies can be determined. This Fourier transform approach and a sample a p p l i c a t i o n are discussed i n the appendix. The response of the model tube to o s c i l l a t o r y inputs was expressed as pressure amplification, A(f), vs. frequency and was calculated according to the equation ' _ p(f)/e(f) 1 A C f ) " F?(f)/f?(0 where P r ( f ) i s the reference pressure at a frequency, f, and P0 (f) i s amplitude of pressure at the o r i g i n of the tapered 117 section of tube and P.,. (f) i s pressure amplitude at the test, s i t e . The advantages of t h i s 'transient analysis' approach over that of applying sinusoidal inputs of varying frequencies are that required data acquistion i s gre a t l y reduced since one t e s t run supplies information on a d i s t r i b u t i o n of frequencies and, since transient pressures are applied to the system, r e f l e c t i o n s from the tube outflow resevoir are d i s t i n c t l y separated i n time from the incident pressure wave and can thus be e a s i l y eliminated from data a n a l y s i s . Normally such terminal r e f l e c t i o n s g r e a t l y complicate t h i s type of analysis. In the present study the frequencies investigated were those which exhibited wave length to taper length r a t i o s varying from 0.1 to 1 which correspond to those observed i n vivo (McDonald, 1974) since for these frequencies the model was hydrodynamically s i m i l a r to the physio-l o g i c a l s i t u a t i o n . Results of the above experiments were compared with the t h e o r e t i c a l predictions of Taylor's (1964, 1965) e l e c t r i c a l transmission l i n e analogue. According to t h i s theory the equation describing pulse wave propagation i n e l a s t i c tubes are (Noordergraaf,1971) 2 cXj_ = _ riR3 oP az 2Eh St 3 dP _ _P 5Q_ dz " "TlR2(i+r,fro) at 118 where P = p r e s s u r e , Q = volume f l o w r a t e , R = i n t e r n a l r a d i u s o f t h e t u b e , E = Young's modulus o f t h e v e s s e l w a l l (a measure o f t h e e l a s t i c i t y o f t h e w a l l m a t e r i a l ) , h - w a l l t h i c k n e s s , p - f l u i d d e n s i t y , ^ = d i f f e r e n t i a t i o n w i t h r e s p e c t t o Z, t h e d i s t a n c e a l o n g t h e tube a x i s , ^ - = d i f f e r e n t i a t i o n w i t h r e s p e c t t o time and 1 J-vF1Q i s , i n g e n e r a l , a f r e q u e n c y dependent parameter but f o r t u b e s o f t h e d i m e n s i o n s s t u d i e s h e r e i s e q u a l t o 1 f o r a l l f r e q u e n c i e s examined. I n a n a l o g y w i t h an e l e c t r i c a l t r a n s -m i s s i o n l i n e ( p r e s s u r e a n a l o g o u s t o v o l t a g e , f l o w t o c u r r e n t ) e q u a t i o n s (2) and (3) can be w r i t t e n as oQ _ _ Q dP dz dt dP _ _ L dQ dz _ ^ dt where t h e c a p a c i t a n c e , C =UR2/2Eh i s a measure o f tube c o m p l i a n c e and t h e i n d u c t a n c e L = p/nR 2 i s a measure o f f l u i d i n e r t i a . F o r s i n u s o i d a l i n p u t s e x p r e s s e d i n complex form (P=P(z)e|a/^Q=Q(z)e'a>*) e q u a t i o n s (4) and (5) become 6 |Q = _ i t o C P dZ a P = - i a , L Q ez where -211 X f r e q u e n c y and i » When tube c o m p l i a n c e i s dependent on p o s i t i o n , i . e . C = C ( z ) , e q u a t i o n ( 6 ) and (7) can 119 can be Integrated numerically by a simple i t e r a t i v e procedure (Carson, 1921; Taylor, 1965) to predict pressure and flow amplitude at a l l s i t e s along the tube provided pressure and flow at a single s i t e are known. B r i e f l y , for a tube which i s i . e l a s t i c a l l y tapered between positions a and b i t follows from (6) and (7) that S Q(z)= Q(a) - /rZiaJC(z')P(z')dz' 9 P(z)= P(a)- fZ ia;LQ(Z')dZ' where Z i s any p o s i t i o n between a and b. I f Q(a), P(a) are known then, as a f i r s t approximation, P(Z) i s set equal to P(a), Q (Z*) to Q(a) and (8) and (9) integrated to obtain a second approximation for P and Q. This second approximation i s again substituted i n equations (8) and (9) for P (Z*) and Q(z') and the integration repeated and thus successive approximations can be refined u n t i l accurate assessments of P(Z) and Q(Z) are obtained. In p r a c t i c e the procedure i s halted when successive i t e r a t i o n s produce no s i g n i f i c a n t change i n approximations of P(Z) and Q(Z). Since, i n the present study, the e l a s t i c a l l y tapered tube was terminated i n a long, uniform section of tubing for which P =-^1 »Q (Taylor, 1966) a single pressure recording at the junction between tapered and uniform sections (reference pressure) provided necessary boundary conditions, P(a) and Q(a). 120 Equations (8) and (9) were integrated for the case when C varied as i n the present model on the LAB 8/E computer and a check for programming errors was performed by analyzing the wave propa-gation c h a r a c t e r i c t i c s of electric transmission l i n e s which have been previously investigated (Taylor, .1965). The above t h e o r e t i c a l computations take no account of the. d i s s i p a t i v e losses which may occur i n the actual tube. Such losses dut to f l u i d v i s c o s i t y should be small for tubes of the diameter of the model but losses due to v i s c o e l a s t i c properties of the wall are more d i f f i c u l t to p r e d i c t . In order to correct t h e o r e t i c a l predictions for such e f f e c t s . a number of tubes, .-. softened uniformly to varying degrees/were placed i n the experimental set-up and pressure was recorded at two s i t e s (1 m apart) to assess damping e f f e c t s as a function of wall s t i f f n e s s . Animal Experiments Young rabbits weighing from 2.0 to 3.6 kg were anaesthetized, thoracotomized and a r t i f i c i a l l y v e n t i l a t e d as described i n Section V. Blood pressure was recorded i n the a o r t i c arch through a catheter attached to a Bio-tec BT-70 pressure trans-ducer. The catheter was either inserted d i r e c t l y through the wall of the aorta or was introduced into a c a r o t i d artery and fed down to the junction of the innominate artery and the aorta. A 2 i n i n c i s i o n was then made in the. lower abdomen and the a o r t i c t r i f u r c a t i o n was exposed. A baloon c u f f occluder was 121 secured around the aorta just proximal to the t r i f u r c a t i o n and a catheter connected to a second BT-70 pressure transducer was inserted into the aorta just proximal to the vessel occluder. The net a l t e r a t i o n of the pressure wave propagated along the i aorta was assessed by comparing the Fourier components of the two pressure signals recorded at the output ( t r i f u r c a t i o n ) and input (arch) of the vessel, i . e . a 'transfer function* of pressure wave propagation (output/input as a function of frequency) was determined. The e f f e c t s of vasoconstriction on the transfer function were assessed by rapid intra-venous i n j e c t i o n of epinephrine (5ml, 4ug) whereas acetylcholine (ACh) infusion (,5ml, 50ug) was used to examine the e f f e c t s of v a s o d i l a t i o n . I n f l a t i o n of the b a l l o o n c u f f occluder at the t r i f u r c a t i o n was employed to introduce a d i s c r e t e r e f l e c t i n g s i t e into the system. McDonald's (1974) investigations indicate that the e f f e c t s of d i s t r i b u t e d r e f l e c t i o n s are best approximated by a single r e f l e c t i n g s i t e i f that s i t e i s located i n the p e l v i c region and therefore i t was hoped that occlusion of the t r i f u r c a t i o n would, i n some sense, simulate increases i n r e f l e c t i o n s of a p h y s i o l o g i c a l o r i g i n . Pressure recordings were stored on an Akai 280D SS tape recorder interfaced with a two channel FM adaptor (Vetter Instruments) and the two pressures were l a t e r d i g i t i z e d simul-taneously by an A-D converter ( D i g i t a l equipment). A Fourier analysis of the d i g i t i z e d signals was performed by a LAB 8/E computer u t i l i z i n g a convential Fourier analysis program and the r e s u l t s were printed out as a transfer function. The same rigorous controls of manometer system frequency response" c h a r a c t e r i s t i c s described i n Section III were exercised i n t h i s study. 123 Results Model Studies F i g . 4-2 i l l u s t r a t e s the v a r i a t i o n i n e l a s t i c modulus of the model artery as determined at the end of experiments. The i l i n e a r dependence on p o s i t i o n predicted by preliminary studies was not s t r i c t l y observed although wall s t i f f n e s s did vary i n a smooth, s t e a d i l y increasing fashion. The e l a s t i c modulus more than doubled along the tapered region, a v a r i a t i o n corres-ponding to an increase of 50% i n pulse wave v e l o c i t y . Although well below the 3 to 5 f o l d increase i n pulse wave v e l o c i t y re-ported i n mammals (McDonald, 1968) i t i s s u f f i c i e n t l y large to produce s i g n i f i c a n t a m p l i f i c a t i o n of the pressure pulse accord-ing to transmission l i n e theory . In F i g . 4-3 experimentally observed pressure wave amp l i f i c a t i o n along the tapered section of the model for frequencies of 1-10 Hz are compared with theo-r e t i c a l l y predicted r e s u l t s . Transmission l i n e theory (no a l -lowance for damping) predicted that low frequency pressure waves would s t e a d i l y increase i n amplitude during propagation along the tube whereas higher frequency waves would exhibit o s c i l l a -tions i n amplitude superimposed on a general a m p l i f i c a t i o n . Similar findings characterised e a r l i e r t h e o r e t i c a l investigations of asigmoidal v a r i a t i o n i n wall s t i f f n e s s , although o s c i l l a t i o n s at higher frequencies were not so pronounced (Taylor, 1965), and i t would appear that these general features of pressure 124 Figure 4-2. Elastic modulus of the model 'artery' as a function of distance from the tube inflow. £ 2 CD c >^  "O o O L U 1J. 25 45 65 85 105 125 145 165 1 1 695 distance from inflow (cm) 125 Figure 4-3. T h e o r e t i c a l l y predicted and experimentally observed pressure wave ampli f i c a t i o n for frequencies of (A) 1 and 2 Hz (B) 3 and 4 Hz (C) 6 Hz (D) 8 Hz (E) 10 Hz. S o l i d curves are t h e o r e t i c a l predictions with no allowance for damping whereas dashed curves (6,8,10 Hz) include a damping cor r e c t i o n . 125b 125c 125d 125e 126 wave propagation would be predicted for any smoothly increasing e l a s t i c taper. Pressure wave ampli f i c a t i o n was experimentally observed at lower frequencies but to a lesser extent than pre-dicted and t h i s deviation between theory and observation increased with increasing frequency with attenuation being observed at a l l frequencies above 4 Hz. These r e s u l t s are suggestive of d i s s i p a t i v e e f f e c t s and indeed when correcti o n was made for such losses the large deviations at higher frequencies were accounted f o r . F i g . 4-4 i l l u s t r a t e s the transfer function (total a mplification vs. frequency) for pressure wave propagation along the tube model. In a l o s s l e s s tube transfer function r i s e s with frequency then o s c i l l a t e s around an equilibrium value at higher frequencies whereas experimental r e s u l t s c l e a r l y exhibit the d i s t o r t i o n of the predicted pattern which r e s u l t s from a se l e c t i v e damping of higher frequencies. Pressure wave propagation i n the aorta Mean a r t e r i a l blood pressure i n the rabbits used i n these experiments (83 .5 +_ 1.8 mm Hg) was below t y p i c a l values for other mammals. These low pressures were apparently not related to experimental protocol since s i m i l a r blood pressures were recorded when pressure manometers were implanted i n the femoral artery under l o c a l anaesthesia. In previous studies blood pressures recorded i n adult rabbits (Dawes et a l . , 1 9 5 7 ; 127 Figure 4-4. Transfer function (to t a l pressure wave a m p l i f i c -atio n along tube) vs. frequency as observed and as predicted (no damping correction) cd n c CD O . O N - I N transfer function co-fl 128 McCloskey and Cleary, 1974) were si m i l a r to those found i n the dog (Patei et a l . , 1963) however young rabbits such as those ;used i n present experiments (3-6 mo.) y i e l d lower values (Bauer, 1938; Dawes et a l . , 1957; McCloskey and Cleary, 1974). Despite these differences i n mean blood pressure the shapes of cent r a l and peripheral p r o f i l e s are v i r t u a l l y i d e n t i c a l to i those found i n dogs (McDonald, 1974) and humans (O'Rourke, 1968).' Central pulse pressures are characterized by a dome-shaped s y s t o l i c wave terminated by an i n c i s u r a as the a o r t i c valves close and d i a s t o l i c pressures are convex and ex h i b i t a second maximum (Fig. 4-5). In peripheral a r t e r i e s the pulse pressure i s much larger than that recorded near the heart and the s y s t o l i c wave i s much more peaked i n form. An i n c i s u r a i s no longer observed and d i a s t o l i c pressures exh i b i t a . secondary o s c i l l a t i o n , the d i c h r o t i c wave. Introducing a disc r e t e peripheral r e f l e c t i n g s i t e by occluding the d i s t a l abdominal aorta tended to accentuate the difference between cen t r a l and peripheral pressure waves. The difference i n pulse pressure at the two s i t e s increased s i g n i f i c a n t l y , l a r g e l y as a r e s u l t of increased pulse pressure at the periphery although c e n t r a l pulse pressure f e l l s l i g h t l y , and the d i a s t o l i c hump of ce n t r a l pressures and the d i c h r o t i c wave recorded at the periphery became more pronounced. The e f f e c t s of adrenalin induced vasoconstriction were very s i m i l a r to those of the Top row. P r e s s u r e s r e c o r d e d i n t h e a o r t i c a r c h ( e a r l i e r r i s i n g p r o f i l e ) and i n t h e d i s t a l a bdominal a o r t a i n t h e c o n t r o l s i t u a t i o n ( n o r m a l ) , d u r i n g o c c l u s i o n o f the t r i f u r c a t i o n and f o l l o w i n g a d r e n a l i n i n f u s i o n . Bottom row. P r e s s u r e s r e c o r d e d i n t h e same s i t e s i n t h e c o n t r o l s i t u a t i o n , d u r i n g ACh i n f u s i o n and w h i l e t h e a o r t i c t r i f u r c a t i o n i s o c c l u d e d d u r i n g t h e r e s p o n s e t o ACh i n f u s i o n . lOOr pressure (mm Hg) 0 occlude trifurcation adrenalin 0-5 sec 130 occlusion experiments although some differences can be observed. The s y s t o l i c wave of the c e n t r a l pulse took on a ,more complex shape e x h i b i t i n g an e a r l i e r maximumdiastolic waves at both s i t e s occurred e a r l i e r and the t r a n s i t time of the pulse between the recording s i t e s decreased. Vasodilation induced by ACh infusion had a marked e f f e c t on both c e n t r a l and peripheral pressure waves. The c e n t r a l pulse exhibited a more peaked s y s t o l i c wave and a reduced d i a s t o l i c hump. The peripheral pressure displayed a dramatic decrease i n amplitude to below that of the c e n t r a l pressure, the d i c h r o t i c wave was l o s t and the peripheral pressure pulse appeared very much l i k e a damped version of the central pulse. Occlusion of the t r i f u r c a t i o n during t h i s response caused an immediate return to p r o f i l e s resembling those of the control s i t u a t i o n . A more quantitative assessment of a o r t i c pressure wave propagation i s achieved by comparing the harmonic content of the two pressures. F i g 4-6 i l l u s t r a t e s the ratio, of peripheral pressure to c e n t r a l pressure (the transfer function) for the f i r s t 5 harmonics of the pressure wave i n the control s i t u a t i o n , during vasoconstriction and during occlusion of the d i s t a l end of the aorta. The rabbits showed l i t t l e scatter i n heart rate (mean control H.R. = 4.39 +_ .19 Hz) and consequently data was grouped at the mean heart rates to allow averaging of data. 131 Figure 4-6. A l t e r a t i o n s i n transfer function for pressure wave propagation along the rabbit aorta caused by adrenalin induced vasoconstriction (squares), ACh induced v a s o d i l a t i o n (open c i r c l e s ) and occlusion of the a o r t i c t r i f u r c a t i o n (closed c i r c l e s ) . Data from the f i r s t 5 harmonics of pressure waves has been averaged and presented at the mean heart rates for each case except ACh infusion for which H.R. exhibited too large a standard error. In t h i s case only a represen-t a t i v e sample i s displayed although a l l animals (4) subjected to t h i s procedure exhibited s i m i l a r transfer function curve. 4 8 12 16 20 FREQUENCY - HZ 132 / • , . . . Under control conditions the pressure wave was amplified during propagation along the aorta (transfer Function ? 1) at a l l frequencies although marked o s c i l l a t i o n s i n transfer function were observed (the pattern of maximum, minimum,maximum i n transfer function was seen i n a l l r a b b i t s ) . Occlusion of the a o r t i c t r i f u r c a t i o n caused i n increase i n wave am p l i f i c a t i o n at a l l but the highest frequencies and the pattern of o s c i l -l a t i o n i n transfer function was maintained. Adrenalin infusion caused an increase i n transfer function at most frequencies and the pattern of o s c i l l a t i o n i n transfer function was spread out over wider ranges i n frequency. Spreading out of these o s c i l l a t i o n s can be interpreted as r e s u l t i n g from the increase i n pulse wave v e l o c i t y which accompanied the increase i n blood pressure during vaso-constriction. 133 Discussion Investigations of the hydraulic model of an artery e x h i b i t i n g e l a s t i c taper support t h e o r e t i c a l predictions of the e f f e c t s of taper when appropriate corrections are made for d i s s i p a t i v e losses. The e f f e c t s of e l a s t i c taper on pressure wave propagation have been discussed previously (Taylor, 1964; 1965) however some further remarks are i n order. The o s c i l l a t i o n s i n transfer function and i n pressure amp l i f i c a t i o n with p o s i t i o n along the tube are d i f f i c u l t to inte r p r e t i n t u i t i v e l y when one considers the very steady increase i n wall s t i f f n e s s of the model. Similar o s c i l l a t i o n s are generated i n uniform tubes, with r e f l e c t i n g s i t e s although i n t h i s case such patterns are e a s i l y described i n terms of the varying phase r e l a t i o n s between outgoing and r e f l e c t e d waves as p o s i t i o n and frequency va r i e s , a maximum i n amp l i f i c a t i o n occurring at s i t e s where the two waves are i n phase and a minimum where they are 180 out of phase. Taylor (1965a,b) has also found that impedance curves for a system of randomly d i s t r i b u t e d r e f l e c t i n g s i t e s (Taylor 1965 (b)) are remarkably s i m i l a r to those of tapered vessels (Taylor 1965 (a)). I t i s d i f f i c u l t to accept that these s i m i l a r i t i e s between e l a s t i c a l l y tapered and r e f l e c t i n g systems are purely co-incidental and since i t i s well known that an abrupt change i n vessel compliance acts as a s i t e of r e f l e c t i o n s (Womersley, 1958) i i i s tempting to 134 i n t e r p r e t t h e e f f e c t s o f e l a s t i c t a p e r as r e s u l t i n g from a summation o f i n f i n i t e s s i m a l r e f l e c t i o n s from each i n c r e m e n t i n v / a l l s t i f f n e s s . Indeed such an i n t e r p r e t a t i o n s t a n d s up t o r i g o r o u s i n s p e c t i o n . G i v e n a tube o f l e n g t h , a, v / i t h a c o n t i n u o u s l y v a r y i n g c o m p l i a n c e , C ( Z ) , where Z i s d i s t a n c e a l o n g t h e tube t h e n , f o r s i n u s o i d a l i n p u t s / f l o w r a t e s and p r e s s u r e w i t h i n the' t u b e a r e g i v e n by e q u a t i o n s ( 8 ) and ( 9 ) . i . e . 1 0 Q(*)= Q(°) - /~ 2 i "C (z ' )P ( z >)dz» 11 P(z)= P(o) - C i w L Q ( z ' ) d z ' Jo I f a second tube o f t h e same l e n g t h c o n t a i n s a number, n, o f e q u a l l y spaced a b r u p t changes i n c o m p l i a n c e such t h a t t h e compliance o f t h e j t h segment i s g i v e n by C j = C(ja/n) t h e n t h e e f f e c t s o f r e f l e c t i o n s from t h e s e s i t e s on p r e s s u r e and f l o w waves p r o p a g a t e d o v e r a number, k, o f t h e s e v e s s e l segments a r e d e t e r m i n e d b y i n t e g r a t i n g e q u a t i o n s ( 5 ) and ( 6 ) , i . e . 12 Q ( z = ka/n) = Q(o) -' r- ' r -/ n i w C , P ( z ' ) d z ' + / " ; w C 2 P ( z ' ) c l z ' + Jq Jo ' o n .ka n .ka 13 p(z=ka/n) = P(o) - / n i w L Q ( z ' ) d z ' Jo E q u a t i o n ( 1 2 ) can be r e w r i t t e n 135 14 Q(z) = Q(°) - E j[j_" ) a P(z')d However, i f the number of segments into which the tube i s divided increases i n d e f i n i t e l y (n -*-00) and the size of each increment i n compliance correspondingly drops so that t o t a l change i n compliance along the tube i s unchanged then r— I. " io>C:P(z')dz- = io.C;P(ja/n)a/n (^j_Da y 1 n and equation (14) becomes k 3 / n Q(z) = Q(o) - Lim E iwC'PCJa/nVa  n -*-oo j = ] 1 However by d e f i n i t i o n of the i n t e g r a l n Lim E iwCj P(j'a/n)-a/n = J TuC(z*)cli' n-^oo j=i so that the summed e f f e c t of these i n f i n i t e number of small r e f l e c t i o n s on pressures and flows within the system are described by Q(z) = Q(o) - f iuC(z')P(z')dz' P(z) = P(o)- /* Z icLQ(z')dz' which are i d e n t i c a l with equations (10) and (11) describing pressures and flows i n an e l a s t i c a l l y tapered tube. Since 136 C(Z) was an a r b i t r a r y continuous function i t follows that any continuous; e l a s t i c taper of a r t e r i e s can be treated simply as an a d d i t i o n a l source of r e f l e c t i o n s within the major vessels of the a r t e r i a l tree. The present i n vivo experiments demonstrate that the nature of pressure wave propagation i n the aorta i s highly s e n s i t i v e to wave r e f l e c t i o n s from both externally applied (cuff occluder experiments) and n a t u r a l l y occurring r e f l e c t i n g s i t e s . Results of these experiments support e a r l i e r contentions that the major source of r e f l e c t i o n s i n the mammalian a r t e r i a l system are located i n the arteriolar beds since r e f l e c t i o n phenomena, which were gre a t l y augmented by drug-induced vaso-c o n s t r i c t i o n , almost disappeared during v a s o d i l a t i o n . C e r t a i n l y some of these changes i n wave propagation c h a r a c t e r i s t i c s may be due to non-vasomotor e f f e c t s of adrenalin and ACh however, since the e f f e c t s of introducing a d i s c r e t e peripheral r e f l e c t -ing s i t e by occluding the a o r t i c t r i f u r c a t i o n were capable of both c l o s e l y mimicking those of vasoconstriction or eliminat-ing those of v a s o d i l a t i o n , i t must be concluded that r e f l e c t i o n phenomena are predominant. It i s conceivable that a l t e r a t i o n s i n pulse wave v e l o c i t y , as blood pressure changes, occur pre-f e r e n t i a l l y i n c e r t a i n regions of the a r t e r i a l tree so that . v a r i a t i o n s i n e l a s t i c taper could contribute to the drug induced a l t e r a t i o n s of r e f l e c t i o n phenomena. However Learoyd 137 i / i -and Taylor (1966) have found that taper i s reduced rather than increased when blood pressure rises so that resultant reflections from this source should be reduced during adrenalin infusion and augmented during ACh infusion. Since peripheral vasodilation almost total l y elimates the effects of reflections on pressure wave propagation i t must be concluded that reflections from sites within the major arteries, both from discrete discontinuities and from elastic taper of major vessels, make a minor contribution to the total reflected wave. This finding seems at odds with the marked elastic taper found in the aorta of mammals including both young and adult rabbits (Saxton, 1942; Cleary and McCloskey, 1962; Cleary, 1963; McCloskey and Cleary, 1974), which exhibit aortic wall properties similar to those of the dog (Harkness et a l . , 1957) and the human (Cleary, 1961). However quantitation of elastic taper is generally performed by measuring pulse wave velocity which, in mammals, increases some 4-5 times (McDonald, 1968) and there is some indication that this approach may considerably overestimate real changes in wall stiffness. Pulse wave velocity i s measure either by recording the time delay between the rising fronts of the pressure wave at two sites a known distance apart (McDonald, 1968) or by measuring a similar time difference between peak rates of change of pressure (present study) and both of these approaches measure 138 the v e l o c i t y of the higher harmonics of the pressure wave. However Learoyd and Taylor (1965) have d i r e c t l y measured the frequency dependence of a o r t i c e l a s t i c i t y and found that while w a l l s t i f f n e s s increases some 5-7 times at high p h y s i o l o g i c a l frequencies (4-10 Hz) increases l e s s than 3-fold are found at lower frequencies (less than 2 Hz). Thus at these-lower frequencies, which make the largest contribution to the pressure wave (McDonald, 1974), e l a s t i c taper approaches the range observed i n the present model studies. Since pressure wave amp l i f i c a t i o n was l i m i t e d to.at most 30% i n these studies, even i f viscous damping does not occur, e a r l i e r conclusions on the major e f f e c t s of e l a s t i c taper on pressure wave propaga-t i o n seem questionable, p a r t i c u l a r l y when the counter-effects of large d i s s i p a t i v e attenuation i n a r t e r i e s (McDonald and Gessner, 1968; Bergel/ 1961) are considered. It may be that e l a s t i c taper i s an adaptation to r e f l e c -t i o n e f f e c t s rather than a major source of r e f l e c t i o n s . Were d i s t a l a r t e r i e s as compliant as proximal vessels then the large pressure swings that r e f l e c t i o n s produce i n these a r t e r i e s would cause equally large st r a i n s i n the a r t e r i a l w a l l . I t i s noriJ a popular theory that dynamic stresses on a r t e r i a l walls are damaging and ultimately r e s u l t i n a r t e r i a l degenerative disease (for a review see Gessner, 1973) and consequently i t i s tempting to view the greater s t i f f n e s s of peripheral vessels 139 as a protection against such damage. However much more information on the e f f e c t s of mechanical stress on a r t e r i e s i s needed before such conjecture can be examined c l o s e l y . I 140 SECTION V Mechanical Interaction Between the V e n t r i c l e s  of the Mammalian Heart  Introduction In amphibia the systemic and gas exchanger c i r c u l a t i o n s are supplied by the same v e n t r i c l e and consequently the nature of ejection to either bed i s affected by the hydraulic load presented to the heart by the opposite c i r c u l a t i o n . On the other hand i n aves and mammals the i n t r a v e n t r i c u l a r septum i s complete and the two sides of the heart are, i n r e a l i t y , two separate pumps « However the degree "to which two v e n t r i c l e s function independently i s c o n t r o v e r s i a l . The volume outflow Of both v e n t r i c l e s must, i n the long term, be equal i f volume loading of one c i r c u i t i s to be avoided; t h i s balanced output being a r e s u l t of the S t a r l i n g mechanism (Starling, 1915) whereby the strength of contraction of either v e n t r i c l e increases or decreases v/ith the venous return from the opposite c i r c u l a t -ion, or more exactly, with the d i a s t o l i c distension of the v e n t r i c l e produced by t h i s return. I t seems l i k e l y that some d i r e c t mechanical i n t e r a c t i o n should also occur between the two v e n t r i c l e s as a r e s u l t of t h e i r s t r u c t u r a l coupling since the free wall of the r i g h t v e n t r i c l e i s continuous with the l e f t v e n t r i c u l a r epicardium 141 and a single wall, the intraventricular septum, divides the cavities. Indeed a number of recent studies (Taylor et a l . , 1967; Laks et a l . , 1967; Bemis et a l , 1974) have established that the diastolic f i l l i n g pressure of either ventricle can inhibit the f i l l i n g rate and alter the geometry of the opposite ventricle and that this interaction is augmented by constraints resulting from the presence of the pericardium (Elzinga et aJL., 1974). However, the physiological importance of interactions between the ventricles during systole is controversial. On the one hand i t has been argued from experiments involving destruction of the right ventricular free wall (Starr et a l . , 1943; Bakos, 1950; Kagen, 1953) or by observing changes in right ventricular pressure (RVP) promoted by instantaneous changes in l e f t ventricular pressure (LVP) (Oboler et a l . ; 1973), that right ventricular pumping is aided by l e f t ventricular contraction. On the other hand increases in preload to one ventricle augment the performance of that ventricle and inhibit the performance of the opposite ventricle when steady state is achieved (Elzinga et a l . , 1974) and Moulopoulos et a l . (1965) report that l e f t ventricular function was impaired by by-pass or distension of the right ventricle. Consequently in order to extend present views on mechanical interaction between the mammalian ventricles, instantaneous alterations in function of either ventricle 142 concurrent v/ith induced changes i n function of the opposite v e n t r i c l e have been examined. 143 Methods Preparations The experiments were performed on 32 young ( 3 - 9 months) ! New Zealand White rabbits weighing from 1.9 to 4.3 kg. A l l animals were anaesthetised with sodium pentobarbital (30 mg/kg, i . v . ) , restrained on t h e i r backs, and the heart was exposed by a median sternotomy. Following sternotomy the animals were a r t i f i c i a l l y r e s p i r a t e d with a Harvard 670 p o s i t i v e pressure r e s p i r a t o r . In three animals experiments were performed following /3 blockade with propranolol (Inderal, I.C.I. Ltd., U.K.) and mid-cervical vagotomy i n order to assess the r o l e of cardiac reflexes i n v e n t r i c u l a r i n t e r a c t i o n . A b o l i t i o n of the inotropic and chronotropic responses to rapid i . v . infusion of 2 ug isoprenaline was taken to indicate complete /8 blockade (peak l e f t v e n t r i c u l a r dP/dt was used as a measure of inotropic s t a t e ) . In a l l other animals the nerve supply to the heart was i n t a c t . Recording methods Blood pressures i n the two v e n t r i c l e s were recorded by d i r e c t v e n t r i c u l a r puncture using Bio-Tec BT -70 pressure transducers equipped with short, wide-bore v i n y l cannulae tipped with 2 cm troc a r s cut from 18 G hypodermic needles. To optimize the dynamic performance of the manometers they were f i l l e d with heparinized de-aerated Tyrode solution (50 I.U./ml) 144 a f t e r f i r s t f l u s h i n g the manometers and t h e i r c o n n e c t i o n s w i t h CO2 g a s . The manometers were c o n n e c t e d v i a s t o p c o c k s t o two o i l - c o v e r e d r e s e r v o i r s o f Tyrode s o l u t i o n 'which a l l o w e d f o r s t a t i c c a l i b r a t i o n . Dynamic c a l i b r a t i o n was per f o r m e d b e f o r e and a f t e r each r e c o r d i n g s e s s i o n by a p p l y i n g a s t e p change i n p r e s s u r e t o t h e t i p o f t h e manometer c a n n u l a (Hansen'pop-test') and r e c o r d i n g t h e f r e e v i b r a t i o n s o f t h e manometer and a s s o c i a t e d r e c o r d i n g system. The manometers c o n s i s t e n t l y y i e l d e d f r e q u e n c y r e s p o n s e s o f 125 Hz o r b e t t e r w i t h r e l a t i v e damping o f l e s s t h a n 0.1. The o u t p u t from t h e t r a n s d u c e r s was c o n v e r t e d t o a f r e q u e n c y modulated s i g n a l by an P.M. a d a p t o r (A.R. V e t t e r , Co., Pa., U.S.A.) and s t o r e d on magn e t i c tape ( A k a i 230 DS3). The unmodulated s i g n a l was s i m u l t a n e o u s l y d i s p l a y e d on a H e w l e t t P a c k a r d 1201 A s t o r a g e o s c i l l o s c o p e . The FM a d a p t o r demodulated t h e t a p e d s i g n a l when t h e r e c o r d e r was i n t h e p l a y b a c k mode. The f i r s t d e r i v a t i v e o f v e n t r i c u l a r p r e s s u r e , d P / d t , was r e c o r d e d u s i n g B i o t r o n i x BL 620 o r BL 622 analogue computers s e t t o a c o r n e r f r e q u e n c y o f 160 Hz. F o r p r e s e n t a t i o n p u r p o s e s . t h e t a p e d d a t a was p l a y e d onto a T e c h n i - r i t e Tr 888 c h a r t r e c o r d e r w r i t i n g on. r e c t i l i n e a r c o - o r d i n a t e s . E x p e r i m e n t a l P r o c e d u r e s A b r u o t -increase i n the a f t e r l o a d p r e s e n t e d to e i t h e r v e n t r i c l e was a c c o m p l i s h e d by d i a s t o l i c o c c l u s i o n o f the a o r t i c 145 o r pulmonary outflow eith e r with a balloon c u f f or snare -occluder. To a l t e r l e f t v e n t r i c u l a r preload a 15 G hypodermic needle connected to an inf u s i o n pump (Cole Parmer, Chicago, U.S.A) was inserted into the l e f t v e n t r i c l e . Switching the pump on resulted i n an infusion of warmed- saline (36-39°C) into the v e n t r i c l e which produced an immediate sharp increase i n l e f t v e n t r i c u l a r pressure. Right v e n t r i c u l a r preload was altered by i n f l a t i n g a balloon implanted i n the r i g h t atrium since i n preliminary t r i a l s .1 found the infusion pump to be incapable of r a i s i n g RVP r a p i d l y enough, an e f f e c t attributed to the greater compliance of the r i g h t v e n t r i c l e . In some experiments a perturbation of LVP during d i a s t o l e or systole was produced by connecting a cannula from a 60 Hz pump to the l e f t v e n t r i c l e . High frequency o s c i l l a t o r y flow (60 Hz, 0.05-0.1 ml/stroke) was applied to the v e n t r i c l e when the pump was switched on. The hearts of ten rabbits, k i l l e d by overdose of sodium pentobarbital (50-90 mg/kg), were excised i n a state of r i g o r and transferred to a bath of warm (37-39°C) Tyrode solu t i o n . The pulmonary outflow as l i g a t e d and a balloon was i n f l a t e d i n the aorta at the valves and t i e d i n place. The l a t t e r served to occlude both the aorta and coronary a r t e r i e s . Pressure and infusion cannulae were implanted i n both v e n t r i c l e s v i a the a t r i a . The in f u s i o n cannulae were connected v i a stopcocks 146 to syringes so that pressure a l t e r a t i o n s i n either v e n t r i c l e could be produced by saline i n f u s i o n . A l l tests were made 1-2 hours a f t e r excision of the heart, a period during which mammalian cardiac muscle exhibits constant maximal r i g o r when held at ph y s i o l o g i c a l temperatures (Kolder et a l , 1963). I t has been reported that r i g o r mortis reduces l e f t v e n t r i c u l a r compliance by some 5-10 times (Laks et a l . , 1967; Kolder et a l , 1963) which appears to be of the order of the change i n compliance between d i a s t o l e and systole i n normal hearts (Templeton e_t a l , , 1970). This was confirmed i n the present experiments by applying o s c i l l a t i o n s from the 60 Hz pump to the l e f t v e n t r i c l e i n r i g o r and comparing the induced pressure o s c i l l a t i o n with the s y s t o l i c o s c i l l a t i o n produced by the pump i n the same heart i n vivo. For t h i s t e s t the v e n t r i c l e was i n f l a t e d to a pressure of 75 mm Hg, the mean peak s y s t o l i c l e v e l recorded i n vivo. 3.4-7 R e s u l t s Changes induced 5.*o RVP c?.»nor?5.on b-«/ alternations in l o f t ; v o n t r i c u l a r func4:.ion At the mean peak s y s t o l i c LVP and. RVP • (74.3 + .2.7' rxvi Hg and 27.1 j_ 0.8 nun Eg respectively) pertaining i n these • experiments suddenly and d r a s t i c a l l y increasing the a f t e r l o a d presented to l e f t v e n t r i c u l a r contraction by occluding a o r t i c outflow caused an. increase i n peal: LVP or 54.9 * 4.7% (mean .increase + 3.E.M. )• and co-incident v;ith t h i s change in LVP was an instantaneous increase i n peal: RVP, which . ;. occasio n a l l y reached values some 30% above those pe r t a i n i n g before a o r t i c occlusion (Fig. 5-1). However the average {. increase i n peak RVP was 11.4 + 1.8% (mean ± S.E.M.). No ;: preparation demonstrated a f a l l i n v e n t r i c u l a r pressure following occlusion of the opposite outflow t r a c t although a snuill number of occlusions gave no change i n pressure. Peak l e f t v e n t r i c u l a r d?/dt was not increased i n the f i r s t contraction following a o r t i c occlusion whereas r i g h t v e n t r i c u l a r dp/dt increased by approximately the same f r a c t i o n as peak RVP (Fig, 5-1). , The dotted p r o f i l e s i n F i g . 5-1 i l l u s t r a t e trie increments in v e n t r i c u l a r pressures resu.l t i n g from a o r t i c occlusions (the d i f f e r e n c e between the l a s t pressure pulse before occlusion \ and the f i r s t , pulse a f t e r occ.1 us ion) . The pressure difference \ 7 1 4 8 Figure 5 - 1 . Response of l e f t and r i g h t v e n t r i c u l a r pressures and rates of change of pressures to a o r t i c occlusion (arrow marks the time of occlusion). The dotted p r o f i l e s i l l u s t r a t e the change i n s y s t o l i c pressures following occlusion (see t e x t ) . Traces (from top to bottom) - f i r s t : time markers separated by . 5 sec. Second: l e f t v e n t r i c u l a r pressure (LVP). Third: rate of change of l e f t v e n t r i c u l a r pressure (LVdP/dt). Fourth: r i g h t .ventricular pressure RVP). F i f t h : rate of change of r i g h t v e n t r i c u l a r pressure (RvdP/dt). 0 0 100 mmHg I U U r -LVP o L. LVdP/dt 3 mm Hg/msec f 25,-RVP mm Hg RVdP/dt 0.2 mm Hg/msec o 149 for the two v e n t r i c l e s are s i m i l a r i n shape and both exhibit a mid-systolic drop, r e s u l t i n g from a narrower pressure peak following occlusion, followed by a second b r i e f r i s e r e f l e c t i n g an extended duration of systole. Instantaneous changes in LVP and RVP caused by a o r t i c occlusion were i d e n t i c a l i n i n t a c t and denervated preparations. Although changing l e f t v e n t r i c u l a r afterload affected generation of RVP t h i s was not the case when l e f t v e n t r i c u l a r preload was a l t e r e d . Rapid infusion of saline i n t o the l e f t v e n t r i c l e produced an immediate, marked increase i n peak LVP of 35% a f t e r one systole and 75% at the t h i r d heart beat while RVP was unchanged u n t i l the e f f e c t s of volume loading the c i r c u l a t i o n altered r i g h t v e n t r i c u l a r preload. Mechanical transference of pressure o s c i l l a t i o n s from the l e f t to r i g h t v e n t r i c l e s was observed during o s c i l l a t o r y infusion of Tyrode solution into the l e f t v e n t r i c l e (Fig 5-2). The 60 Hz o s c i l l a t i o n s i n LVP produced co-incident o s c i l l a t i o n s i n RVP which were about 1/4 the magnitude of those i n the l e f t v e n t r i c l e . This i n t e r a c t i o n i s considerably greater than that seen during a o r t i c occlusion where RVP increase was 1/14 as large as LVP increase (Fig. 5-1). No pressure o s c i l l a t i o n s were observed during d i a s t o l e confirming that the infusion method caused no v i b r a t i o n a r t e f a c t s . 150 Figure 5-2. L e f t and r i g h t v e n t r i c u l a r pressures during sinusoidal infusion of s a l i n e into the l e f t v e n t r i c l e . Top trace i s l e f t v e n t r i c u l a r pressure (LVP) and bottom trace i s r i g h t v e n t r i c u l a r pressure (RVP). I 1 J 1 / Changes induced i n LVP generation by a l t e r a t i o n i n r i g h t  v e n t r i c u l a r function. Occlusion of the pulmonary outflow caused an instantaneous increase i n s y s t o l i c RVP and a co-incident r i s e i n peak LVP (Fig. 5 - 3 ) . However, the magnitude of the r i s e was extremely va r i a b l e , the major cause of t h i s v a r i a t i o n being the l e v e l of systemic blood pressure (Fig. 5 - 3 A and B). At normal LVP the induced pressure r i s e caused by occlusion of the pulmonary a r t e r i e s was n e g l i g i b l e (Fig. 5 - 3 A ) whereas during systemic hypotension (produced i n t h i s case by con t r o l l e d haemorrhage) the a f f e c t of increased RVP, was a prominent increase i n LVP (Fig. 5 - 3 B ) . Nevertheless t h i s marked change i n LVP was not accompanied by a change i n peak l e f t v e n t r i c u l a r dP/dt. Unlike the case noted above, i n which changes i n l e f t v e n t r i c u l a r preload has no e f f e c t on RVP, a decrease i n r i g h t v e n t r i c u l a r preload (accomplished by i n f l a t i n g a balloon i n the r i g h t atrium to diminish d i a s t o l i c f i l l i n g ) caused an instantaneous drop i n pressure i n both v e n t r i c l e s . The instantaneous changes i n LVP induced by changes in. r i g h t v e n t r i c u l a r preload or afterload were the same i n animals with i n t a c t cardiac innervation and i n denervated animals. The r i g h t to l e f t v e n t r i c u l a r i n t e r a c t i o n was further investigated in excised hearts i n r i g o r mortis. LVP was raised by i n j e c t i o n of saline and monitored while i t f e l l due to stress 152 Figure 5 - 3 . The e f f e c t s of pulmonary outflow occlusion (at arrows) on v e n t r i c u l a r pressures and rates of change of pressure before (A) and a f t e r (B) induced systemic hypotension (see t e x t ) . Abbrevia-tions as i n F i g . 5 - 2 . A \ 153 r e l a x a t i o n . When LVP has f a l l e n to a predetermined l e v e l (e.g. 130, 100, 75 or 55 mm Hg i n the heart used i n F i g . 5-4A and B) the e f f e c t of sudden increased i n RVP, caused by saline i n j e c t i o n , on LVP was monitored. Suddenly increasing RVP caused a concomitant increase i n LVP which l a t e r declined due to stress r e l a x a t i o n . Consequently i t was possible to study the e f f e c t on LVP of step changes i n RVP at the same mean l e v e l of LVP (see i n s e r t , Figure 5-4). In a l l hearts a range of mean LVP l e v e l s was applied, i n random order, spanning from about 50 to 150 mm Hg and the same r e s u l t s were repeatedly obtained with a single heart. The change i n LVP was compared to the step change i n RVP which provoked the change i n LVP and the r a t i o LVP: RVP was expressed as a % to indicate the degree of pressure transfer from the r i g h t to the l e f t v e n t r i c l e (Fig. f-4A). Figure 5-4A shows that at a given LVP the i n t e r -action from the r i g h t v e n t r i c l e becomes more s i g n i f i c a n t as the l a t t e r i s distended and furthermore the degree of pressure transfer decreases as mean LVP increases at any given value of mean RVP. This finding suggests that pressure transfer from the r i g h t to l e f t v e n t r i c l e i s determined by the r e l a t i v e distension of the r i g h t compared with that of the l e f t and t h i s was confirmed by r e p l o t t i n g the data of F i g . 5-4A with RVP expressed as a f r a c t i o n of LVP (Fig. 5-4B). When t h i s experiment was reversed, i . e . when r i g h t v e n t r i c u l a r volume was 154 F i g u r e 5-4. P r e s s u r e t r a n s f e r e n c e from r i g h t t o l e f t v e n t r i c l e i n the e x c i s e d h e a r t i n r i g o r m o r t i s as a f u n c t i o n o f r i g h t v e n t r i c u l a r , p r e s s u r e a t a s e r i e s o f m a i n t a l l i e d l e f t v e n t r i c u l a r p r e s s u r e s . I n 'a' RVP i s i n d i c a t e d i n a b s o l u t e u n i t s whereas i n 'b' RVP i s e x p r e s s e d as a per c e n t o f LVP. Pressure, t r a n s -f e r e n c e i s e x p r e s s e d as a p e r cent, o f a p p l i e d i n c r e m e n t s i n RVP. 154a l O O i 80 6 0 40 20 L V P • 5 5 m m H y » 75 ' o 100 i ' 1 3 0 " mm 10 20 30 40 50 60 R V P ( m m Hg ) 70 80 100i 80 6 0 4 0 20 10 20 30 40 50 60 70 80 90 R V P / L V P ( PER C E N T 100 155 held constant and the l e f t v e n t r i c l e i n f l a t e d i n steps, the degree of i n t e r a c t i o n c l o s e l y matched that observed i n vivo when 60 Hz o s c i l l a t i o n s were imposed on LVP. Step increases i n RVP were about 1/4 - 1/5 the size of the increases i n LVP throughout the ph y s i o l o g i c a l range of RVP and LVP. When high frequency (60 Hz) perturbation were applied to the l e f t v e n t r i c l e , at a mean LVP of 75 mm Hg,«the o s c i l l a t i o n s i n LVP were of the same magnitude as the s y s t o l i c o s c i l l a t i o n s observed when t h i s perturbation was applied t o the v e n t r i c l e i n vivo. This confirmed that the mechanical state of the myocardium approximated that observed during systole. 156 /' Discussion The present r e s u l t s have established that the l e f t and r i g h t v e n t r i c l e s do not function independently of one another i n respect to pressure generation. However, the degree of i n t e r a c t i o n which occurs i n the i n t a c t animal and i t physio-l o g i c a l s i g n i f i c a n c e remains to be elucidated. There can be no doubt that marked changes i n l e f t v e n t r i c u l a r afterload, accompanied by increased LVP, w i l l promote an increase i n the time deri v a t i v e and absolute pressure generated i n the r i g h t v e n t r i c l e . This e f f e c t has been noted previously (Oboler et a l , 1973), but the present data shows that the e f f e c t s of increasing l e f t v e n t r i c u l a r afterload are transferred to the r i g h t v e n t r i c l e throughout ej e c t i o n and are not r e s t r i c t e d to early systole (Oboler et a l , 1973). Since RVP responds to changes i n LVP induced by a l t e r i n g l e f t v e n t r i c u l a r afterload but not by a l t e r i n g preload i t i s u n l i k e l y that the l e f t to r i g h t i n t e r a c t i o n represents a d i r e c t transfer of i n t r a - c a v i t y pressure but i s probably a r e f l e c t i o n of a change i n the mode of l e f t v e n t r i c u l a r contraction following a o r t i c occlusion. During normal contraction the l e f t v e n t r i c l e i n i t i a l l y shortens along the apex to base length with a co-incident increase i n circumference (Rushmer, 1956; M i t c h e l l et a l , 1965; Salisbury et a l , 1965) and some septal protrusion 157 i n t o the r i g h t v e n t r i c l e i s l i k e l y to occur. The f a c t that high frequency pressure o s c i l l a t i o n s were transferred from the l e f t to the r i g h t v e n t r i c l e during systole suggests that these geometrical changes of the l e f t v e n t r i c l e are responsible for the i n t e r a c t i o n observed during a o r t i c occlusion. During the imposed o s c i l l a t i o n s the pressure increments would tend to make the l e f t v e n t r i c l e more spherical, i n order to minimize stretch of the e l a s t i c components of the myocardium, and septal swelling would cause pressure transference to the r i g h t v e n t r i c l e the pressure decrements would cause the c a v i t y to become more e l l i p t i c a l as the v e n t r i c l e moved towards i t s unloaded geometry. This conclusion i s supported by the f a c t that no i n t e r a c t i o n was observed when LVP \vas changed by a l t e r i n g the preload for Liedtke et al_ (1972) report that changes i n preload a f f e c t only end-diastolic dimensions whereas increases i n a f t e r l o a d tend to augment the shortening and circumferential swelling of the l e f t v e n t r i c l e . Although the present data has suggested a mechanism for l e f t to r i g h t v e n t r i c u l a r i n t e r -action the moderate changes i n r i g h t v e n t r i c u l a r pressure during severe a l t e r a t i o n s i n l e f t v e n t r i c u l a r function.do not appear s u f f i c i e n t to support the theory that the l e f t v e n t r i c l e plays a predominant r o l e i n generating r i g h t v e n t r i c u l a r pressure (Starr et a l , 1943; Bakos, 1950; Kagan, 1952). The influence of r i g h t v e n t r i c u l a r pressure on the l e f t 158 v e n t r i c l e , unlike the reverse i n t e r a c t i o n , does not. depend on the pattern of contraction of the- .vcuitricles ninco pressure transfer occurred i n the excised heart i n r i g o r . This suggests that r i g h t v e n t r i c u l a r pressures.arc, i n part, d i r e c t l y superiraposcd on LVP. Since the r i g h t v e n t r i c l e p a r t i a l l y encapsulates the l e f t i t should be expected that v i l l contribute to the' extramural pressure over which the l e f t v e n t r i c l e contracts. C e r t a i n l y during pulmonary hypertens ion the septum i c displaced to the l e f t and becomes les s convex (Denis o+ aJU 1574; .Stool et a l . 1974.) further suggesting that the r i g h t v e n t r i c l e compresses the l e f t v e n t r i c u l a r cavity.. The present r e s u l t s obtained' on excised hearts i n r i g o r showed that as the r i g h t v e n t r i c l e was distended or the l e f t deflated, s i t u a t i o n s that w i l l lead to the r i g h t more completely surround-ing the l e f t v e n t r i c l e , a p r e d i c t a b l e increase i n r i g h t to l e f t pressure transference was obtained. At large r e l a t i v e d istension of the r i g h t v e n t r i c l e almost t o t a l r i g h t to l e f t pressure t r a n s f e r should occur and t h i s was i n f a c t observed in_ vivo during systemic hypotension. The fact that these i n t e r a c t i o n s were observed a f t e r s u r g i c a l and chemical denervation of the heart further supports the suggestion that these instantaneous changes are due to a mechanical i n t e r a c t i o n . Furthermore, 0 blockade with propranolol was chosen over s u r g i c a l sympathectomy since 159 homeometric autoregulatory mechanisms, i n t r i n s i c myocardial adaptations to a l t e r a t i o n s i n load (Sarnoff et a l . , I960), are known to be sharply diminished by t h i s drug (Monroe et al.,1963) and were therefore shown to be of l i t t l e importance i n v e n t r i -cular i n t e r p l a y . Consequently the present r e s u l t s show that, due to t h i s mechanical i n t e r a c t i o n , the v e n t r i c l e s cannot be regarded as independent moieties. Fortunately, because of the i n s e n s i t i v i t y of peak l e f t v e n t r i c u l a r dP/dt to r i g h t v e n t r i c u l a r function, these interactions do not argue against the usefulness of indices of myocardial c o n t r a c t i l i t y based upon time derivatives of l e f t v e n t r i c u l a r pressure. The independence of l e f t v e n t r i c u l a r dP/dt presumably r e s u l t s from the s l i g h t l y asynchronous contraction of the two v e n t r i c l e s since r i g h t v e n t r i c u l a r pressures are comparatively low when peak l e f t v e n t r i c u l a r dP/dt i s attained. 160 General Discussion The development of wave transmission models of a r t e r i a l haemodynamics has advanced r a p i d l y i n the l a s t two decades la r g e l y as a r e s u l t of the i n a b i l i t y of the windkessel approach to explain fundamental aspects of pressure flow r e l a t i o n s h i p s i n a r t e r i a l systems and as a consequence there has been a tendency to regard the windkessel model as outmoded (e.g.,. see Attinger, 1968). There i s no doubt that the reason for r e j e c t i o n of the windkessel approach i s that i t assumes that the e f f e c t s of cardiac ejection occur simultaneously throughout the a r t e r i a l tree (McDonald and Taylor, 1959) a s i t u a t i o n apparently never approximated i n mammalian systems. However t h i s s i t u a t i o n i s encountered i n the b u l l f r o g and there i s reason to believe that the c i r c u l a t i o n s of other species are also well described by such an approach. Consideration of the cardiovascular features conducive to generation of wave transmission phenomena have indicated that low heart rates and short a r t e r i a l trees are prerequisites for a windkessel approach. In homeotherms higher heart rates of smaller species o f f s e t the e f f e c t s of shorter a r t e r i a l lengths (Kenner, 1970) and undoubt-e d l y t h i s l a r g e l y accounts for the u n s u i t a b i l i t y of a wind-kessel model; thus i t would appear that small poikilotherms are the most l i k e l y candidates for t h i s approach. It i s 161 generally believed that wave transmission e f f e c t s , s p e c i f i c a l l y wave r e f l e c t i o n s , are advantageous and contribute to c i r c u l a t o r y e f f i c i e n c y . Changes i n impedance patterns caused by r e f l e c t -ions r e s u l t i n a reduction i n work expended i n producing the p u l s a t i l e component of blood flow (Taylor, 1964; O'Rourke, 1967) although t h i s factor i s a r e l a t i v e l y small contributor to t o t a l cardiac work. In addition, however, r e f l e c t i o n s r e s u l t i n a node of the pressure wave occurring at the heart for normal heart rates (McDonald, 1974) and the r e s u l t i n g decrease i n pulse pressure implies that the s y s t o l i c pressures against which the heart ejects are lower. As a r e s u l t there must be a concomitant reduction i n the tension-time i n t e g r a l (tot a l work) of the contracting myocardium. A l l other things being equal i t would be expected that the pressures of natural s e l e c t i o n would r e s u l t i n heart rates and pulse wave v e l o c i t i e s i n poikilotherms which would generate these wave r e f l e c t i o n phenomena, and therefore i t must be concluded that the costs of such adaptions i n these species outweigh the advantages. While models of a r t e r i a l systems permit de s c r i p t i o n of a r t e r i a l pressure-flow i n t e r r e l a t i o n s h i p s a complete under-standing of a r t e r i a l pressures and flows requires a knowledge of the ejection pattern of the heart. Conversely t h i s ejection pattern i s highly dependent on the hydraulic load presented by the a r t e r i a l system (Milnor, 1975) and thus investigations of 162 the mechanics of cardiac contraction and of the p h y s i c a l ' properties of the a r t e r i a l bed must be viewed as complementary, rather than independent studies and a major facet of the present study has been ah extension of t h i s approach to non-mammalian vertebrates. Integration of studies on cardiac pumping and a r t e r i a l haemodynamics in mammals i s highly complicated owing to the complex dynamic properties of the a r t e r i a l beds and the non-linear connection between the heart and a r t e r i e s , i . e . v i a the a o r t i c and pulmonic valves (Hilnor, 1975). Results of the present study, which indicate that some vertebrate a r t e r i a l systems are well described by simple windkessel models, suggest that a more tractable approach to t h i s problem may be gained by examining non-mammalian species. \ 163 Summary Pressure-flow r e l a t i o n s h i p s i n the a r t e r i a l system of the b u l l f r o g were well described i n terms of a two component windkessel model whereas wave transmission e f f e c t s were n e g l i g i b l e . During apnoea blood flow r e d i s t r i b u t i o n away from the lungs was accomplished by vasomotion of the peripheral c i r c u l a t -ions. No 'active shunting* role could be ascribed to the conus a r t e r i o s i s . Contraction of the conus a r t e r i o s i s generated a s i g n i f i c a n t portion of pulmocutaneous a r t e r i a l flow while making only a minor contribution to systemic e j e c t i o n . Contraction also served to draw the synangial and pyl a n g i a l valves of the conus s u f f i c i e n t l y close together to ensure competency. Since the conus did not r e f i l l before the next v e n t r i c u l a r contraction the conus presents undistended valves to the v e n t r i c l e and a r t e r i a l arches during d i a s t o l e . Occlusion of the coronary blood supply resulted i n a complete loss of c o n t r a c t i l i t y of the conus a r t e r i o s i s . The compliance of the dorsal aorta of the cod is not ne g l i g i b l e and as a r e s u l t dynamic i n t e r a c t i o n between the g i l l . a n d systemic c i r c u l a t i o n s i s complex. P u l s a t i l i t y of g i l l blood flow was augmented and a marked 'damping* 164 of the pressure pulse d i s t a l to the g i l l s observed. 5. Mean a r t e r i a l pressure (143 + 2 mm Hg) and cardiac output (219 ml/min per kg.) of the duck. Anas p1atyrhynchos, were high compared with those of mammals of si m i l a r size and 75% of t h i s cardiac output i s delivered to the wings, f l i g h t muscles and head by the brachiocephalic a r t e r i e s . 6. Wave transmission e f f e c t s , s p e c i f i c a l l y wave r e f l e c t i o n s , had a marked e f f e c t on systemic pressure-flow r e l a t i o n s i n the duck i n d i c a t i n g that t h i s a r t e r i a l system i s not well described by a windkessel model. 7. In the r a b b i t , a r t i f i c i a l l y induced di s c r e t e r e f l e c t i o n s from the abdominal aorta c l o s e l y mimicked the e f f e c t s of peripheral vasoconstriction and masked those of vas o d i l a t i o n ; thus the suggestion that the major s i t e s of r e f l e c t i o n i n the mammalian a r t e r i a l system are i n the a r t e r i o l a r . resistance vessels was supported. D i s t r i b u t e d , r e f l e c t i o n s from continuous v a r i a t i o n s i n a r t e r i a l wall s t i f f n e s s also contribute to the t o t a l r e f l e c t e d wave although t h i s contribution does not appear to be predominant. 8. The immediate e f f e c t of abrupt a l t e r a t i o n i n the function of either v e n t r i c l e on pressures i n both v e n t r i c l e s has been examined i n ra b b i t s . Maximal increases i n l e f t v e n t r i c u l a r a f t e r l o a d (aortic occlusion) caused not only a near doubling of peak l e f t v e n t r i c u l a r pressure (195% 165 + 5% but also an immediate s i g n i f i c a n t increase (13.2% + 1.3 %) i n r i g h t v e n t r i c u l a r pressure. On the other hand when s i m i l a r increases i n l e f t v e n t r i c u l a r pressure were induced by sudden changes i n preload no a l t e r a t i o n i n r i g h t v e n t r i c u l a r pressure was seen. High frequency o s c i l l a t o r y i nfusion of saline into the l e f t v e n t r i c l e produced co-incident o s c i l l a t i o n s i n both v e n t r i c u l a r pressures during systole. These findings were interpreted i n terms of present knowledge of the asynchronous patterns of contraction of the mammalian heart. 9. 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B i o l . , Paris 44: 571-606. Westerhof, N. Sipkema, P., Van Den Bos, G.C. and Elzinga, G. ( 1 9 7 2 ) . Forward and backward waves i n the a r t e r i a l system. Cardiovas. Res. 6_: 648-656. White, F.N. (1968). Functional anatomy of the heart of r e p t i l e s . Am. Zool. Q: 211-219. Womersley, J.R. (1958). The mathematical analysis of the a r t e r i a l c i r c u l a t i o n i n a state of o s c i l l a t o r y motion. Wright A i r Development Center, Technical Report WADC-TR56-614. 182 Appendix To demonstrate the a p p l i c a b i l i t y of Fourier transform techniques i n determining frequency dependent parameters of a physical system the amplitude response of a manometer system was evaluated as follows. The manometer system to be tested and a very high frequency manometer system capable of accurately recording pressure signals throughout the range over which the te s t system i s to be examined (0-60 Hz) were connected to the same pressure source. The pressure source applied a transient pressure to both manometers and F i g . A-1A i l l u s t r a t e s the dis t o r t e d pressure signal recorded by the t e s t manometer and 'true* p r o f i l e recorded by the reference manometer. F i g . A-lB i l l u s t r a t e s the frequency response for the tes t manometer determined by comparing the Fourier transforms of the two pressure signals. A'pop-test* was also applied to the tes t manometer to determine i t s resonant frequency and damping c o e f f i c i e n t so that a t h e o r e t i c a l frequency response curve could be predicted from manometer theory (see McDonald, 1974). This curve i s also shown i n F i g . A-lB. A l i m i t a t i o n of t h i s Fourier transform approach i s that the transient input to the system of i n t e r e s t , e.g. the pressure pulse i n the above example, must exhib i t a frequency spectrum which overlaps the frequency range one wishes to examine. Although for a r b i t r a r y transients t h i s spectrum cannot be p r e c i s e l y determined u n t i l 183 Figure A-1. A. Output of reference (upper trace) and test (lower trace) manometers i n response to a transient pressure pulse. B. Test manometer frequency response curve calcu-lated from Fourier transforms of the signals i l l u s t r a t e d i n (A) (dots) and according to manometer theory ( s o l i d l i n e ) . r e s p o n s e 184 i data analysis has been completed most u n i d i r e c t i o n a l transient signals (as opposed to transient o s c i l l a t i o n s ) e x h i b i t a f l a t amplitude spectrum up to frequencies which approach 1/T, where T i s the duration of the transient. Thus i n Section IV by applying u n i d i r e c t i o n a l pressure pulses l a s t i n g at most 0.2 sec. to the hydraulic model an appropriate input spectrum for examining the frequency range, 1-10 Hz, was always attained. Additional precautions are required to avoid ' a l i a s i n g ' errors (Blackmand and Tukey, 1959) which are errors that r e s u l t from recording frequencies too high to be detected at the sampling rate of the A-D conversion system. Such errors can be avoided by sampling at a rate far above the highest frequency of i n t e r e s t and e l e c t r o n i c a l l y f i l t e r i n g out a l l signals o s c i l l a t i n g more r a p i d l y than h a l f the sampling frequency. 185 Bibliography Blackmail, R.B. and Tukey, J.W. (1959). The Measurement of Power Spectra. New York: Dover. McDonald, D.A. (1974). Blood Flow i n A r t e r i e s . Baltimore: Williams and Wilkins. 

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