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The effect of decerebration on the reflex response to left atrial distension Albrook, Sally Milton 1971

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THE EFFECT OF DECEREBRATION ON THE REFLEX RESPONSE TO LEFT ATRIAL DISTENSION •by SALLY MILTON ALBROOK B.Sc. (Honours) Chatham College, 1969 A thesis submitted i n p a r t i a l f u l f i l l m e n t of the requirements f o r the degree of Master of Science i n the Department o f Physiology We accept t h i s t h e s i s as conforming to the required standard The Unive r s i t y of B r i t i s h Columbia September, 1971 In presenting t h i s thesis i n p a r t i a l f ulfilment of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t freely available for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the Head of my Department or by his representatives. I t i s understood that copying or publication of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department The University of B r i t i s h Columbia Vancouver 8, Canada Date rffnjLnJujv3£', /j>/ i • ABSTRACT An increase i n heart rate brought about by stimulation of the re centers at the junction of the pulmonary veins and the l e f t atrium i n dogs ha? been reported by Led some and Linden, (1964). Although extensive experimentation has shown the afferent pathway for such tachycardia i s i n the vagus nerve, and efferent impulses arpear to t r a v e l v i a the cardiac sympathetics, the l o c a t i o n of central synapses, and the degree of c e n t r a l control necessary f o r i t s existence are not known. Also unknown i s the s i g n i f i c a n c e of t h i s cardiovascular control mechanism in the unanaest.hetized animal. The series of experiments described i n t h i s paper were designed to answer both these questions. A method f o r decere-brating mongrel dogs (#-13 Kg) by electrocoagulation was devised which avoided traumatic loss of blood, leaving a stable decerebrate preparation. The tachycardia i n i t i a t e d by the i n f l a t i o n of small balloons at the junction of the pulmonary veins with the l e f t atrium was found to be unchanged by such a m i d c o l l i c u l a r decerebration. Both magnitude and neural c h a r a c t e r i s t i c s of the increase i n heart rate were unaltered. However, c a r e f u l studies of these c h a r a c t e r i s t i c s with both drugs and lesions of the s p i n a l cord, revealed a discrepancy with nrevious reports. The tachycardia produced by balloon i n f l a t i o n could not be t o t a l l y abolished by the infusion of the J sympathetic blocking agent propranolol, e i t h e r before or a f t e r decerebration. In addition small, but s i g n i f i c a n t , i n -creases i n heart rate remained upon section of the spinal cord at the l e v e l of the f i r s t c e r v i c a l vertebra. These r e s u l t s i i i ndicated that the efferent pathway for t h i s r e f l e x , though predominantly relayed by the cardiac sympathetica, may rossess a vagal component. Using the same decerebrate preparation, two v o l a t i l e anaesthetics were used to study the e f f e c t s of anaesthetics on the response to balloon i n f l a t i o n . Halothane, or a nitrous oxide-sodium pentothal combination were administered p r i o r to decerebration, then discontinued at completion of the section. Throughout the duration of both anaesthetics, cardiovascular reflexes such as the carotid sinus r e f l e x , were depressed. The l e f t a t r i a l r e f l e x vras s i m i l a r l y small or absent as compared to dogs under chloralose anaesthesia. Removal of the anaesthetic c i r c u i t a f t e r successful decerebration coincided with the appearance of small but s i g n i f i c a n t increases i n heart rate at balloon i n f l a t i o n , and t y p i c a l carotid sinus a c t i v i t y at occlusion of the carotid a r t e r i e s . Neither r e f l e x attained the magnitudes observed i n dogs under chloralose anaesthesia, despite prolonged waiting, up to s i x hours a f t e r decerebration. i i i TABLE OF CONTENTS Page ABSTRACT i TABLE OF CONTENTS i i i LIST OF TABLES i v LIST OF FIGURES v ACKNOWLEDGEMENTS v i INTRODUCTION 1 Review of central cardiovascular control 1 Review of l e f t a t r i a l receptors 6 Scone of present i n v e s t i g a t i o n # METHODS 9 General s u r g i c a l preparation 9 Method of decerebration 11 Spinal Transection 13 Protocol 16 RESULTS 20 Results of i n d i v i d u a l series 20 E f f e c t s of i n f l a t i n g the balloons at the pulmonary vein l e f t a t r i a l junction 27 E f f e c t s of decerebration 27 E f f e c t s of propranolol 32 E f f e c t s of atropine 34 E f f e c t s of spin a l section 41 E f f e c t s of anaesthetics 43 DISCUSSION 46 Introduction 46 Central control of the l e f t a t r i a l r e f l e x 47 Relative roles of the sympathetic-parasympathetic d i v i s i o n s i n the response to balloon i n f l a t i o n 48" The l e f t a t r i a l r e f l e x i n the anaesthetized i n t a c t or unanaesthetized decerebrate dog 54 Central nervous system integration of cardio-vascular reflexes 55 BIBLIOGRAPHY 59 VITA i v LIST OF TABLES' Table T i t l e Page I Experimental protocol 19 II Summary of r e s u l t s of Series I ?1 III Summary of re s u l t s of Series II 22 IV Summary of r e s u l t s of Series III 23 V Summa ry of r e s u l t s of Series IV 2U VI Summary of r e s u l t s of Series V 25 VII Summary of r e s u l t s of Series VI 26 VIII Changes in heart rate and blood pressure IX XI XII at decerebration 29 Changes i n heart rate and blood pressure a f t e r v / receptor stimulation with isoprenaline LO A b i l i t y of nropranolol to block e f f e c t of isoprenaline and the response to pulmonary vein distension - 50 E f f e c t s of decerebration,^ blockade, and vagotomy on the changes i n heart rate and blood pressure caused by distension of the pulmonary veins 51 Percent of control response'to pulmonary vein distension remaining a f t e r 4 blockade with propranolol 52 LIST OF FIGURES T i t l e Sagittal section of Tyr>ical response to a t r i a l distension a dog's brain pulmonary vein l e f t Typical response to pulmonary vein l e f t a t r i a l distension in a decerebrate dog Response to pulmonary vein l e f t a t r i a l distension Response to pulmonary vein l e f t a t r i a l distension after ^  blockade Response to pulmonary vein l e f t a t r i a l distension after decerebration and J blockade The effect of $ blockade with propranolo on the response to isoprenaline Typical response to pulmonary vein l e f t a t r i a l distension following | blockade with propranolol ACKNOWLEDGEMENTS The author wishes to express her appreciation to the following people: to J.R. Ledsome for ideas and c r i t i c i s m to Olenda Bennion and Mort Clarke f o r t h e i r t e c h n i c a l assistance and patience to Kurt Henze for photography and reproduction of record to Dr. F. Garrett for advice on neuroanatomy and i n t e r -pretation to James Mason f o r unusual encouragement to Yvonne Heap f o r advice on decerebration techniques to Ria Orr f o r patient typing. 1 INTRODUCTION C l a s s i c a l l y , central neural control of cardiovascular reflexes has been relegated to the "vasomotor centers" of the medulla. The ablation studies of Owsjannikow and Dittmar in the nineteenth century, followed by those of Porter i n the twentieth, consolidated a formidable experimental basis f o r the medulla as chief repository of c e n t r a l cardiovascular c o n t r o l . (Dittmar, 1#73 ; Owsjannikot^, 1^71; Porter, 19X5). As reviewed and c l a r i -f i e d i n 1946 by Alexander, there seemed l i t t l e r e b u t t a l to the claim for the existence of a "pressor center" l y i n g l a t e r a l l y , and a "depressor center" more medially i n the f l o o r of the fourth v e n t r i c l e , (Alexander, 1946). Both tonic and phasic out-puts from these centers could be demonstrated by stimulation of the medulla, recording from peripheral nerves, or truncation (Wang and Ranson, 1939; Alexander, 1946). Despite a few contentious voices, (Manning, 1965; Peiss, I960), as recently as 1963, Chai and Wang repeated many of the e a r l i e r studies, and were able to come to the "inescapable conclusion that cardio-vascular reflexes e l i c i t e d from baroreceptors and other afferents are integrated at the medullary l e v e l " . Such repeated success at confirming t h i s single f a c t does not of course preclude the existence of dissenters, modifiers and t h e o r i s t s . These s c i e n t i f i c prefects f l u o r i s h i n t h i s f i e l d , p r i m a r i l y as a re s u l t of the extreme p a u c i t y of any other d e t a i l e d information concerning the nervous pathways and processes involved i n central cardiovascular c o n t r o l . I f the medulla acts as the keystone i n an i n t r i c a t e structure of 2 cardiovascular control, the nature of the other stones i s not yet discernable. In a recent review of the central control of cardiovascular events, the state of our knowledge was revealed by a l i s t i n g of f i v e major areas of uncertainty: 1) we do not know the s i t e of central sympathetic i n h i b i t i o n induced by baroreceptor stimulation; 2) we do not know the s i t e of o r i g i n of vagal neurons; 3) we do not know the l o c a t i o n of basic synaptic s i t e s i n baroreceptor a c t i v a t i o n of the autonomic system, nor the processes involved; 4) we do not know the true influence of more r o s t r a l structures on medullary a c t i v i t y . (Gebber, 1970). Granted that we i n f a c t know so l i t t l e about the d e t a i l s of c e n t r a l organization, i t i s not s u r p r i s i n g that p a r a l l e l to the development of the staunch c l a s s i c a l viewpoint, there e x i s t equally long h i s t o r i e s of studies of other c e n t r a l nervous system structures and t h e i r possible influences on cardiovascular events. Foremost among these structures i s the hypothalamus, with i t s r o l e as highest center of autonomic in t e g r a t i o n , regulating such v i s c e r a l functions as temperature, food intake, f l u i d balance, sugar and f a t metabolism, i t i s only normal that i t should be associated with cardiovascular r e f l e x e s . E a r l y studies, i n v o l v i n g crude stimulation of parts of the hypotha-lamus while monitoring nerve impulses i n sympathetic ardiac nerves i n conjunction with blood pressure and heart rate, revealed marked increases i n a l l parameters ( P i t t s et al.,1941). 3 More discrete stimulation of the hypothalamus designed to e l i c i t the "defence reaction" in cats produces large increases in heart rate and contractility with only slight rises in systemic blood pressure, (Hilton, 1963). Such a response could not be possible i f some centrally mediated inhibition or altera-tion of the normal baroreceptor response pattern had not taken place. Djojosugito has recently demonstrated that such hypo-thalamically induced inhibition of baroreceptor impulses is indeed highly specific, acting primarily on heart performance as reflected in aortic blood flow and l e f t ventricular work load, rather than peripherally (Djojosugito, et.al.,1970). This differentiated interaction between hypothalamus and medulla-ry centered baroreceptor reflexes indicates a very high degree of integration. Much work has been done stimulating specific areas of the cerebral cortex and noting the effects evoked on both phasic and tonic cardiovascular events. The fronto-orbital cortex, the various structures of the "limbic system", including the septal area, preoptic area, amygdala, and hippocampus, have a l l been shown to have possible modulating effects on cardiovascular reflexes (Hochman et.al.,1969; Klevans and Gebber, 1Q70; Newman et.al.,1960). However i t i s d i f f i c u l t to interpret the physio-logical significance of these reports. Whether such evoked responses are normally active is not known. In addition, a l l of these areas have both afferent and efferent connections to the hypothalamus, and perhaps the effects noted are being mediated primarily via activation of hypothalamic-medullary pathways. Taken together the hypothalamus and these more rostral 4 structures cannot be denied an important role in cardiovascular c o n t r o l . The very f a c t that decerebration at the c o l l i c u l a r plane causes d r a s t i c changes in heart•rate and blood pressure, emphasizes the existence of such a function. The precise nature of that role cannot be stated with c e r t a i n t y at t h i s point. An area r e c e i v i n g renewed in t e r e s t recently i s the cerebellum, l y i n g d i r e c t l y over the vasomotor centers i n the f l o o r of the fourth v e n t r i c l e . The experiments of Moruzzi, dating from the 1940's, showed that stimulation of the paleo-cerebellum could a l t e r cardiovascular reflexes evoked by stimu-l a t i o n of sensory nerves, p a r t i c u l a r l y i n h i b i t i n g pressor responses (Moruzzi, 1940). H i s t o l o g i c a l studies have confirmed a large network of both a fferent and efferent connections between the vasomotor centers and the medullary r e t i c u l a r forma-t i o n , and the pyramis, uvula, a n t e r i o r lobe and f a s t i g i a l nucleus of the cerebellum (Brodal, 1954; Miura and Reis, 1 9 6 9 ) . Cerebellectomy, following decerebration, can be shown to s i g n i f i c a n t l y increase heart rate, as well as modify the carotid sinus r e f l e x i n cats, (Reis and Cuenod, 1965). Direct stimula-t i o n of the f a s t i g i a l nucleus can e l i c i t large ( i . e . +100 mm.Hg.) pressor responses i n cats (Miura and Reis, I 9 6 9 ) . Considering the ancient o r i g i n s of the cerebellum, and i t s intimate connection with the r e t i c u l a r formation of the medulla i t i s probably not u n l i k e l y that some s i g n i f i c a n t i n t e -grative function f o r cardiovascular control may e x i s t . At present, although we can only report a few scattered f a c t s , i t would be wise to observe more caution i n decerebrate studies to 5 avoid damage to the cerebellum, as i s frequently done. We can not ignore the possible effects of such damage without a better understanding of the cerebellum's role i n cardiovascular regula-ti o n . Caudal to the medulla i s the spin a l cord, center of r e f l e x a c t i v i t y , which, i n the absence of the b r a i n , appears to be canable of increasingly comolex c i r c u l a t o r y adjustments. Careful measurements of lat e n c i e s of sympathetic vasomotor responses evoked by stimulation of cardiac and renal nerves have revealed that the latency of type II response remains the same i n spinal cats, as i n cats with an inta c t brain (Katunsky and Khayutin, 1970; Khayutin and Lukoshkova, 1970). I f these vaso-motor responses were normally relayed via the medullary centers such a r e s u l t would not be possible . Despite the problems attendant with the spinal animal, v i z . the long delay i n the return of v i s c e r a l r e f l e x e s , and the profound trauma of sp i n a l shock, there i s no doubt at present that many autonomic r e f l e x areas, inclu d i n g cardiovascular r e f l e x e s , possess both long c i r c u i t i n g (supraspinal) and short c i r c u i t i n g ( s p i n a l ) . Whether the long or short c i r c u i t i s predominant i n the normal animal i s not yet determined. Indeed, there i s evidence that both pathways may be capable of functioning,depending on the condition which the animal faces, (Coote and Downman, 1966). In summary, i t i s probably f a i r to say that, given our current understanding, we cannot deny the existence of a very powerful integrating center f o r cardiovascular reflexes located in the medulla. This can be based, as i t o r i g i n a l l y was, on the 6 simple f a c t that basic cardiovascular reflexes do not function without an i n t a c t medulla. However, we should r e c a l l Alexander's enjoinder to appreciate the r e t i c u l a r nature of t h i s control center (Alexander, 1946). A constant barrage of c o r t i c o -hypothalamic, s p i n a l and c e r e b e l l a r impulses impinges on these cardiovascular neurons in the brain stem, c e r t a i n l y playing a v i t a l r o l e i n c e n t r a l s e t t i n g of autonomic tone and responsive-ness . The study reported i n t h i s t h e s i s was undertaken to determine the l e v e l and extent of c e n t r a l nervous sytem control exerted on the tachycardia produced by distension of the l e f t atrial-pulmonary vein junctions. Although the increase i n heart rate i n i t i a t e d by s p e c i f i c stimulation of baroreceptor endinfrs located i n the l e f t atrium had been shown to be r e f l e x i n nature, with vagal a f f e r e n t s , and efferents i n the cardiac sympathetic nerves, i t had not yet been determined whether the c e n t r a l connections of the arc were located i n the medulla or at some other CNS l e v e l . Before describing the methods and protocol used i n t h i s endeavor, a b r i e f review of the h i s t o r y of the l e f t a t r i a l r e f l e x under discussion w i l l be included. Reports of r e f l e x changes i n heart rate i n i t i a t e d by the a t r i a a l l stem d i r e c t l y from the . i n f u s i o n experiments of Bainbridge i n 1915, (Bainbridge ,1915). Years of confusion marred the development of any r a t i o n a l explanation f o r t h i s so-called r e f l e x . Tachycardia could be produced i n a v a r i e t y of ways such as the i n f u s i o n of large quantities of f l u i d i n the venous side of the c i r c u l a t i o n or i n f l a t i n g "umbrellas" and other 7 contrivances i n the right atrium. Unfortunately, increases i n heart rate were not consistent; i n fact bradycardia was often observed, (Aviado e t . a l . ,1951). Indeed, an examination of a l l the evidence up to 195$ brought no l e s s eminent a u t h o r i t i e s than Heymans and N e i l , i n t h e i r chapter on "Reflexes of un-c e r t a i n o r i g i n " , to the conclusion that "there was no evidence that any of the receptors so f a r described can i n i t i a t e cardio-acceleratory r e f l e x e s " , (Heymans and N e i l , 195$). Despite that p o n t i f i c a l laying to rest of the "Bainbridge r e f l e x " , there i s no disagreement as to the e x i s t -ence of nerve endings i n the- subendocardial t i s s u e of the a t r i a , p a r t i c u l a r l y concentrated at the region of the pulmonary vein junctions, (Coleridge et.al.,1957; Nonidez, 1937). Although there are no recent experiments supporting the contention that large scale infusions of the Bainbridge type could stimulate these receptors s p e c i f i c a l l y , there i s evidence that tachycardia can be produced by t h e i r d i s c r e t e stimulation. Ledsome and Linden i n 1962 reported that small balloons inserted through the pulmonary veins so as to l i e at the junction with the l e f t atrium could c o n s i s t e n t l y bring about an increase i n heart rate of approximately ?0 beats/minute. Nervous pathways were demon-strated i n the vagus (afferent) and the cardiac sympathetics. No peripheral changes i n vascular resistence have been revealed to explain t h i s increase, (Carswell, Hainsworth and Ledsome, 1970). Recordings from a t r i a l receptors have shown them to be active with each heart beat, continually r e l a y i n g messages to the CMS concerning the state of a t r i a l f i l l i n g and performance, (HakumSki, 1970; Korner, 1971). The present i n v e s t i g a t i o n was carried out to c l a r i f y the CMS connections of the a t r i a l receptors involved i n the increase i n heart rate observed unon i n f l a t i o n of small balloons at the pulmonary vein l e f t atrium junction i n anaesthetized dogs. Simple truncation at the c o l l i c u l a r and sp i n a l l e v e l s was used to determine the l o c i of central c o n t r o l . Various drug regimens were imposed on the preparations to exrose s p e c i f i c autonomic pathways. F i n a l l y , a study was made of the l e f t a t r i a l response under various anaesthetics, and i n the decerebrate unanaesthetized dog. 9 METHODS One h a l f hour p r i o r to administration of anaesthetic, mongrel dogs of ei t h e r sex, #-16 kg, were given 0.5 mg/kg morphine sulfate subcutaneously. Under l o c a l anaesthesia (Winthrop Laboratories; carbocaine - 1%), a cannula was i n -serted i n the saphenous vein and c^-chloralose ( B r i t i s h Drug Houses: 1% solution i n 0.9$ sodium chloride) infused i n a dose of 10 ml/kg of body weight. The l e v e l of anaesthesia was main-tained throughout the experiment by the addition of approxi-mately 10/o of the o r i g i n a l dose every h a l f hour. The dog's oesophageal temperature was kept constant at 37°C (+2) by a heated ta b l e . Tn those animals not re c e i v i n g chloralose, no pre-anaesthetic was given, but 300 mg of sodium pentothal (Abbott Laboratories; pentothal) was administered intravenously at the onset to permit the i n s e r t i o n of an endotracheal tube and the connection of the tube to a Fluotec 3 (Cyprene Ltd.) v o l a t i l e anaesthetic machine. Those animals receiving halothane (Ayerst Laboratories: Fluothane) were maintained on a closed c i r c u i t of halothane and oxygen at a flow rate of 200-300 ml/minO^ with l^-2/o halothane. No further pentothal was reauired and adjust-ments i n the flow rate or the percentage of halothane could be made throughout surgery to allow an adeouate and steady state of anaesthesia. The animals r e c e i v i n g nitrous oxide and pentothal, a f t e r the i n i t i a l dose of pentothal, were kept anaesthetized 10 with a mixture of #0$ nitrous oxide at a flow rate of 2 L/min and 20$ oxygen at 500 ml/min i n a semi-closed c i r c u i t . For s u r g i c a l purpose, t h i s was augmented by the intravenous i n -fusion of 30 mg of pentothal every half hour, or l e s s , as required by the i n d i v i d u a l animal. The right femoral artery was cannulated with a 6 inch length of t e f l o n tubing ( l mm. bore) and femoral a r t e r i a l pressure measured by a Statham s t r a i n gauge manometer (model p23Gb). Pressure was recorded on a d i r e c t w r i t i n g Honeywell u l t r a v i o l e t recorder (Model 1505, V i s i c o r d e r ) a f t e r a m p l i f i c a t i o n by an Accudata 113 a m p l i f i e r . The freouency response of such a system was f l a t {±5%) to 35 HZ. Mean pressure was obtained e l e c t r i c a l l y . C a l i b r a t i o n with a mercury and water pressure system was done p r i o r to each exper-iment. Samples of a r t e r i a l blood were taken at i n t e r v a l s throughout the experiment and PQQ , PQ ,and pH measured using appropriate electrodes and an Instrumentation Laboratories blood gas analysing system. Additions of sodium bicarbonate (1 M.) or adjustments i n the r e s p i r a t o r y pump stroke volume were used to attempt to keep pH and PQQ within the normal ranges of 7.3 - 7.4, and 35-40 mm Hg, r e s p e c t i v e l y . The animal was then turned so that the l e f t side was exposed and the chest opened at the 5th i n t e r c o s t a l space. A Harvard r e s p i r a t o r was attached to the tracheal cannula with a stroke volume of approximately 50 ml./3kg of body weight at a rate of l#/min. One l i t r e per minute of oxygen was added to the inspire d a i r to ensure adequate oxygenation. Once the chest was opened a resistance of 3 cm. of H 90 was added to the expiratory 11 o u t l e t . Blood volume l o s t during surgery was replaced by the infusion of dextran (Travenol) to approximate 10% of estimated blood volume. After d e f l e c t i n g the l e f t lungs so as to expose the pulmonary veins, small balloons, with a capacity of one ml, were inserted i n the veins so that when i n f l a t e d they lay at the junction of the veins and the l e f t atrium. The l e f t lungs were then t i e d o f f with stout cord to prevent backflow and interference i n the l e f t atrium. The chest was closed and the animal placed i n an upright p o s i t i o n . For decerebration, the head was fi x e d i n a stereo-taxic frame (La Precision Cinematographique; Paris) by i n s e r t i n g the ear bars through the external auditory meatus. After center-ing the head by moving the ear bars, the angle of the head was determined by lowering the jaws u n t i l the eyes were i n the same hori z o n t a l plane with the ear bars, a f t e r which the jaw was immobilized by the use of the face plate and mandibular clamps. The ear bars, which were at 40 on the frame, were then taken as the 0 point of reference. A standard 2 lead ECG was attached to the chest and a f t e r pre-amplification (Grass Instruments Model P15 Preampli-f i e r ) displayed simultaneously on the u l t r a - v i o l e t recorder and dual beam oscilloscope (Tektronix type RM 565). Heart rate was also recorded using a Honeywell Cardiotachometer triggered by the R wave of the ECG. A l l heart rates used i n the experimental r e s u l t s were counted from the ECG record over periods of at least 0.5 min. 1? Decerebration was accomplished by the means of a high frequency coagulation system c o n s i s t i n g of nine electrodes fastened together to form a f o r k - l i k e apparatus tapered at both ends so as to f i t the base of the s k u l l . The electrodes were constructed of size 23 s t a i n l e s s s t e e l tubing approximately 17 cm long, and coated with a t h i n even layer of i n s u l a t i o n . To insulate the electrodes they were slowly lowered into a beaker of Insul-X (Insul-X, Ossining, New York), then baked f o r one hour at 70°C. The procedure was repeated three times, a f t e r which 2-3 mm. at the t i n s were scraped bare to permit passage of current between adjacent t i p s only. Checks f o r breaks i n the in s u l a t i o n were made p r i o r to each experiment with an AVO meter (Hioki E l e c t r i c Works - Model AF-105) and recoatings made as necessary. After exposing the s k u l l , a small rectangular hole, approximately 40 mm x 10 mm, was made using a hand d r i l l . The hole was made i n three sections, a small square on either side being removed f i r s t . The bridge of bone remaining across the center was then c a r e f u l l y d r i l l e d at each end and l i f t e d of with bone cli p p e r s to avoid damage to the large s a g i t t a l sinus i n the mid l i n e . Bone wax was used to stop bleeding from the p e r i -meter of the rectangle. The p o s i t i o n of the hole was determined by placing the electrodes i n t h e i r holder at 0, perpendicular to the surface of the s k u l l . Experience had shown that lowering the electrodes at these coordinates would e f f e c t i v e l y sever the brainstem at a m i d - c o l l i c u l a r l e v e l i n dogs of #-13 kg, with small heads of normal s k u l l structure. 1? To lower the electrodes, the dura was removed with fine s c i s s o r s on both sides of the s a g i t t a l sinus. Care had to be taken when lowering the electrodes that they separated over the sinus, yet entered without undue splaying. They were then lowered u n t i l the resistance of the bone at the base of the brainstem was f e l t ; u s u a l l y around 40 mm from the brain surface. Coagulation was then performed with a Wyss Coagulator (Geneva; J . Monti) i n ten 2 mm steps, passing approximately 100 m Amps, f o r 15 seconds between the t i p s of neighbouring elec-trodes at each l e v e l . Decerebrate r i g i d i t y was seldom observed, but muscular extension, bladder incontinence, and a large f a l l i n heart rate were common occurrences. Smaller, but s i g n i f i c a n t reductions i n femoral a r t e r i a l blood pressure were also frequently noted. The success of the decerebration procedure was assessed at the completion of each experiment by bleeding the animal and removing the cerebral hemispheres. I f decerebrate, the brain stem f e l l away i n a clean l i n e between the c o l l i c u l i , with evidence of burning shown by darkened spots and softened t i s s u e . A s a g i t t a l section of such a decerebration i s presented i n Figure 1. The section was prepared from a dog's head removed at the completion of an experiment a f t e r bleeding. The head was then frozen, f o r one week, skinned and sectioned with a handsaw. In the 4th s e r i e s , where s p i n a l sections were performed, the animals were also f i x e d i n the stereotaxic frame for convenience and s t a b i l i t y . The neck muscles were separated in the midline and retracted. In some animals simply opening the dura over the foramen magnum allowed s u f f i c i e n t access to 14 the cord to permit safe section. In others, the cap of the f i r s t c e r v i c a l vertebra was removed with bone c l i p p e r s a f t e r d r i l l i n g with a hand d r i l l . A fter paralyzing the animal with 0.5 mg/kg (IV) succinyl choline (E.R. Souibb & Sons; Sucostrin Chloride) transection of the cord was accomplished by means of a spatula and s c i s s o r s , taking care to avoid the b a s i l a r artery on the ventral side of the cord. Gel foam (Upjohn Co.) packed into the c a v i t y staunched any severe bleeding. Anaesthetic l e v e l s were maintained throughout the preparation, transection, and postsection periods by the i n f u s i o n of 10% of the o r i g i n a l dose of chloralose every \ hour. In a l l series where drugs were used they were administered intravenously through the saphenous vein cannula followed by a 5 ml wash of s a l i n e . An exception was series 5, where the femoral vein was used, the wash remaining the same. Propranolol, 0.5 mg/kg (Ayerst Laboratories; Ay-64043) was used to block sympathetic ^ receptors and was judged to have done so i f i t was successful i n blocking 90$ or more of the response to ft stimulation by 0.5*/ g/kg of Isoprenaline (K.& K. Laboratories Inc.; Isoprenaline s a l t s u l f a t e ) . Atropine s u l f a t e (E.R.Squibb and Sons, Ltd.) used i n s e r i e s I I , was given i n an 0.4 mg/kg dosage. i 15 scale i 1 lcm Figure 1. Sagittal section of a dog's brain made decerebrate by the electrocoagulation method. A midsaggital section of a dog's brain approximately 1.2 x enlarged. The lesion is the darkened area just rostral to the cerebellum and destroying the col l i c u l a r region. In the actual specimen the lesion extended 0.5 cm in width. 16 EXPERIMENTAL PROTOCOL In the f i r s t series of experiments, a f t e r general surgery and opening of the s k u l l and dura had been completed, the animal was allowed to recover f o r at le a s t 10 minutes, or u n t i l a steady state had been achieved, before beginning the period of experimentation. Testing f o r the presence of the l e f t a t r i a l r e f l e x was always done i n the same manner. Following a control period, the pulmonary balloons were i n f l a t e d f o r two minutes, a f t e r which a period of i n f l a t i o n was recorded, and the balloons deflated. After a two minute recovery period another record was taken, and changes i n heart rate and blood pressure calculated from mean values before and a f t e r balloon i n f l a t i o n . When three such t r i a l s had been completed, the animal was made decerebrate using the high frequency electrode system and, a f t e r e o u i l i b r a t i o n the r e f l e x t e s t i n g procedure repeated. To study the nature of the r e f l e x , various drug regimens were applied and t h e i r e f f e c t s on the r e f l e x noted. In series I, t h i s consisted of f i r s t blocking the response to ft receptor stimulation by isoprenaline (0.5 g/kg IV) with pro-pranolol (0.5 mg/kg IV). The balloons were then i n f l a t e d , and the response recorded as before. At the completion of each test period a repeat dose of isoprenaline (0.5 g/kg IV) was given to ascertain the degree of $ blockage. I f necessary a further dose of propranolol was administered. After 3 such t r i a l s c e r v i c a l vagotomy was performed and the r e f l e x tested once more. 1 7 In series I I , general procedures were the same as i n series I but i n place of propranolol, atropine (0.4 mg/kg IV) was given. After t e s t i n g the r e f l e x three times, i f any increase i n heart rate remained upon i n f l a t i o n of the balloons, propranolol was given and the t e s t repeated. The t h i r d group of experiments consisted of i n i t i a -t i n g a ^ receptor blockade p r i o r to decerebration, a f t e r the control r e f l e x had been recorded. The same isoorenaline-propranolol check was used as previously with frequent admini-s t r a t i o n of isoprenaline to insure adequate blocking. Since the propranolol did not wear of as evenly or r a p i d l y as desired, further doses of propranolol were given as required to maintain the ^ blockade a f t e r decerebration. After 3 further t r i a l s , i f any increase i n heart rate remained upon i n f l a t i o n of the balloons, c e r v i c a l vagotomy was performed and the balloons re-i n f l a t e d . Where halothane or nitrous oxide and pentothal were used as anaesthetics, the procedures were simply those of series I with the removal of the v o l a t i l e anaesthetic and the d i s -continuence of pentothal upon successful completion of the decerebration. At l e a s t 10 min. - 1 hour were necessary f o r the anaesthetic to be blown o f f and i t s e f f e c t s reduced. After t e s t i n g the r e f l e x , 1 hour waits were i n t e r j e c t e d to attempt to augment f u l l recovery from anaesthesia. The same procedure of (5> blockade and c e r v i c a l vagotomy was then carried out. The group of experiments included i n series 4, spi n a l transection, followed a somewhat d i f f e r e n t course. After I S surgery was complete, three control i n f l a t i o n s were performed. The sninal cord was then prepared as described by opening the dura over the foramen magnum and f i r s t c e r v i c a l vertebra. Because t h i s often altered the p h y s i o l o g i c a l state as r e f l e c t e d by heart rate and femoral a r t e r i a l blood pressure, the r e f l e x was again tested a f t e r a new steady state had been established. After transection of the cord, i n f l a t i o n of the balloons was done i n series as r a p i d l y as possible i n an attempt to remain within the period i n which the animal exhibited a steady state with a degree of vagal tone. C e r v i c a l vagotomy was done to assess the degree of vagal tone remaining and the balloons again i n f l a t e d . Series Number I II III IV V VI Anaesthetic Chloralose Chloralose Chloralose Chloralose Halothane N 20 and Pentothal Number of dogs 6 6 7 7 4 7 Protocol Control Control Control § Blockade Control Control Control Decerebration Decerebration Decerebration Spinal Section Decerebration Decerebration Decerebrate control Blockade Decerebrate control Atropine £ Blockade Decerebrate control Spinal Control Vagotomy No anaesthetic Decerebrate control No anaesthetic Decerebrate control Vagotomy Vagotomy Atropine Vagotomy 4 Blockade Vagotomy $ Blockade Vagotomy TABLE I. EXPERIMENTAL PROTOCOL RESULTS The results of a l l six series of experiments are summarized separately below in tables II - VII. A discussion the significance of these results in terms of the reflex response and i t s nervous pathways follows. 21 CONTROL AFTER DECEREBRATION AFTER PROPRANOLOL AFTER VAGOTOMY Number of dogs 6 6 6 6 Number of t r i a l s ia is 18- 17 HR BP HR BP HR BP HR BP Mean 10 0.1 15 0.3 10 0.6 -0.3 -1.5 Standard error of the mean 1.48 0.96 1.60 0.70 1.45 0.37 0.76 0.94 A) Heart rate (beats/min.) and blood pressure (mm.Hg.) changes occurring at distension of the pulmonary vein l e f t a t r i a l junction f o r 2 minutes. CONTROL VS DECEREBRATE DECEREBRATE VS J> BLOCKED BLOCKED VS VAGOTOMY HR BP HR BP HR BP Standard error of difference 3.9 0.6 1.605 0.349 NS NS 4.4 0.2 1.783 0.195 NS NS 10.3 2.2 5.168 2.594 2p^0.01 2p<i0.05 T Level of Significance B) Results of T te s t f o r paired data using a studentized range. NS = not s i g n i f i c a n t . TABLE I I . SUMMARY OF RESULTS OF SERIES I. 22 CONTROL AFTER DECEREBRATION AFTER ATROPINE AFTER PROPRANOLOL Number of dogs Number of t r i a l s 7 21 7 21 7 21 4 10 HR BP HR BP HR BP HR BP Mean 27 -2.0 32 0.5 2.5 -0.5 -0.4 -0.7 Standard error of the mean 2.92 1.12 3.57 0 .79 0.71 0.65 1.00 1.05 A) Heart rate (beats/min.) and blood pressure (mm.Hg.) changes at distension of the pulmonary vein l e f t a t r i a l junction f o r 2 minutes. CONTROL VS DECEREBRATE DECEREBRATE VS ATROPINE ATROPINE VS $ BLOCKED HR BP HR BP HR BP Standard error of difference 4.1 2.4 0.660 1.572 NS NS 25.3 1.0 4.633 0.624 2p<0.01 NS 5.1 0.4 2.924 0.571 2p<0.10 NS T Level of sign i f i c a n c e B) Results of T tes t f o r paired data using studentized range. NS = not s i g n i f i c a n t . TABLE I I I . SUMMARY OF RESULTS OF SERIES I I . CONTROL AFTER b BLOCKADE (!> BLOCKADE + DECEREBRATION AFTER ATROPINE Number of dogs 6 6 6 4 Number of t r i a l s 19 13 20 12 HR BP HR BP HR- BP HR BP Mean 23 -2.2 6 0.7 3 0.4 -3 -1.9 Standard error of the mean .3.49 0.52 1.27 0.63 1.25 0.57 3.33 0.74 A) Heart rate (beats/min.) and blood pressure (mm.Hg.) changes occurring at distension of the pulmonary vein l e f t a t r i a l junction f o r 2 minutes. CONTROL VS 4 BLOCKED 0 BLOCKED VS DECEREBRATE DECEREBRATE VS ATROPINE HR BP HR BP HR BP Standard error of difference 13 -2.9 3.511 3.655 2p<0.0 5 2p<0£5 2 0 1.795 0.042 NS NS 19 3.5 3.321 7.269 2p^0.05 2p<0.01 T Level of sig n i f i c a n c e F) Results of T tes t f o r paired data using a studentized range. NS = not s i g n i f i c a n t . TABLE IV. SUMMARY OF RESULTS OF SERIES I I I . ?4 CONTROL AFTER SPINAL SECTION AFTER VAGOTOMY Number of dogs 7 7 7 Number of t r i a l s 29 30 14 HR FTP HR BP HR BP Mean 12 -0.2 6 -1.8 -0.6 -4.8 Standard error of the mean '1.73 0.79 1.27 1.00 0.48 1.82 A) Heart rate (beats/min.) and blood pressure (mm.Hg.) changes at distension of the pulmonary vein l e f t a t r i a l junction f o r two minutes. CONTROL VS SPINAL SECTION SPINAL SECTION VS VAGOTOMY HR BP HR BP Standard error of difference 7.0 0.8 1.897 0.663 NS NS 6.3 2.5 3.270 2.457 2p^0.05 2p<0.05 T Level of sig n i f i c a n c e B) Results of T tests f o r paired data using a studentized range. NS = not s i g n i f i c a n t . TABLE V. SUMMARY OF RESULTS OF SERIES IV. CONTROL NO ANAESTHETIC DECEREBRATE I HOUR LATER AFTER & BLOCKADE AFTER VAGOTOMY Number of dogs 4 13 4 13 4 9 4 10 4 9 Number of t r i a l s X HR BP HR BP HR BP HR BP HR BP 4 -2.3 0.93 1.37 5 -2.4 1.34 1.13 7 0.4 1.02 1.29 3.5 1.3 1.22 1.57 0 -3.9 0.46 2.37 SEM A) Heart rate (beats/min.) and blood pressure (mm.Hg.) changes at distension of the pulmonary vein l e f t a t r i a l junction f o r two minutes. After the control period and decerebration, no further anaesthetic was used i n these dogs. CONTROL VS DECEREBRATE DECEREBRATE VS I HOUR LATER DECEREBRATE VS ^ BLOCKED DECEREBRATE VS VAGOTOMY HR BP HR BP HR BP HR BP Standard error of difference T Level of sign i f i c a n c e 1.9 0.9 0.363 0.799 NS NS 1.4 1.9 0.341 2.509 NS NS 3.7 2.5 1.496 1.393 NS NS 6.9 2.3 3.749 1.037 2p<0.10 NS B) Results of T test f o r paired data using a studentized range. NS = not s i g n i f i c a n t . TABLE VI. SUMMARY OF RESULTS OF SERIES V. CONTROL NO ANAESTHETIC DECEREBRATE I HOUR LATER AFTER p BLOCKADE AFTER VAGOTOMY Number of dogs 7 21 7 22 7 14 5 15 6 18 Number of t r i a l s X HR BP HR BP HR BP HR BP HR BP 2 -3.8 0.65 1.08 9 -1.3 1.02 0.83 8.5 -1.3 0 .98 1.18 3 -3.0 1.68 1.74 0 -2.2 0.22 0.64 SEM A) Heart rate (beats/min.) and blood pressure (mm.Hg.) changes at distension of the pulmonary vein l e f t a t r i a l junction f o r 2 minutes. After the control period and decerebration, no further anaesthetic was used i n these dogs. CONTROL VS DECEREBRATE DECEREBRATE VS I HOUR LATER DECEREBRATE VS 4 BLOCKED DECEREBRATE VS VAGOTOMY HR BP HR BP HR BP HR BP Standard error of difference 6 . 8 2 . 4 5 . 0 1 9 1.412 2p ^ 0 . 0 1 NS 0 . 3 0 . 2 0 . 3 0 8 0 . 2 6 0 NS NS 7 . 5 2 . 4 3 . 2 0 6 1 . 9 4 3 2 T ><0.05 NS 9 . 5 0 . 2 6 . 0 5 5 0 . 0 9 9 2 t > < 0 . 0 1 NS T Level of sign i f i c a n c e B) Results of T tests f o r paired data using the studentized range. NS = not s i g n i f i c a n t . TABLE VII. SUMMARY OF RESULTS OF SERIES VI 27 I i_Brrects_or_inflatinig; the balloons at the pulmonary vein -l e r t_atrial_junction I n f l a t i n g the pulmonary vein balloons with 0.5 (3-11 Kg.) - 1.0 ml saline (12-13 Kg.) for two minute periods produced a s i g n i f i c a n t increase i n mean heart rate without a s i g n i f i c a n t change i n femoral a r t e r i a l blood pressure. In 94 t r i a l s i n 23 dogs under chloralose anaesthesia the mean increase i n heart rate was 17 beats/min.(SEM + 1.4), with a mean blood pressure change of -0.9 mmHg(SEM + .5). This increase i n heart rate was s i g n i f i c a n t at p 0.001 using a T t e s t f o r paired data with the studentized range. Because of the raoid onset of the increase i n heart rate, and the fac t that i t could be p a r t i a l l y or wholly blocked by various combinations of sympathetic and parasympathe-t i c blocking agents, i t was presumed to be of r e f l e x o r i g i n . The increase i n heart rate was sim i l a r to that reported by Ledsome and Linden (1964) and there was no doubt that distension of the pulmonary v e i n - a t r i a l junctions i n the control state did indeed cause an increase i n heart rate. Because i t i s of importance i n assessing the r e l a t i v e magnitude of any change i n heart rate or blood pressure, we should discuss the e f f e c t s of decerebration on control values of these parameters, before considering i n d e t a i l the influence of decerebration on the l e f t a t r i a l r e f l e x described above. In the 31 dogs made decerebrate by the electrocoagulation method, mean heart rate f e l l from 142 beats/min. (SEM + 7.5, Range 34-223) to 123 beats/min. (SEM + 9.4, Range 43-240). a f t e r decerebration. ?8 Blood pressure followed a s i m i l a r pattern, decreasing from control values of 120.2 mmHg (SEM ±3.6, range 80-174) to 106.9 mmHg (SEM + 2.9; range 72-113). Refer to table VIII.These changes occurred immediately upon section of the brainstem at the m i d - c o l l i c u l a r l e v e l and were i n general sustained during the 4-6 hours of experimentation a f t e r "recovery" from decere-brati o n . Even i n dogs from Series I I I , which had been treated p r i o r to decerebration with propranolol (0.5 mg/Kg), changes of the same magnitude were observed, i n d i c a t i n g that much of the change i n heart rate was due to a change i n vagal tone. When the pulmonary vein balloons were i n f l a t e d at these new post-decerebration control l e v e l s , the mean increase i n heart rate was s l i g h t l y augmented while blood pressure changes were n e g l i g i b l e . In 39 t r i a l s i n 13 dogs, from Series I and I I , the r e f l e x increase i n heart rate during balloon i n f l a -t i o n rose, from a mean of 19 beats/min (SEM + 2.2) before decere-bration to 24 beats/min (SEM + 2.5) a f t e r decerebration. Blood pressure changed from a control mean of -1 mmHg (SEM +0.3) to 0.4 mmHg (SEM +0.6) following decerebration. However, when compared s t a t i s t i c a l l y with a T test f o r paired data, there was no s i g n i f i c a n t difference between the r e f l e x changes i n heart rate and blood pressure before and a f t e r decerebration i n these dog^i. An example of the record i n a representative experiment i s shown i n figures 2 and 3. It was concluded from these data that the central control mechanism for the l e f t a t r i a l r e f l e x was not r o s t r a l to the superior c o l l i c u l u s as i t s t i l l existed in the decerebrate animal. To determine i f the c h a r a c t e r i s t i c s ?9 CONTROL AFTER DECEREBRATION HEART RATE BLOOD PRESSURE HEART RATE BLOOD PRESSURE 144 120 144 102 57 123 74 112 PROPRANOLOL 92 110 72 112 BEFORE > 54 123 30 110 DECEREBRATIONI 130 124 160 116 35 132 54 126 114 143 76 113 190 106 119 72 130 126 150 90 113 146 30 116 CHLORALOSE 156 130 114 116 111 124 114 112 114 152 64 116 193 140 193 116 117 133 90 100 130 106 210 91 130 112 152 100 96 92 170 112 163 122 106 102 103 103 96 90 116 100 43 106 HALOTHANE 126 103 34 104 96 90 73 126 102 116 36 105 162 100 177 72 150 132 90 116 NITROUS OXIDE 210 100 204 104 AND PENTOTHAL 225 174 240 156 130 126 163 100 144 30 120 50 136 114 163 114 I 142 7.5 34-223 120.2 3.6 30-174 123 9.4 43-24C 106. 9 2.9 72-il5 SEM RANGE TABLE VIII. CHANGES IN HEART RATE (beats/min.) AND BLOOD PRESSURE (mm.Hg.) AT DECEREBRATION. Heart Rate B e a t s / m i n . 160 r -100 Femoral Arterial Blood Pressure (mm.Hg.) >° I 4 0 r — IOOI— mum 'Figure 2. A t y p i c a l record of the response to distension of the pulmonary vein l e f t a t r i a l junction i n a dog anaesthetized with chloralose. In sequence from l e f t to r i g h t are shown sections of a control period, during . i n f l a t i o n of the pulmonary balloons, and two minutes a f t e r d e f l a t i o n . Each v e r t i c a l time l i n e represents ten seconds. 31 E C G H e a r t R a t e B e a t s / m i n . Femora l A r t e r i a l B lood P r e s s u r e (mm. Hg.) •Figure 3. A . t y p i c a l record of the response to distension of the pulmonary vein l e f t a t r i a l junction i n a decerebrate dog anaesthetized with chloralose. From l e f t to r i g h t are shown sections of a control period, during i n f l a t i o n of the pulmonary balloons, and two minutes a f t e r d e f l a t i o n . Each v e r t i c a l time l i n e represents ten seconds. This record v/as taken from the same dog as i n Figure 2. 3 ? of the r e f l e x had been altered by the removal of higher centers, a c l o s e r study of the nature of the r e f l e x i n the decerebrate state was undertaken using drugs, vagotomy and s p i n a l section. I I I . The ef f e c t s of propranolol It was noted i n Series I, that the ^ sympathetic blocking agent, propranolol (0.5 mg/Kg) did not abolish the l e f t a t r i a l r e f l e x , and i n fa c t did not even s i g n i f i c a n t l y a l t e r the magnitude of the heart rate increase. In 1$ t r i a l s i n 6 decerebrate dogs, the mean increase i n heart rate during balloon i n f l a t i o n was 15 beats/min. (SEM + 1.6). After blockade with propranolol, the r e f l e x increase i n heart rate had amean value of 10 beats/min. (SEM + 1.4), which was not s i g n i f i c a n t l y d i f f e r e n t from the control value i n a T test f o r paired data. Blood pressure changes were n e g l i g i b l e and not s t a t i s t i c a l l y d i f f e r e n t . This f i n d i n g was i n c o n f l i c t with that of Ledsome and Linden (1969) who had shown that the same dose of propranolol administered to chloralose anaesthetized dogs could s i g n i f i c a n t l y reduce the heart rate increase associated with balloon i n f l a t i o n . To determine whether we were indeed observing an altered r e f l e x , a study was made i n which propranolol was given both before and a f t e r decerebration (see Methods - Series I I I ) . In t h i s p a r t i c u l a r group of 6 dogs we observed very marked i n -crease i n heart rate during control balloon i n f l a t i o n , ranging from 7-53 beats/min. with a mean of ?3 beats/min. (SEM + 3.5). Blood pressure f e l l an average of mmHg (SEM + 0.8). The infus i o n of 0.5 mm/Kg. of propranolol abolished most of the 33 increase i n heart rate, as well as a l t e r i n g blood pressure changes. After pronranolol, the mean increase in heart rate was 6 beats/min. (SEM + 1.3), while blood pressure increased 0.7 mrnHg (SEM + 0.6). Both values were s i g n i f i c a n t l y d i f f e r e n t from control i n f l a t i o n values i n a T test for paired data at2p^.0.05. Decerebration at t h i s point, with the l e v e l of $ blocking kept constant by ad d i t i o n a l doses of propranolol, did not s i g n i f i -cantly a l t e r t h i s response. Mean heart rate increase was 3 beats/min.(SEM + 1.?); blood pressure increase was 0.4 mrnHg (SEM + 0.6). A t y p i c a l l e f t a t r i a l r e f l e x blocked with propra-n o l o l both before and a f t e r decerebration i s shown i n figures 4, 5 and 6. It might be argued at t h i s point that the increases i n heart rate observed at balloon i n f l a t i o n a f t e r propranolol, were i n f a c t , a r e f l e c t i o n of an incomplete ^ blockade. The use of isoprenaline i n t h i s case, can be used as an index of the effectiveness of the blockade. I f isoprenaline i s administered p r i o r to (} blockade, large changes i n heart rate and blood pressure can be observed. Referring to table IX, i n 20 dogs heart rate increased an aver-age of 90 beats/min. (SEM + 11.7, range 27-136) as blood p r e s s u r e decreased -41.6 mrnHg. (SEM +3.9, range -10 to-72) 30 seconds a f t e r the infusion of isoprenaline. After propranolol however, changes i n both parameters were either abolished or n e g l i g i b l e . Figures 7 and 3 i l l u s t r a t e a t v p i c a l response to isoprenaline before and a f t e r (i blockade with propranolol. Since the same dose of isoprenaline could be administered at any time 34 throughout the experiment, any increase i n p a c t i v i t y could e a s i l y be detected by an increased response to isoprenaline. Further doses of propranolol could then be given to ensure complete (J blocking. It i s i n t e r e s t i n g that while the f i r s t series demon-strated that propranolol was able to abolish only about 1 / 3 of the t o t a l increase i n heart rate during balloon i n f l a t i o n , the second series showed that propranolol was able to abolish over 2 / 3 of the increase i n heart rate. However, the amount of r e f l e x remaining i n both cases, 10 beats/min. i n Series I versus 7 beats/min. i n Series I I , i s not very d i f f e r e n t . The difference may therefore a r i s e i n the magnitude of the control r e f l e x i t -s e l f ; 14 beats/min. i n Series I as opposed to 2 3 beats/min. i n Series I I . This i s suggestive of the v a r i a t i o n i n the r e l a t i v e roles of the sympathetic and vagal components i n determining the magnitude of the l e f t a t r i a l r e f l e x i n d i f f e r e n t animals under d i f f e r e n t circumstances. In a l l cases tested, the increase i n heart rate remaining a f t e r propranolol could be abolished by the i n f u s i o n of 0.4 mg/kg atropine. IV._The effects_of_atropine To further investigate the contribution of parasympa-t h e t i c and sympathetic components to the l e f t a t r i a l reflex,the opposite procedure to that discussed above was followed v i z . blocking the muscarinic postganglionic parasympathetic a c t i v i t y f i r s t with atropine (0.4 mg/Kg IV), then blocking sympathetic p r e c e p t o r s with propranolol, (Methods - Series I I ) . Results from t h i s procedure are given i n Table H I . There i s no doubt 35 H e a r t R a t e B e a t s / m i n . ECG Femora l A r t e r i a l B l o o d P r e s s u r e (mm. Hg.) Figure l+* Response to pulmonary vein l e f t a t r i a l distension i n a dog anaesthetized with chloralose. In sequence from l e f t to right are shown sections of a control period, during i n f l a t i o n of the nulmonary balloons, and two minutes a f t e r d e f l a t i o n . V e r t i c a l time l i n e s represent 10 seconds. 36 Figure 5. Typical response to pulmonary vein l e f t a t r i a l distension following blockade with propranolol (0.5 mg/Kg IV.). From l e f t to right are shown sections of a control period, i n f l a t i o n of the pulmonary balloons, and two minutes a f t e r d e f l a t i o n . Each v e r t i c a l time l i n e represents 10 seconds. This record was taken from the same dog as that i n Figure 4. 37 Figure 6. Typical response to pulmonary vein l e f t a t r i a l distension i n a decerebrate dog following $ blockade with propranolol (0.5 mg./Kg.IV.). This record was taken from the same dog as Figures L and 5. From l e f t to r i g h t are shown sections of a control period, during i n f l a t i o n of the pulmonary balloons, and two minutes a f t e r d e f l a t i o n . V e r t i c a l time l i n e s represent 10 seconds. 33 ECG Heart Rate Beats/min. Femoral Arterial 1 2 0 Blood Pressure (mm. Hg.) 100 Figure 7. The e f f e c t of $ blockade on the response to isoprenaline. In section 1, the marker indicates the inf u s i o n of 0.5 *fg/Kg IV. of isoprenaline. V e r t i c a l time l i n e s represent 10 seconds. Section 2 of the record i l l u s t r a t e s the e f f e c t of the same dose of isoprenaline infused approximately two minutes a f t e r blockade with propranolol (0.5 mg/Kg IV.) i n the same dog. 39 Figure #. A record of the response to distension of the pulmonary vein l e f t a t r i a l junction following blockade with propranolol (0.5 mg./Kg.IV.). This record was taken from the same dog as i n Figure 7, immediately following section 2. From l e f t to r i g h t are shown sections of a control period, during i n f l a t i o n of the pulmonary balloons, and two minutes a f t e r d e f l a t i o n , v e r t i c a l time l i n e s represent 10 seconds. CONTROL AFTER BLOCK WITH PROPRANOLOL HEART BLOOD HEART BLOOD RATE PRESSURE RATE PRESSURE +150 - 3 2 +12 0 +72 -72 0 +2 +99 - 3 2 +6 +2 +114 - 2 6 - 2 - 2 +33 -46 0 0 +24 -24 - 6 -4 +46 - 5 6 0 +4 +30 -24 0 0 +136 -60 +16 - 6 +120 -60 +6 0 +173 -62 -9 - 4 +135 -10 +5 0 +156 - 2 0 -1 +2 +48 -44 0 - 2 +62 -60 0 -16 +111 - 4 8 +3 -4 +108 - 3 2 +6 - 4 +66 -24 +6 0 +27 - 4 6 0 0 +36 -54 0 +6 X 89.300 -41.600 2.100 - 1 . 3 0 0 SEM 11.684 3 . 8 7 8 1.263 1.013 RANGE 24-136 (-10)-72 (-9)-16 +6-(-16) TABLE IX. CHANGES IN HEART RATE AND BLOOD PRESSURE AFTER 4 RECEPTOR EXCITATION BY ISOPRENALINE. Heart rate and blood pressure are i n beats/min. and mm.Hg. resp e c t i v e l y , and represent changes i n heart rate and blood pressure recorded 30 seconds a f t e r the infusion i n the femoral vein of 0 . 5^g/Kg isoorenaline. The changes a f t e r $ blockade were recorded s i m i l a r l y , approximately 2 -5 minutes a f t e r i n f u s i o n of 0 . 5 mg/Kg of propranolol. 41 that atropine was able to v i r t u a l l y a bolish the r e f l e x . However, i f we take into consideration the o v e r a l l e f f e c t s of atropine, as r e f l e c t e d i n changes i n control values of heart rate and blood pressure, i t i s obvious that we are dealing with a completely new ph y s i o l o g i c a l state. In seven decerebrate dogs, heart rate increased from a mean control value of 172 beats/min. (SEM + 10, range 133-222) to 214 beats/min. (SEM + 12, range 156-246) with the administration of atropine. Blood pressure also increased, though only s l i g h t l y , from a control l e v e l of 91 mrnHg (SEM + 4.9, range 76-103) to 100 mrnHg (SEM + 5 . 4 , range 72-114). I f we now reconsider the amount of r e f l e x remaining a f t e r atropine, i t must be admitted, that though 3 beats/min. i s a very small increase, i t i s s i g n i f i c a n t that the heart i s able to consistently increase i t s rate at a l l from a baseline of 214 beats/min. C e r t a i n l y we could not conclude from these experiments alone, that the l e f t a t r i a l r e f l e x i s s o l e l y mediated by the vagus. V_._Effects o f _ s p i n a l section A transection of the s p i n a l cord of the dog at the l e v e l of the foramen magnum does two major things to the physio-l o g i c a l state of the animal; one, i t i n i t i a t e s a period of "spinal shock" of unknown duration; and, two, i t severs the sympathetic central connections while leaving vagal pathways to and from the hindbrain i n t a c t . It i s d i f f i c u l t to assess the f i r s t of these two events, though changes i n heart rate and blood pressure can give us an idea of the v a s t l y altered state with which we are dealing. 42 Immediately following; section of the cord at the l e v e l of the f i r s t c e r v i c a l vertebra i n 10 dogs, the heart rate f e l l d r a s t i c a l l y from a control mean of 123 beats/min. (SEM + 13, range 66-174) to #0 beats/min. (SEM + 11.7, range 43-135), while blood pressure decreased from 139 mmHg (SEM + 2.2, range 128-15?) to 116.7 mmHg (SEM + 10.2, range 60-164). The heart rate change was however not sustained, within a h a l f hour, mean heart rate was even higher than control values, at 135 beats/ min. (SEM + 11.3, range 77-177). Blood pressure, however, continued to f a l l , reaching 86 mmHg (SEM + 5.9, range 58-112). This was a curious phenomena to observe, as the increase i n heart rate seemed to be correlated with the disappearance of "vagal tone". I f c e r v i c a l vagotomy was performed within the period of decreased heart rate, heart rate increase upon section of the nerve could be observed. However, i f the heart rate had s t a b i l i z e d at the 120-150 beats/min. range, c u t t i n g the vagus had l i t t l e e f f e c t on heart rate. Correlated with t h i s loss of "vagal tone" was the absence of the c a r o t i d sinus r e f l e x i n i t i a t e d by occlusion of the common carotid a r t e r i e s . In 22 t r i a l s i n 6 dogs, t h i r t y seconds a f t e r carotid occlusion i n the control period heart rate increased an average of 15 beats/min. (SEM + 5.30, range -19 to + 107.5) as blood pressure increased 18.2 mmHg (SEM + 5.30, range -2 to +32). Approximately one hour a f t e r spinal transection i n these same six dogs, nine t r i a l s of carotid occlusion produced no change i n heart rate (0 beats/min. SEM + 1.39, range -6 to +7.5) while blood pressure increased 5 mmHg. U3 (SEM + 1.34, range +1 to +13). This created some d i f f i c u l t y i n the examination of the l e f t a t r i a l r e f l e x f o r what was presumed to be a D o s s i b l e vagal component. The object was to observe the r e f l e x , a f t e r s p i n a l section, during some degree of steady state, yet within the period of vagal a c t i v i t y . Obviously from the data presented above i t was not possible to meet a l l these conditions. Despite these problems, i n 31 t r i a l s i n 7 dogs, a mean increase i n heart rate during balloon i n f l a t i o n was 6 beats/ min. (SEM + 1.3), while blood nressure decreased-1.7 mrnHg (SEM + 1.0). This increase could be abolished i n a l l cases by c e r v i -c a l vagotomy, or i f s u f f i c i e n t time was allowed to elapse f o r heart rate to reach a steady state i n the 120-150 range, the r e f l e x could be observed to disappear i n approximate c o r r e l a t i o n with the disappearance of "vagal tone". A l l of the above r e s u l t s were obtained from dogs under chloralose anaesthesia. It was thought that i t might be of int e r e s t to oberve the l e f t a t r i a l r e f l e x under the influence of other anaesthetics, and e s p e c i a l l y v o l a t i l e anaesthetics, which might be discontinued upon decerebration. Two a l t e r n a t i v e anaesthetics were used: halothane, and a nitrous oxide-nentothal combination (see Methods, Series V -VI ). The four dogs included i n the halothane study consis-t e n t l y presented us with a condition i n which cardiovascular reflexes were depressed. The ca r o t i d sinus r e f l e x , i n i t i a t e d by occlusion of the carotid a r t e r i e s , was absent or very small i n 44 12 t r i a l s i n the four dogs during the control neriod. Mean changes i n heart rate 20 seconds a f t e r occlusion were -2 beats/ min. (SEM + 1.13, range -9 to +6) as blood pressure increased 2.3 mmHg. (SEM + 0.78, range -2 to +7). The l e f t a t r i a l r e f l e x was nresent, though small, and followed the c h a r a c t e r i s t i c pattern observed previously in chloralose anaesthetized dogs (see table V I ) . Decerebration and the removal of the halothane c i r c u i t altered t h i s picture only s l i g h t l y . The caro t i d sinus r e f l e x was now present. In seven t r i a l s i n 3 dogs, twenty seconds a f t e r carotid occlusion, heart rate increased an average of 6 beats/min. (SEM + 2.26, range -3 to +12) as blood pressure rose 4.7 mmHg.(SEM + 2.68, range -2 to +8). The l e f t a t r i a l r e f l e x was augmented, though not s i g n i f i c a n t l y . Waiting as long as s i x hours a f t e r removal of the anaesthetic c i r c u i t did not change the magnitude or d i r e c t i o n of these responses to carotid occlusion or distension of the pulmonary vein l e f t a t r i a l junction. With nitrous oxide we hoped to avoid t h i s same d i f f i c u l t y of long l a s t i n g depression but the necessity of adding pentothal to achieve a s a t i s f a c t o r y depth of anaesthesia f o r surgery was detrimental. The combination of nitrous oxide and pentothal consistently gave us an animal i n which a high heart rate tended to obscure the l e f t a t r i a l r e f l e x . The more often pentothal was administered, the more severe t h i s problem. During the control period, where heart rate had a mean of 180 beats/min.(SEM + 11.7, range 144-228), the increase i n heart rate to 21 balloon i n f l a t i o n s i n 7 dogs was only 2 beats/min. 45 (SEM + 0.6). Blood pressure changed -3.3 mmHg. (SEM + 1.1). Dis-continuing the nitrous oxide following decerebration did not always change t h i s pattern. In 22 t r i a l s i n 7 dogs, mean re f l e x increase i n heart rate to balloon i n f l a t i o n was 9 beats/ min. (SEM + 1.0), which was s i g n i f i c a n t l y d i f f e r e n t from the control value at 2n 0.01. Blood pressure changes were not s i g n i f i c a n t l y d i f f e r e n t from control changes. Prolonged waiting, up to s i x hours a f t e r removal of nitrous oxide did not a l t e r t h i s resnonse. Propranolol abolished most of the r e f l e x , only 3 beats/min. (SEM + 1.7) remaining i n 15 t r i a l s i n 5 dogs, while c e r v i c a l vagotomy t o t a l l y abolished i t . h6 DISCUSSION A perusal of the r e s u l t s reveals three major areas of concern which merit further discussion: 1) The location of the central synapse f o r the l e f t a t r i a l r e f l e x ; 2) The p o s s i b i l i t y of the existence of a vaeral efferent component; 3) The role of the l e f t a t r i a l r e f l e x i n the unanaesthetized animal. Although the data presented above can not with pr e c i s i o n answer the f i r s t of these questions, they at least t e l l us with a degree of ce r t a i n t y where the central connections of the l e f t a t r i a l r e f l e x are not. Decerebration at the mid-c o l l i c u l a r plane did not s i g n i f i c a n t l y a l t e r the magnitude or neural c h a r a c t e r i s t i c s of the response to pulmonary vein distension (see Table X ) . Thus i t does not seem l i k e l y that structures r o s t r a l to the superior c o l l i c u l u s , such as the hypothalamus, are necessary for the appearance of the f u l l r e f l e x e f f e c t . This leads us to believe that the region of central nervous system (CSN) control i s located either i n the medulla, along with other cardiovascular centers, or, at the spinal l e v e l . The presence of the cardiovascular centers, and the r e t i c u l a r nature of the medulla, with i t s multisynantic i n f i n i t y of connections, serve to prejudice us in i t s favor. More concrete evidence may exist in the work of Calaresu and Henry i n t h e i r study of the e f f e c t s of stimulation 47 of the "parahynoglossal area" (PHA) in the medulla of the c a t 3 (Calaresu and. Henry, 1971). This region of the f l o o r of the fourth v e n t r i c l e includes the hynoplossal i n t e r f a s c i c u l a r n u c l e i , the medial longitudinal f a s c i c u l u s (MLF), and the para-median r e t i c u l a r nucleus (PMRN). Careful nerve degeneration studies by Brodal have demonstrated extensive afferents to the PMF.N. from the f r o n t o - p a r i e t a l cortex, the v e s t i b u l a r n u c l e i , f a s t i g i a l nucleus, the r e t i c u l a r n u clei of the brainstem, and some ascending f i b e r s from the dorsal funiculus of the sp i n a l cord, (Brodal, 1957). Direct projections of carotid sinus nerve f i b e r s have been found to the PMRN. (Homma, Miura, and. Reis, 1970). E l e c t r i c a l stimulation of the PHA i n the cat caused short latency (1-5 seconds) increases i n heart rate and blood pressure e i t h e r simultaneously or s i n g l y . These increases were not effected by decerebration, and could be s i g n i f i c a n t l y de-creased by infusions of propranolol, or abolished by c e r v i c a l vagotomy. Evoked potentials were recorded p e r i p h e r a l l y i n the cardiac sympathetic nerves. Although there i s no evidence that t h i s region i s the s i t e of central synapses f o r the tachycardia observed at distension of the pulmonary veins, the s i m i l a r i t i e s i n the response are s t r i k i n g , and i t would be i n t e r e s t i n g to test the l e f t a t r i a l response a f t e r discrete lesions of the PHA, s p e c i f i c a l l y the PMRN. As to the existence of a sninal control center f o r t h i s r e f l e x , while we cannot deny that such a center may e x i s t , there i s no r e a l evidence supporting such a conclusion. While limited i n scope, the experiments i n series IV showed a 50% 48 reduction in the response to pulmonary vein distension a f t e r section of the cord at the l e v e l of the f i r s t c e r v i c a l vertebra. Admittedly, the d r a s t i c changes i n the p h y s i o l o g i c a l state of the animal a f t e r section, as well as severing central sympathe-t i c connections may explain part of t h i s reduction. However, the f a c t that the tachycardia that remained at balloon i n f l a t i o n seemed to p e r s i s t only as long as vagal a c t i v i t y , and was abolished by b i l a t e r a l c e r v i c a l vagotomy, tends to contra-indicate b e l i e f in a spinal center of c o n t r o l . More controlled experiments regarding spinal mediation of l e f t a t r i a l impulses would be necessary before reaching any assured conclusions i n t h i s case. What the spinal series does do f o r the purpose of these studies, i s to add weight to the evidence i n favor of a vagal efferent component. The f a c t that propranolol, given i n doses s u f f i c i e n t to block 9$% of the p receptor e x c i t a t i o n by i s o -prenaline, could not abolish the response to pulmonary vein distension strongly indicates that the remaining increases in heart rate do not r e s u l t from sympathetic a c t i v i t y . The a l t e r -native explanation, that the balance of the increase could be caused by |» receptors not effected by propranolol i s not l i k e l y . The chance of "wearing o f f " , or incomplete blockage i s slim when using isoprenaline frequently. In addition, the dose of propranolol used, 0.5 mg/Kg TV., i s that recommended as capable o d i s t i n g u i s h i n g sympathetic from parasympathetic a c t i v i t y to the heart, and blocking " c e r t a i n l y more than 75%, and probably more than 90% of changes i n heart rate caused by r e f l e x changes i n sympathetic nervous a c t i v i t y . " (Ledsome e t . a l . , 1Q65). In a l l 49 cases, as seen in tables X and XI, we have over ?$% of the in-crease in heart rate at pulmonary vein distension remaining; after P r o p r a n o l o l . It should be remembered that this figure is a mean of many t r i a l s in many animals; individually, the percent of control response remaining after propranolol varied from 0#-100# (see tableXII). The fact that an increase in heart rate of approximately the same magnitude remains after spinal section at the f i r s t cervical vertebra can only add weight to the in-creasing suspicion that part of the reflex may be mediated by efferent activity in the parasympathetic nerves. Although cardioacceleration caused by the vagus nerve has been reported by Smith, such fibers have been shown to terminate in intracardiac adrenergic ganglia, so presumably they would also be blocked by propranolol, (Smith, 1970). Therefore, i f cardioacceleration caused by the vagus exists, i t must be brought about by the usual mechanism of reducing vagal inhibi-tion. From our records, the earlier claim by Ledsome and Linden that the efferent pathway for the l e f t a t r i a l reflex resides solely in the cardiac sympathetics cannot be supported, (Ledsome and Linden, 1969). Their experiments were performed on only a few animals, and bretylium tosylate chiefly used as a sym-pathetic blocking agent. When in fact propranolol vras used in one dog, a slight increase (2 beats/min.) in heart rate remained upon stimulation of a t r i a l receptors. In a more recent paper,two dogs showed increases of 3# beats/min., and #1 beats/min. at balloon i n f l a t i o n . These increases v/ere reduced to 1? beats/min. {Jlfo of control) and 16 beats/min. (?S)% of control), respective-ly following the administration of propranolol (0.5 mg/Kg.), 1. CHANGE IN HEART RATE AND MEAN BLOOD PRESSURE 30 SECONDS AFTER ISOPRENALINE (0.5 <fg/Kg) Control (n=20) After Block.(n=?0) HEART RATE (beats/min) +90+11 +2+1. ^  BLOOD PRESSURE (mm/Hg) -42+L -1.3+1 2. CHANGE IN HEART RATE AND MEAN BLOOD PRESSURE DURING PULMONARY VEIN DISTENSION Control (n=l3) After Block.(n=l8) HEART RATE (beats/min) +23+3 +6+1.2 BLOOD PRESSURE (mm/Hg) -2.2+0.8 -0.7+0.7 TABLE X. ABILITY OF PROPRANOLOL (0.5 mg/Ktr) TO BLOCK EFFECT OF ISOPRENALINE AND THE RESPONSE TO PULMONARY VEIN DISTENSION. HEART RATE (beats/min) BLOOD PRESSURE (mm/Hg) Control (n=5*) +^0+l. 86 -1.4+0.57 After Decerebration +24+2.46 +0.4+0.57 After Decerebration + $ -Blockade(n=33) +9+0.95 +0.5+0.34 After Decerebration + J-Blockade + Vagotomy (n=44) -0.1+0.31 -2.3+0.72 TABLE XI. EFFECTS OF DECEREBRATION,$ -BLOCKADE, AND VAGOTOMY ON THE CHANGES IN HEART RATE AND BLOOD PRESSURE CAUSED BY DISTENSION OF THE PULMONARY VEINS. 52 AFTER PROPRANOLOL AFTER PROPANOLOL AND DECEREBRATION INITIAL HEART RATE (beats/min) % RESPONSE INITIAL HEART RATE (beats/min) % RESPONSE 119 59 130 100 30 100 114 25 114 45 64 77 144 0 144 6 57 25 74 27 92 37 72 50 34 31 30 33 130 3 160 49 35 56 54 41 SERIES I SERIES I I I TABLE XII. PERCENT OF CONTROL RESPONSE TO PULMONARY VEIN DISTENSION REMAINING AFTER J> BLOCKADE WITH PROPRANOLOL (0.5 mg/Kg.IV). ( v% Resnonse" eauals the percent of the control increase i n heart rate at pul-monary vein distension remaining a f t e r ^ blockade.) 53 (Carswell e t . a l . , 1970.). These amounts are s i m i l a r to those ob-served i n ^he decerebrate studies, and the increases remaining a f t e r spinal section. I f we accent propranolol as a r e l i a b l e 3^ blocking agent, and the spinal section as a means of d i s t i n g u i s h i n g vagal]y mediated responses, then we can accent the f a c t that a vagal efferent component f o r the l e f t a t r i a l increase i n heart rate may e x i s t . C e r t a i n l y we have not proved that such a component e x i s t s . The f a c t that bretylium tosylate which blocks post-ganglionic adrenergic neurons, can t o t a l l y abolish the increase in heart rate at pulmonary vein distension, i s a formidable argument against such a component. Despite the prolonged sympathomimetic actions of bretylium, "vagal tone" i s markedly present a f t e r subsidence of sympathetic e x c i t a t i o n , as evidenced by the vigorous carotid sinus and lung stretch r e f l e x e s , (Ledsome and Linden, 1964). It i s also possible that propranolol, a competitive i n h i b i t o r of norepinephrine, may allow high l o c a l concentrations of norepinephrine to accumulate. In such a case, the amount might be s u f f i c i e n t to permit sympathetic e x c i t a t i o n , yet not detectable by isoprenaline. Bretylium, which blocks the release of norepinephrine would obviate t h i s problem, and perhaps provide more complete blockade. It would be useful to observe the e f f e c t s of bretylium tosylate on the percent of the response remaining i n the decerebrate preparation a f t e r blockade with propranolol. As noted above, the percent of control increase i n heart rate remaining a f t e r <6 blockade with propranolol may vary widely i n a group of dogs. However, i n any one dog, the amount 54 tends to stay r e l a t i v e l y the same both i n the in t a c t and decere-brate animal. It i s l i k e l y that t h i s could r e s u l t from the degree of "autonomic tuning" e x i s t i n g in a s p e c i f i c animal at a s p e c i f i c time. I f we suppose that two possible efferent path-ways f o r heart rate increases i n i t i a t e d by l e f t a t r i a l receptor stimulation might function, the predominance of e i t h e r pathway at any one time might r e s u l t from the i n i t i a l l e v e l of heart rate and blood pressure at the moment of stimulation and the r e l a t i v e contribution of sympathetic or parasympathetic a c t i v i t y to that l e v e l . Animal In the unanaesthetized decerebrate dog, the l e f t a t r i a l r e f l e x appears much reduced as compared to i t s magnitude in the chloralose anaesthetized i n t a c t or decerebrate dog. Whether t h i s i s the r e s u l t of an exaggerated appearance with chloralose, or a depressed appearance with halothane or nitrous oxide and pentothal cannot be determined. C e r t a i n l y v o l a t i l e anaesthetics have been known to depress cardiovascular function, while chloralose i s famous f o r potentiation of spinal r e f l e x a c t i v i t y , v i z "chloralose jerks". In our own experiments, the v o l a t i l e anaesthetics produced a condition i n which the carotid sinus r e f l e x as well as the l e f t a t r i a l response to balloon i n f l a t i o n , was very small or even absent. Blood pressure could be lowered or raised at w i l l by simply a l t e r i n g the depth of anaesthesia, i n d i c a t i n g a powerful involvement i n cardiovascular events. Recovery from anaesthesia, as judged by the return of rapid, normally patterned re f l e x e s , i . e . carotid sinus r e f l e x , 55 wa? slow. Indeed, while i t i s d i f f i c u l t to believe that the e f f e c t s of halothane or nitrous oxide could l i n g e r beyond one half hour a f t e r removal of the anaesthetic c i r c u i t , recovery of normal reflexes sometimes took up to six hours. Perhaps a l l that can be stated at present i s that the increase i n heart rate brought about by pulmonary vein distension, does appear i n a v a r i e t y of circumstances; i . e . the chloralose anaesthetized i n t a c t or decerebrate dog, the halothane or N^O-nentothal anaesthetized i n t a c t dog, and the unanaesthetized decerebrate dog. Cardiovascular Reflexes and CMS Integration Returning to the larger picture of cardiovascular control and the r o l e of l e f t a t r i a l receptors i n p a r t i c u l a r , these r e s u l t s can be interpreted i n a broader manner. As noted previously, the current view of the central cardiovascular control mechanism consists of a medullary cardiovascular center, r e t i c u l a r i n nature, and receiving multiple inputs from s p i n a l , c o r t i c a l , c e r e b e l l a r , and receptor neurons. The output at any one time i s the r e s u l t of the entire input from a l l sources and the degree of integration that takes place. Increasingly, the importance of t h i s concept of integrative control i s being ap-preciated as the key to the extensive range of cardiovascular adjustments possible i n normal and emergency s i t u a t i o n s . The r e l a t i v e l y r i g i d barorecentor-vasomotor center system previously envisioned simply cannot explain the d i v e r s i t y of reactions possible. While the newer understanding i s a t t r a c t i v e f o r i t s f l e x i b i l i t y and range of responses, i t i s d i f f i c u l t to approach 56 experimentally. Recently, some idea of the type of differentiated out-nut that is P o s s i b l e with this system was demonstrated by Oberg and White (1970). Measuring rapid phasic shifts in blood flow by plethysmography, they examined the kinds of responses resulting from interruption or stimulation of either cardiac vagal or carotid sinus afferents. Interruption of the cardiac vagal afferents by a cold block of the cervical vagi in a dog with sectioned aortic nerves resulted in tachycardia and i n -creased renal blood flow resistance. A lesser increase in muscle blood flow resistance was also recorded. However, reducing baroreceptor inputs by carotid occlusion in the same animal caused l i t t l e change in heart rate with predominant effects on the resistance to flow in skeletal muscle. Similar ouantitati-vely differentiated responses were observed unon e l e c t r i c a l stimulation of the vagal afferents or carotid sinus nerve. Decreases in heart rate and vasodilatation in the renal bed predominated at stimulation of the cervical vagi, while baro-receptor stimulation brought large changes in skeletal muscle blood flow, with later, less significant reductions in both heart rate and renal flow. Such a dist i n c t l y differentiated response pattern would not be possible without a reticular multisynantic neuron pool capable of a high degree of integration. The extent of overlap P o s s i b l e with such an arrangement is exemplified by the work of Calaresu and Thomas (1971). Stimu-lation of the paramedian reticular nucleus could inhibit sympa-thetic drive in anaesthetized, intact or decerebrate vagotomized cats, causing bradycardia. However, i f both vagi were intact, 57 stimulation of the same structure caused increases in heart rate. Such r e s u l t s led to the suggestion that two neuron pools might e x i s t within the D M R N ; one exerting an i n h i b i t o r y i n -fluence on sympathetic a c t i v i t y , the other an i n h i b i t o r y i n -fluence on parasympathetic a c t i v i t y . Whatever the s p e c i f i c orga-n i z a t i o n of t h i s nucleus may be, these r e s u l t s emphasize the fact that all-or-none type massive i n h i b i t i o n or e x c i t a t i o n to a l l segments of the cardiovascular system are probably not usually the case. The response to stimulation of the l e f t a t r i a l receptors by pulmonary balloon i n f l a t i o n , i n which primary e f f e c t s are ob-served on heart rate and renal volume control mechanisms no longer seems untenable i n the l i g h t of such an understanding of c e n t r a l cardiovascular c o n t r o l . Although a report of vascular peripheral resistance changes at pulmonary balloon i n f l a t i o n has been published, (Edis, Donald and Shepherd, 1970) the stimulus applied to a t r i a l receptors could not have been comparable to our own. They observed large changes i n a o r t i c blood pressure as well as e i t h e r bradycardia or tachycardia, depending upon the control heart rate. Pulmonary vein distension by our methods has consistently given tachycardia with i n s i g n i f i c a n t f l u c t u a t i o n s in a r t e r i a l blood pressure from a l l l e v e l s of control heart rate. It has been previously demonstrated that t h i s increase i n heart rate i s not accompanied by a l t e r a t i o n s i n peripheral vascular resistance i n the hind limbs, ( C a r s w e l l , Hainsworth, and Ledsome 1970). From the decerebration studies, i t seems l i k e l y that the d i f f e r e n t i a t i o n of t h i s response i s carried out at a medullary l e v e l , and i s not c o r t i c a l l y or hypothalamically imposed. This 53 i s somewhat s u r p r i s i n g as t h e o n l y o t h e r r e p o r t o f d i s c r e t e c a r d i o a c c e l e r a t i o n unaccompanied by changes i n b l o o d p r e s s u r e o r c a r d i a c c o n t r a c t i l i t y was t h a t produced by s t i m u l a t i o n o f p o i n t s i n t h e hypothalamus (Fang and Wang, 1 9 6 ? ) . The p r e c i s e l o c a l i z a t i o n o f t h e c e n t r a l m e d u l l a r y synapses o f the l e f t a t r i a l r e f l e x r e s p o n s e t o pulmonary v e i n d i s t e n s i o n must a w a i t more d e t a i l e d s t u d i e s o f a c t i v i t i e s i n t h e f l o o r o f the f o u r t h v e n t r i c l e d u r i n g r e c e p t o r s t i m u l a t i o n . S i m i l a r l y , t h e p o s s i b i l i -t y o f t h e e x i s t e n c e o f a v a g a l e f f e r e n t component r e q u i r e s b o t h p h a r m a c o l o g i c a l and t i m e c o u r s e a n a l y s e s f o r s u b s t a n t i a t i o n . P r i m a r i l y t h e n t h e s e r e s u l t s have s e r v e d t o r e d i r e c t o u r a t t e n -t i o n s once more t o t h e " i n t e g r a t i v e a c t i o n o f the nervous system" Perhaps when we r e a l i z e t h e d e t a i l s o f c e n t r a l o r g a n i z a t i o n o f b o t h t h e low p r e s s u r e and h i g h p r e s s u r e system r e c e p t o r s , t h e i r f u n c t i o n i n c a r d i o v a s c u l a r h o m e o s t a s i s i n h e a l t h and d i s e a s e w i l l be f u l l y a p p r e c i a t e d . 59 BIBLIOGRAPHY Alexander, Robert S., (1946). Tonic and Reflex Function of Medullary Sympathetic Cardiovascular Centers. J. Neurophys. 9, 205-217. Albrook, S.M., and Ledsome, J.R. , (1971). 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