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The vascular role of vasopressin and sympathetic nervous system Tabrizchi, Reza 1986

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THE VASCULAR ROLE OF VASOPRESSIN AND SYMPATHETIC NERVOUS SYSTEM By REZA TABRIZCHI B.Sc.  (Hon.), Sunderland Poly, 1983  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE  in THE FACULTY OF GRADUATE STUDIES Department of Pharmacology & Therapeutics, Faculty of Medicine  We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH COLUMBIA April 1986 ©Reza T a b r i z c h i , 1986  In  presenting  requirements  this for  thesis  an  of  British  it  freely available  agree for  that  by  for  understood  that  his  that  reference  for  or  be  her  at  the  shall  and  study.  I  copying  granted  be  by  the  allowed  of  Pharmacology & T h e r a p e u t i c s  The U n i v e r s i t y o f 1956 Main M a l l Vancouver, Canada V6T  Date  >E-6  (3/81)  1Y3  15 A p r i l  1986  British  Columbia .  v  make  further this  head It  without  Reza T a b r i z c h i  of  of  this  permission.  Department  the  Library  publication  not  of  University  representatives.  or  shall  fulfilment  the  extensive  may  copying  f i n a n c i a l gain  degree  agree  purposes  or  for  I  permission  department  partial  advanced  Columbia,  scholarly  in  thesis  of  my  is  thesis my  written  - ii  -  ABSTRACT  The aim of my study was to  investigate  the  influence  of arginine vaso-  pressin (AVP) and the sympathetic nervous system in the control of peripheral  resistance  and  to  examine  the  constrictor  actions  of  various  pressor  agents in capacitance vessels. In the f i r s t set of experiments, the vascular e f f e c t of AVP in the presence and absence of  influence  from angiotensin  II  (Ag II)  or a-adrenergic  system was investigated in pentobarbital  anaesthetized r a t s .  (CO) and the d i s t r i b u t i o n of blood flow  (BF) were determined by the micro-  spheres  technique  antagonist (I),  prior  to  and following  an AVP pressor  of  rats:  saline-treated  saralasin-treated  (II) and phentolamine-treated  (III).  The AVP antag-  in  onist decreased MAP and TPR in a l l  three  muscle and s k i n .  Groups  Groups and i t  effect in Groups II and III than in I. BF to the stomach and skin.  injection  output  of  [d(CH2)gTyr(Me)AVP]  the  Cardiac  caused a greater depressor  In Group I, AVP antagonist  increased  In Group I I , AVP antagonist increased BF to the  In Group I I I , AVP antagonist markedly increased BF to the  muscle. The second set of experiments investigates the physiological role of the a-adrenoceptors rauwolscine CO and i t s  in the  vasculature.  (c^-blocker) distribution  The effects  and phentolamine were investigated  of  prazosin  (a-^-blocker),  (nonselective a-blocker) in  halothane  anaesthetized  A l l three a-antagonists caused similar decreases of MAP and a l l % d i s t r i b u t i o n of CO to the lungs and muscle.  on MAP, rats.  increased of  During the infusion of prazo-  sin,  TPR was decreased but CO was not  creased  but  TPR was not  phentolamine. receptors,  it  Since  altered  during  CO was reduced  appears that  changed. the  after  receptors  In  contrast,  infusions  the  of  blockade  CO was de-  rauwolscine  of  (*2 but  are responsible for  and  not a-^  the control  of  venous capacitance. A final of  various  rats.  We  set of experiments were carried out to vasoconstrictor investigated  (a^-agonist), a-agonist),  B-HT 920  agents  the  on the  capacitance  dose-response  (c^-agonist),  investigate  relationships  noradrenaline  AVP and Ag II on MAP, mean c i r c u l a t o r y  and heart rate but not s a l i n e ,  (HR) in conscious r a t s .  vessels  B-HT  <*2 adrenergic tone.  actions  conscious  methoxamine non-selective  pressure (MCFP)  all  the agonists,  caused dose-dependent increases in MAP and decreases in HR.  The infusions of saline and methoxamine did not affect sions of  (NA,  of  of  of  filling  The infusions  the  920, NA and Ag II agonists  and Ag  increased MCFP. II  are  involved  MCFP while the  Therefore, in  the  infu-  receptors  control  of  for  venous  -iv TABLE OF CONTENTS CHAPTER  Page  1 INTRODUCTION 1.1 1.2 1.3 1.4  Renin-angiotensin system Vasopressin Sympathetic Nervous System Nature of the problem  2 MATERIALS AND METHODS 2.1 2.2 2.3 2.4 2.5 2.6  Surgical preparation of rats Microspheres Experimental protocol Drugs Calculations S t a t i s t i c a l analyses  3 RESULTS 3.1 3.2 3.3 3.4 3.5  Effect of antagonisms of pressor systems on MAP, CO and TPR Effect of AVP antagonist on MAP, CO and TPR Effect of AVP antagonist on the d i s t r i b u t i o n of BF S e l e c t i v i t y of prazosin and rauwolscine Effects of rauwolscine, prazosin and phentolamine on BP, CO, TPR and the d i s t r i b u t i o n of CO 3.6 Effects of methoxamine, B-HT 920 noradrenaline, angiotensin II and vasopressin on MCFP 4 DISCUSSION 4.1 Summary 5 REFERENCES  1 2 8 14 18 21 21 23 24 27 27 28 29 29 29 38 41 43 45 60 68 70  - V -  LIST OF TABLES TABLE  Page  1  Control values of mean a r t e r i a l pressure, cardiac output and total peripheral resistance in Group I, II and I I I .  30  2  Effect of vasopressin antagonist on mean a r t e r i a l pressure, cardiac output and total peripheral resistance in Groups I, II and I I I .  35  3  Control of mean a r t e r i a l pressure, mean c i r c u l a t o r y f i l l i n g pressure and heart r a t e .  51  - vi LIST OF FIGURES FIGURE  Page  1  Effect of AVP antagonist on MAP, CO and TPR in anaesthetized, s u r g i c a l l y stressed r a t s : intact and s a l i n e pretreated (Group I ) , saralasin-pretreated (Group II) and phentolamine-pretreated (Group I I I ) .  31  2  Effect of AVP antagonist on regional d i s t r i b u t i o n of BF in rats from Group I (saline-pretreated).  33  3  Effect of AVP antagonist on regional d i s t r i b u t i o n of BF in rats from Group II (saralasin-pretreated).  36  4  Effect of AVP antagonist on regional d i s t r i b u t i o n of BF in rats from Group III (phentolamine-pretreated).  39  5  Tracings of two typical experiments showing the s e l e c t i v i t y of prazosin (a) and rauwolscine (b) in antagonizing pressor responses to iv injections of methoxamine and B-HT 933 in pentobarbital anaesthetized r a t s .  42  6  Effect of rauwolscine, phentolamine and prazosin on MAP, CO and TPR in halothane anaesthetized r a t s .  43  7  Effect of rauwolscine on regional d i s t r i b u t i o n of BF in anaesthetized rats  44  8  Effect of phentolamine on regional d i s t r i b u t i o n of BF in anaesthetized r a t s .  46  9  Effect of prazosin on regional d i s t r i b u t i o n of BF in anaesthetized r a t s .  47  10  Effect of rauwolscine on % d i s t r i b u t i o n of CO in anaesthetized r a t s .  48  11  Effect of phentolamine on % d i s t r i b u t i o n of CO in anaesthetized r a t s .  49  12  Effect of prazosin on % d i s t r i b u t i o n of CO in anaesthetized rats.  50  - vii  -  FIGURE  Page  13  MAP, HR and MCFP during the infusion of normal saline at d i f f e r e n t rates.  52  14  Dose-respones curves of MAP for methoxamine, B-HT 920, NA, AVP and Ag I I .  53  15  Dose-respones curves of HR for methoxamine, B-HT 920, NA, AVP and Ag I I .  56  16  Dose-response curves of MCFP for methoxamine, B-HT 920, NA, AVP and Ag I I .  58  - viii  -  ABBREVIATIONS Angiotensin = Ag Arginine Vasopressin = AVP Blood Flow = BF Cardiac Output = CO Final A r t e r i a l Pressure = FAP Heart Rate = HR Mean A r t e r i a l Pressure = MAP Mean Circulatory F i l l i n g Pressure = MCFP Noradrenaline = NA Plasma Renin A c t i v i t y = PRA Total Amount of Radioactivity = cpm Total Peripheral Resistance = TPR Venous Plateau Pressure = VPP  - ix ACKNOWLEDGEMENTS The  author  excellent  wishes  advice,  to  thank  Dr.  Catherine  supervision and guidance.  Cheuk  Ying  Pang  The contributions  for  her  made by her  are gratefully acknowledged. The author also wishes to thank a l l  the other members of the Department  of  Pharmacology & Therapeutics who offered  L.  Jan  for  secretarial  assistance  and Mr.  advice Glenn  and guidance, Collins  for  Ms.  Elaine  statistical  analysis. While this work was carried out, the author was a recipient of a B r i t i s h Columbia Heart Foundation Research Traineeship, and would l i k e to thank the BCHF for their f i n a n c i a l  support.  1 INTRODUCTION The  role  of  the  peripheral  circulation  in  the  maintenance  of  homeostasis is of great importance, the maintenance of a suitable and stable  environment  Bernard  (1885-86)  for  the tissue;  characterized  cardiovascular system.  the  it,  "milieu  is  the  interieur"  primary  as  function  Claude of  the  The supply of nutrient, oxygen, the removal of  waste products, bulk transport between organs, maintenance of a normal tissue  fluid  volume and f a c i l i t a t i o n  of  food absorption  are among a  number of functions ascribed to the c i r c u l a t i o n . A number of factors control  the c a l i b r e of the blood vessels and,  hence, the c i r c u l a t i o n of blood through the tissues which i t supplies. Nervous, thermal, hormonal, metabolic and myogenic influences  consti-  tute  may be  the  most  important  of  these  factors  affected by any, or a l l , of these stimuli  and blood  vessels  in varying degrees  in  dif-  ferent circumstances; the ultimate stimulus to which the smooth muscle of  the  vessel  responds,  however,  is  a chemical  that have been reported to participate  one.  Three  systems  in the maintenance of vascular  tone are: the renin-angiotensin, arginine vasopressin (AVP) and sympathetic nervous systems (SNS). Knowledge  of  the  interrelationship  of  these  systems  with  each  other, and their interactions with other systems, are s t i l l  at a r u d i -  mentary stage and, to say the l e a s t , are poorly understood.  For exam-  ple, i t has been reported that AVP is involved, in varying degrees, in the aetiology of various pathophysiological  conditions  such as deoxy-  corticosterone/salt hypertension, (Ben, et a l . , 1984; Crofton, et a l . ,  2  1980; Mohring, et a l . , 1978a; Mohring, et a l . , 1977; Mohring, et a l . , 1978b),  acute  (Arnauld  et  al_.,  1981), adrenal al.,  renal  failure  1977;  (Hofbauer,  Cousineau  insufficiency  et  al_.,  derangements  of  al  1977),  1973;  hemorrhage  Fyhrquist  et  al_.,  (Ishikawa and Schrier, 1984; Schwartz, et  1983) and congestive heart f a i l u r e  tainly,  et  multiple  (Uretsky, et a l . , 1985).  systems  in  addition  to  Cer-  vasopressin  occur in these conditions. The aim of my research was to consider and sympathetic nervous systems  in  ever,  discuss  it  may be appropriate  to  the  the vascular roles  peripheral  of AVP  circulation.  the vascular  three vasopressor systems, and consider the conditions  roles  How-  of  that  these  alter  the  a c t i v i t i e s of these systems. 1.1  Renin-angiotensin system The  first  group  investigators of Goldblatt  of  people  who  a pressor role for  and his  co-workers  caught  the  attention  the renin-angiotensin  in 1934.  The description  of  system was  given at  time by these investigators was in essence the existence of genous pressor substance released from the renal artery  was  to  hypertension.  be  constricted,  it  subsequently  modern  that  an endo-  system; i f  the renal  produced  persistent  E a r l i e r , Tigerstedt and Bergman (1898) had described a  substance of renal origin which caused the elevation of blood pressure and  it  was  later  realized  that  the  substance  of  renal  origin  was  actually an enzyme, "renin", which activated the formation of an endogenous pressor substance from a precursor in the blood.  It was Braun-  Menendez et a l . (1940) and Page and Helmer (1940) who showed that the  3 c a t a l y s i s of a blood protein in v i t r o by renin would lead to the f o r mation of a potent  pressor agent which was also  found in  effluent  the  substance  blood  of  ischemic  kidneys.  This  the venous was  later  named angiotensin (Ag) (Braun, Menendez and Page, 1958). In order to determine the Ag levels in the blood, one t r a d i t i o n a l ly  measures  the  plasma  renin  concentration  released from the juxtaglomerular can be divided into four d i s t i n c t  or  activity.  (JG) apparatus,  a structure  parts: 1) granular c e l l s ,  densa c e l l s , 3) agranular c e l l s and 4) mesangial c e l l s Barajas and Lata, 1963).  Renin  (Barajas, 1964;  The c e l l s which are responsible for the synwhich are  b a s i c a l l y smooth muscle c e l l s found in the media of the renal Lying  close  to  granular  JG c e l l s  c e l l s , which are either columnar or cuboidal. JG are composed of in  some areas,  the walls of afferent  the  which  2) macula  thesis and the storage of renin are the granular JG c e l l s ,  arterioles.  is  agranular  JG  cells  are  the  afferent  macula densa  The c e l l s of agranular  and efferent completely  arterioles  replace  and  vascular  smooth muscle c e l l s lying in close contact with the macula densa c e l l s . The c e l l s of the JG apparatus which form the extension to the glomerulus  are the mesangial  cells  (Barajas,  1964;  Barajas  and Lata, 1963;  Biava and West, 1966). Renin,  an  enzyme  of  approximately  40,000  molecular  weight,  is  released into the c i r c u l a t i o n from the granular JG c e l l s that l i n e the afferent glomerular a r t e r i o l e s . tensinogen to form Ag I,  It cleaves the leu-leu bond of angio-  a decapeptide.  bulin which is synthesized in the l i v e r ,  Angiotensinogen, is  largely  an o^-glo-  present  in blood  4  and other e x t r a c e l l u l a r space.  The carboxyl  terminal His-Leu of Ag I  is cleaved by Ag converting enzyme (kininase octapeptide.  This  reaction  takes  place  in  II) to y i e l d the  vascular  Ag II,  an  endothelium  and the catalysis has been shown to be retarded by low pH and lack  of  calcium ions.  is  acted  Ag I has limited pharmacological  upon by another  enzyme,  angiotensinase  properties. A,  to  Ag II  form Ag  III,  a  heptapeptide which has been shown to be p h y s i o l o g i c a l l y  and pharmaco-  logically  (McCaa, 1978;  Toda et  less al.,  active 1978).  as a vasoconstrictor  than Ag II  However,  II  Ag III  and  are  equi-effective  in  stimulating the secretion of aldosterone. Ag II has a h a l f - l i f e of 30 sec in the blood and i t s synthesis dependent  on  the  amount  of  circulating  renin.  It  is  important  understand the mechanisms which affect renin release, since the of c i r c u l a t i n g Ag II is primarily dependent upon plasma renin There are a number of  physiological  concentration of renin. Primarily,  pressure controls  the plasma  Tobian et a l . (1959) showed that mean renal the release of  dogs (with non-functional  renin.  Later,  affer-  perfusion  Blaine et a l .  (1970)  in conscious  macula densa system) lead to an increase in  plasma renin a c t i v i t y  (PRA).  if  arterioles  afferent  level  levels.  baroreceptors located in the  showed that hemorrhage and suprarenal aortic constriction  the renal  to  These can be divided into three main classes.  there are the internal  ent a r t e r i o l e s .  factors which control  is  The l a t t e r  authors have also shown that  are dilated  hage-induced renin secretion is prevented.  by papaverine,  Later,  the level  haemorrof pros-  taglandins was shown to affect the baroreceptor-mediated renin release:  5 blockade of to  renal  prevent  prostaglandins  synthesis by indomethacin was shown  baroreceptor-mediated  (Blackshear et  al.,  1979).  increase  Overall,  in  renin  secretion  there appears to be two mechan-  isms by which baroreceptors-mediate the release of renin: cal change in afferent a r t e r i o l e s  (Tobian, 1962) and ( i i )  (i)  physi-  a change in  the amount of renal prostaglandins (Blackshear and Wathen, 1978). Secondly,  the  renin release. the  afferent  autonomic nervous  Noradrenergic arteriole  innervation  near  the  Barajas et a l . , 1977; Barajas renal  nerves  circulation  granular  and Muller,  has been shown to (Vander, 1965).  system has is  been  shown to  present JG  in  cells  1973).  affect  the walls  (Barajas,  1964;  The stimulation  cause the release of  renin  of  into  of the  It has been shown that renin release, as  a r e s u l t of renal nerve stimulation, can be inhibited by the B-adrenoceptor antagonist  propranolol  (NA) infusion  into  (Ueda et  1970).  al.,  (Loeffler et a l . ,  1972).  Noradrenaline  anaesthetized dogs has been shown to This  action  increase PRA  was prevented by propranolol,  not by the a-adrenoceptor antagonist,  Two other  systems  have been implicated as influencing the release of renin via  altera-  tion  of  receptors acute  activities in  carotid  of  the  the carotid sinus  autonomic  sinus  area  dibenamine.  but  nervous  system:  (Cunningham et  hypotension was shown to  (i)  al.,  produce  the  baro-  1973) where  an increase  in  PRA, and ( i i ) the l e f t a t r i a l  low-pressure receptors, which respond to  volume changes (Zehr, 1976).  In this  case, an increase in blood v o l -  ume which resulted in mechanical distension of the l e f t  atrial-pulmon-  ary region was reported to cause a decrease in PRA (Zehr, 1976).  This  6 decrease in PRA was prevented by renal denervation or b i l a t e r a l cal  vagotomy.  fibres  cervi-  Thus, renin release can be modified by afferent  arising from the  cardiopulmonary region.  sory f i b r e s constitute the afferent  sympathetic  nerve  1978).  been  to  Acetylcholine  has  release from rat renal s l i c e acetylcholine may affect  shown  in v i t r o  renin  These afferent  limb of a reflex arc that  renin release via efferent  fibres  have  no  indirectly  sen-  affects  (Thames et effect  on  (DeVito et a l . 1970).  release  vagal  al., renin  However,  by changing sodium  excretion (Itskovitz and Campbell, 1976) or adrenergic neural  activity  (Loffelholz and Munscholl, 1969). The f i n a l mechanism that affects renin release involves the macula densa segment.  Brown et  al.  (1963)  leads to the elevation of PRA in man.  observed  that  sodium  depletion  This observation led Vander and  Luciano (1967) to suggest that a decrease in tubular sodium concentration Other  in  the  region  investigators  related  to  of  the macula densa stimulates  have also  sodium transport  shown that at  the  renin  renin  release  macula densa area  is  secretion. inversely  (Churchill  et  a]_., 1978; Freeman et a l . , 1974; Nash et a l . , 1968; Meyer et al .1973). However, some investigtors have proposed an opposing hypothesis:  renin  release is related to sodium transport at the macula densa area (Meyer et a l . , 1968; B i r b a r i , 1972).  In many of these studies loop d i u r e t i c s  (furosemide or ethacrynic acid) were used to increase the transport of sodium to the macula densa area. these  diuretics,  the concentration  it of  was concluded  Since renin release was increased by that  sodium present  at  renin release was related the macula densa area.  to  How-  7 ever, i t has been shown that both these diuretics port at the macula densa c e l l s fore,  these  signaling  drugs  could  mechanism  whether sodium is  have  of  the  (Schnerman et prevented  macula  the  densa  for example,  the release of  al.,  1976)  generation  cells.  It  and,  of is  there-  the  ionic  not  clear  the only ion sensed by the macula densa c e l l s ;  seems that there are species differences In r a t s ,  i n h i b i t ionic trans-  it  renin  appears  that  in  it  the signaling mechanism.  chloride  by the macula densa c e l l s  ions  are  involved  (Galla et  al.  in  1977;  Kotchen et a l . , 1976). The most important by-product of renin's a c t i v i t y is Ag I I . has a very short h a l f - l i f e 1967) and i t s hence,  the  continued  release  pharmacological  of  (30 sec)  prodution renin.  actions.  in the blood is  Ag  The most  (Ferreira and Vane,  dependent on the presence and,  II  has  diverse  important  of  physiological  which  constriction of the a r t e r i o l e s to maintain a r t e r i a l tion of the adrenal  Ag II  cortex to enhance the synthesis  include  and vaso-  pressure, stimulaand secretion  of  aldosterone, a mineralocortcoid, and stimulation of JG c e l l s to modulate renal hemodynamics and renin secretion.  Ag II also has a direct  vasoconstrictor action on the resistance blood vessels and an indirect effect al.,  on a r t e r i o l e s  1972).  by the stimulation  Stimulation of  of NA release  the synthesis  (Zimmerman, et  and release of  aldosterone  enhances the reabsorption of sodium ions and the excretion of sium and hydrogen ions by the d i s t a l aldosterone  release,  renal tubule.  stimulation  of  Ag II plays  the control  of sodium balance and blood volume.  potas-  Therefore, by the  an indirect  role  in  Ag II also increases  8  cardiac c o n t r a c t i l i t y  (Blumberg et a l . , 1975; Koch-Weser 1965) d i r e c t -  ly and i n d i r e c t l y by the enhancement of NA release 1975; Starke, 1970). been  defined,  to  (Blumberg et  al.,  The actions of Ag II on the venous bed has not  this  end controversies  experiments have shown that  i.v.  or  appear  to  intra-arterial  exist.  In  vivo  administration  of  Ag II has negligible effect on small and large veins of the limb and splanchnic  area (Folkow et  al.,  1961; Rose,  1962).  On the  contrary,  Ag II has been shown to cause contractions on isolated veins 1965; Somylyo and Somlyo, 1966).  (Sutter,  It is not clear at a l l whether Ag II  contributes to the maintenance of venous tone. 1.2  Vasopressin The primary role of AVP, also known as a n t i d i u r e t i c  hormone, was  f i r s t described by Verney (1947) to be in the conservation of water in the body. cular  AVP is synthesized primarily in the supraoptic,  and suprachiasmatic  nuclei  of  the  hypothalmus  paraventri-  (Zimmerman  and  Defendi, 1977; Choy and Watkins, 1977; Dierickx and Vandesanale, 1977) and is stored in the neurohypophysis.  The anatomy of the hypothalamic  neurohypophyseal tract consists of perikarya which are located specific  hypothalamic  nuclei.  Their  axons  which  traverse  in to  the the  supraoptic hypophyseal tract terminate in the median eminence and pars nervosa of the neurohypophysis. The hypothalamo-hypophyseal the study of  system has become a useful  secretory mechanisms for  phases have been defined: neurosecretory granules,  synthesis  of  model  the release of hormones. the molecule,  transport to the s i t e  of  packaging  release  for Four into  and subse-  9 quent release (Pickering, 1978). mechanism of  AVP release  (Pearson,  1977).  taneously  possibly  has  Most of the evidence concerning the  come from studies  Vasopressin and neurophysin from precursors  are  neurons simul-  al.,  1977,  Brown-  calcium-dependent  (Thorn  et a l . , 1978) and probably involves exocytosis Impulses coming from "osmoreceptors"  cultured  synthesized  (Brownstein  stein and Gainer, 1977) and their release is  of  et  (Thorn, et a l . , 1978).  to stimulate  the supraoptic  and  paraventricular area lead to the depolarization of the nerve membrane and ultimately  the release of  AVP  (Thorn et  al_., 1978;  Grastzl,  et  al_., 1977; Theodosis et a l . , 1977). The physiological  stimuli for the release of AVP are divided  two major categories: plasma  level  al_.,1976). osmolality  of The  ( i ) osmotic and ( i i )  AVP in  man is  secretion  (Landgraf  of  about  AVP  and Gunther,  Woods and Johnstone, 1983).  is  0.5  non-osmotic. to  affected  1983;  5 pg/ml  into  The normal  (Robertson  by changes  in  Szsczepanska-Sadowska,  However, in pathophysiological  et  plasma 1972;  conditions  such as hemorrhage and surgery very large amounts of AVP (as much as 40-fold above physiological  levels) were shown to be released.  Thus,  non-osmotic factors also affect the release of AVP. In 1947, Verney suggested that  a change in plasma osmolality was  the major contributor to the release of AVP. mechanism for  the release of  AVP was that  responded to changes in osmolality ( i . e . , lar  fluid.  accepted  for  The over  osmoreceptor three  hypothesis  decades.  His description of  of  an osmoreceptor  the  which  t o n i c i t y ) of the e x t r a c e l l u put  However,  forward  by  a significant  Verney was number  of  10 observations  involving  administrations  of  intracarotid  hypo- or  and/or  hypertonic  intracerebro-ventricular  solutions  to  animals  during  antidiuresis or water diuresis were inconsistent with the osmoreceptor hypothesis  proposed by Verney.  mechanism: tricular  In  1978,  Anderson  postulated  a new  the release of the hormone was controlled by a juxta-ven-  sodium sensitive  system.  Bie  (1978) produced evidence con-  sistent with both hypotheses of receptors concentration of sodium.  sensitive  to osmolality  or  McKinley et a l . (1978) proposed a compromise:  the existence of dual osmoreceptor-sodium sensor systems.  It was sug-  gested that, perhaps, the osmoreceptors are located in areas where the blood-brain-barrier supraoptic c r e s t .  is  lacking  such  as  the  sub-fornical  organs  and  The sodium sensitive receptors, on the other hand,  are located within tfie blood-brain-barrier.  The concept of the osmol-  a l i t y sensing mechanism is by no means c l e a r . The non-osmotic  factors  that  affect  the  release  changes in blood pressure, blood volume and hormonal surgical s t r e s s , etc. released jH.,  during  non-hypotensive Sadowska,  hemorrhage  AVP.  (Claybaugh  Both a f a l l  to  carotid  baroreceptors  sinus  levels,  hemorrhage  et a l . , 1981; Landgraf  were reported  Silva,  Hypotensive  and  1972) have both been shown to  amounts of  AVP  include hypoxia,  Reyden and Verney (1938) have shown that AVP is  hemorrhage.  1984; Fyhrquist,  of  increase  in  the  blood  release  and/or  and Gunther,  Share, cause  pressure of  left  1973;  the  atrial  the  et  1983,) and  Szczepanska-  release  and/or  AVP by  J r . and Rosenberg, 1969; Share, 1976).  (Cousineau,  of  blood  large volume  activation  receptors  (Rocha  of e  Severe and mild hypoxia  11 have been shown to cause an increase  in  plasma AVP levels  sheep (Stark et a l . , 1984) and dogs (Wang et a l . , 1984). mones have also been implicated  in  fetal  Several hor-  to influence the release of AVP, for  example, thyroid stimulating hormone or thyroid hormone (Skowasky and Fisher, 1977), estrogen, progesterone and androgen (Skowasky and Swan, 1977). Vasopressor actions of AVP were reported as early as 1949 when i t was suggested by E l l i s and Grollman that AVP may play a role in hypertension. and  in  The vascular action of situ.  (Altura  AVP has  and A l t u r a ,  AVP has been studied  been shown to  1977).  It  has  be a potent  been  reported  both  in  vitro  vasopressor  agent  that,  in  the  rat  mesenteric artery, the amplitude of response to AVP was reduced in the presence  of  the  Horrobin,  1977).  prostaglandin  inhibitor  indomethacin  AVP was shown to potentiate  (Manku  the constrictor  of NA, Ag II and potassium in isolated mesenteric artery of  the rat  veins  (Karmazyn et  appears  al.,  1978).  to be negligible  The e f f e c t  (Sutter,  1965;  of  and  effect  preparation  AVP in  isolated  Stamm, 1972).  In the  human umbilical vein, large concentrations of AVP were shown to induce relaxation  (Somylo  et  al_.,  1966).  The  degree  of  vasoconstriction  caused by AVP, same as that by other vasoconstrictor agents, varies in different  vascular  beds.  Infusion  of  pharmacological  were shown to cause constriction of splenic d i l a t a t i o n s of hepatic a r t e r i a l al.,  1970).  doses  and i n t e s t i n a l  beds in anaesthetizied cats  Vasopressin was reported to have greater  of  AVP  beds,  but  (Cohen e_t  vasoconstrictor  e f f e c t in g r a c i l i s muscle than that in mesenteric beds which, in turn,  12 is greater than that  in renal  al.,  investigators  1974).  effects of  Other  beds of  anaesthetized  have  also  dogs  reported  (Schmid e_t differential  infusions of AVP on d i f f e r e n t vascular beds (Heyndrickx et  al_. 1976; Iwamoto et a l . , 1979). In an attempt to show that AVP plays a role in the maintenance of blood pressure, different investigators have infused AVP into animals. Infusions of pathophysiological hemorrhage  or  surgery)  (Szczepanska-Sadowska, dogs,  infusions  inactivation Rosenberg, of  of  were  found  1973).  similar  to  In  be  pressor  of  dogs  of  pressor  AVP were  baroreceptor  levels  conscious  surgically-stressed  reflexes  It has also been shown that,  pathophysiological  in  anaesthetized  levels  of sino-aortic  1969).  levels of AVP (amounts released during  AVP  did  not  after  (Rocha e S i l v a and although an infusion  increase  pressure of anaesthetized surgically-stressed cats, decrease of superior mesenteric a r t e r i a l  only  it  conductance.  the  arterial  caused a small An infusion  of  the dose of AVP following the removal of influence from endogenous AVP and Ag II  resulted  in  an  increase  in  arterial  greater decrease in superior mesenteric a r t e r i a l al.,  1979).  ogical  pressure  and a much  conductance  (Pang et  Infusion of low doses of AVP (two to f i v e times p h y s i o l -  levels)  into conscious dogs was reported  increases of pressure after  baroreceptor  denervation  1974; Montani et a l . , 1980) and after total blockade (Pullan et al •, 1980).  to cause  (Cowley et  pharmacological  al.,  autonomic  It has been shown by Mohring et a l .  (1978a) that hypertension induced by the administration of ticosterone and sodium chloride  significant  salt  deoxycor-  (DOCA/salt) was associated with  13 an increase in the plasma level of AVP and that the blood pressure of DOCA/salt hypertensive rats could be reduced by the administration a s p e c i f i c AVP anti-serum.  of  Hypertension produced as a r e s u l t of daily  injections of lysine AVP was found to persist several months after the cessation of lysine AVP i n j e c t i o n s .  This hypertension was associated  with an increase in the a c t i v i t y of the renin-angiotensin system, and increase in the turnover of NA and serotonin (Szadowska et a l . , 1976; Szmigielska et a l . , 1978). Another  approach to assessing the vascular  inactivate the AVP system.  Cowley et a l .  the absence of the a r t e r i a l tensin  system,  AVP  released  during  responsible  for  the  compensation  hemorrhage  since  the  injection  dPVDAVP, completely following hemorrhage.  AVP is  to  (1980) have shown that,  in  baroreceptor reflex  prevented  of  and the  hypotensive  renin-angio-  hemorrhage  of  arterial  pressure  a  specific  antagonist  of  the  a  effects  compensation  Laycock et a l .  of  arterial  was  following of  AVP,  pressure  (1979) showed that a small  loss  of blood (1 percent of body weight) was nonhypotensive in control r a t s . However, t h i s amount of blood loss was hypotensive in Brattleboro rats with diabetes insipidus. conscious pressure. ial  dogs,  mild  Schwartz and Reid (1981) have shown that  hemorrhage  (15 ml/kg)  did  not  change  in  arterial  However, the same hemorrhage s i g n i f i c a n t l y decreased a r t e r -  pressure following the injection of a s p e c i f i c antagonist of AVP.  It has been shown that the injection  of a s p e c i f i c  antagonist of  the  vasopressor e f f e c t of AVP in halothane-anaesthetized rats subjected to hypotensive hemorrhage caused a decrease of a r t e r i a l  pressure due to  14 the  reduction  of  total  peripheral  increase in the d i s t r i b u t i o n  resistance  of blood flow  cum, colon and skin (Pang, 1983).  and  a  significant  (BF) to the stomach, cae-  This suggests that following hypo-  tensive hemorrhage, endogenously-released AVP contributed to the maintenance of a r t e r i a l injections  of  an  pressure and peripheral AVP  antagonist  in  vascular resistance.  conscious,  water-deprived  (Aisenbrey et a l . , 1981) and anaesthetized rats with acute  renal  marked f a l l these  failure  (Hofbauer  in a r t e r i a l  of  AVP  in  al.,  1981)  were  glycerol-induced  shown  states.  The  waterdeprived  administration  anaesthetized  conscious rats  to cause a greater f a l l  (Burnier et a l . ,  in a r t e r i a l  to  indicate  cause  a vascular  a  a  role  for  specific  (Andrews  1983a) were shown inactiva-  Thus, there is a lot AVP  in  and  (Burnier et a l . ,  pressure following the  tion of other cardiovascular r e f l e x systems. evidence  to  of  rats  Brenner, 1981), conscious DOCA/salt hypertensive rats 1983a) and control  rats  pressure suggesting a vascular role of AVP in  pathophsiological  antagonist  et  The  physiological  of and  pathophysiological states. 1.3.  Sympathetic Nervous System The (SNS) plays a major role in the control of vascular resistance.  Oliver and Schafer (1895) reported a pressor effect produced by suprarenal  extracts.  by Abel that  This observation  in 1899 (Hartung,  stimulation  of  the  1931).  led to the discovery of Cannon and U r i d i l  sympathetic  hepatic  release of an adrenaline-like substance that and heart rate (HR).  nerves  adrenaline  (1921) reported resulted  in  the  increased blood pressure  Banger and Dale (1910) reported that the effects  15 of sympathetic nerve stimulation were more closely  reproduced by the  injection of sympathomimetic primary amines than by that of  adrenaline  or other secondary amines.  Dale (1933) suggested the use of the term  "adrenergic" for  nerves that release NA.  peripheral  Euler,  in 1946,  showed that the sypathomimetic substance in p u r i f i e d extracts pathetic  nerves  and  effector  organs  resembled  NA.  Burn  of symand  Rand  (1959) postulated that sympathetic nerves release acetylcholine at the pre-ganglionic f i b e r s which lead to the release of NA at the postjunctional  fibers.  clear until  The anatomy of  noradrenergic  the use of histochemical  tion of NA (Falk et a l . , 1962). with  the  lar  techniques for  The morphological  electrophysiological  co-workers  evidence  which  suggests  that  NA  did  not  direct  by  become  visualiza-  evidence,  presented  (1966), precipitated a model for  junction,  nerves  together  Bennett  and  the autonomic neuromuscu-  (synthesized  from  tyrosine  through a number of steps (Blaschko, 1939)) is stored in the granules (Burnstock nerve  and  Robinson,  stimulation.  The  1967),  and  transmitter  is  subsequently  released,  appropriate receptor located on the effector It  has  receptors was  become clear  over  are not homogeneous.  initiated  by Dale  the  partially Alquist  first,  responsible  past  hence,  in  terms  for  the  acts  upon  upon the  cell.  eighty years  The d i v i s i o n  of  that  adrenergic  adrenergic  (1906), who made s i g n i f i c a n t  concept in r e l a t i o n to the SNS. probably  the  released  use of  receptors receptor  His work with the ergot alkaloids was of  receptor  discovery  antagonism, of  and  this  was  adrenoceptors.  ' It  was  (1948) who studied the actions of NA, adrenaline and isopro-  16 pylnoradrenaline  and distinguished  sues to the mentioned agonists. ceptors  the  This  into a- and ^-adrenoceptors  receptors were into  sensitivity  of  different  led to the d i v i s i o n of  and further  subdivison  tis-  adreno-  of  the  e  and ^-adrenoceptors (Alquist 1948).  The receptors that predominantly mediate the actions of the SNS in vascular  smooth  muscles  are  they are responsible for  the  a-adrenoceptors  the maintenance of  (Burnstock,  1961);  tone in the vasculature.  In recent years i t has become evident that the a-adrenoceptors are not of  a single  showed that  population.  As  early  as  1956-57,  dibenamine and phenoxybenzamine  evoked overflow of NA from the cat spleen.  Brown  and  increased the  Gillespie  stimulation  These investigators postu-  lated that the combination of the blockers with a-adrenoceptors of the effector organ was responsible for the overflow of NA.  The f a c i l i t a -  tion of NA release by phenoxybenzamine was considered, but was r e j e c t ed by Kirpekar and Cervoni as  more  evidence  was  (1963).  gathered  This concept gained support  (Hedquist  1969,  1970;  the  effects  later  Farnebo  and  Hamerger 1970, 1971; Stark et a l . , 1971). Langer et  al.  (1970, 1971)  investigated  of  benzamine on NA release, metabolism and uptake in the cat membrane.  He found that,  metabolism and uptake of for  the  increase  phenoxybenzamine. tolamine,  in  the  even though phenoxybenzamine NA, t h is amount  inhibition of  nictitating  inhibited  could not f u l l y  NA released  in  As w e l l , not only phenoxybenzamine,  phenoxy-  the  the  account  presence  of  but also phen-  increased the stimulation evoked overflow of NA (Farneb and  Hamberger 1970, 1971a; Stark  et a l .  1971a).  It was proposed by Hag-  17 gendal  (1970) that the blockers might d i r e c t l y increase the release of  the transmitter the  nerve  per  impulse by some negative  terminal.  In 1970,  feedback  two a-adrenoceptor  mechanisms on  agonists,  namely,  xylasin and clonidine, were found to reduce the stimlated evoked overflow of NA from the cat spleen (Heise and Knoneher 1970, Stark et a l . 1972).  A hypothesis was put forward by Stark  (1971) to  explain  the  phenomenon that adrenergic nerve terminals have a structure related to the a-adrenoceptors nerve  terminal  of the effector  would  attenuate NA release. in the overflow of  inhibit  the  cell, release  whereby stimulation of  NA,  of  antagonism  the  would  Langer (1971) also postulated that the increase  NA in  the presence of a-adrenoceptor  antagonists  was due to a presynaptic e f f e c t . This ultimately resulted in the subdivision of a-adrenoceptors Langer (1974).  Langer proposed that the post-junctional  a-adrenocep-  tors be known as a^, and the pre-junctional a-adrenoceptors as This hypothesis of Langer a-adrenoceptors  a^.  (1974) assumed a homogeneous population  at the post-junctional  level.  by  of  Bentley and co-workers  (1977) reported that the existence of a sub-population of a-adrenoceptors mediating vasoconstriction and that  the vasoconstriction  in the vasculature of the cat and rat mediated through these receptors  not be abolished by a selective a-adrenoceptor  antagonist,  could  prazosin.  A similar observation, that the contraction induced by NA involved two distinct  sets  of  a-adrenoceptors  v i t r o by Moulds et a l . (1977).  was  reported  in  human  Despite these observations,  tional a-adrenoceptors were not c l a s s i f i e d until 1979.  arteries  in  post-junc-  18 Drew  et  al.  (1979)  a-adrenoceptors  at  showed  the  the  post-junctional  and p i t h e d r a t . The p r e s s o r e f f e c t be  partially  effect  by  be  abolished  totally  site  of  in  two  the  either  prazosin  or  if  antagonists  both  yohimbine,  T h i s l e d t o the s u b - c l a s s i f i c a t i o n o f  a-adrenoceptors  into  been  shown  that  the  vasoconstriction  Zweiten 1980; K o b i n g e r Meel  et  al.  and Lues  et  et  al.  1980;  then  al.  given  it  has both  and  Van  and R e i d 1983; Van  1984) and v e n o c o n s t r i c t i o n  a l . 1983; Kalkman e t  the  cause  Timmermans  1980a,b; E l l i o t  but  were  can  a^-adrenoceptor  MaGrath  and P i c h l e r  1983; H i c k e s  1983; S h o j i  and  cat  post-junctional  Since  a2~adrenoceptors.  post-junctional  (Flanvhan  of  anaesthetized  simultaneously.  a^ and  sub-classes  induced by p h e n y l e p h r i n e c o u l d o n l y  antagonized  could  existence  (Schumann  1984; Steen e t  al.  1984) i n response t o nerve s t i m u l a t i o n o r NA i n f u s i o n . 1.4  Nature of t h e problem The aim o f  tive  influence  resistance  the of  i n v e s t i g a t i o n was, the  AVP  and, s e c o n d l y ,  and the  firstly,  SNS i n  the  to  consider  control  t o examine the c o n s t r i c t o r  the  of  rela-  peripheral  actions  of  vari-  ous p r e s s o r agents i n the c a p a c i t a n c e v e s s e l s . 1.4.1  Influence  the c o n t r o l  of  of  vasopressin  vascular resistance.  and s y m p a t h e t i c In the f i r s t  the v a s c u l a r r o l e o f e n d o g e n o u s l y - r e l e a s e d in AVP  pentobarbital were  shown  anaesthetized to  be  released  Bonjour and M a l v i n , 1 9 7 0 ) . to  participate  in  the  rats  was  during  nervous set of  system  experiments,  AVP d u r i n g s u r g i c a l examined.  surgery  Large  (Moran  in  et  stress  amounts al.,  of  1964;  AVP r e l e a s e d d u r i n g s u r g e r y has been shown  control  of  mean  arterial  pressure  (MAP)  and  19 peripheral cular the  resistance  (McNeill  and Pang, 1982; Pang, 1983).  The vas-  role of endogeously-released AVP was shown to be attenuated  presence  of  opposing reflexes  from the  the SNS (Burnier et a l . , 1983a; Waeber et 1984).  renin-angiotensin  al.,  1984; Dipette  in  and/or et  al.,  The study was designed to investigate the vascular role of AVP  in the presence and absence of  influences  system or the a-adrenergic system.  from the  renin-angiotensin  Saralasin, a competitive  antagon-  i s t of Ag I I , was used to remove the influence of the renin-angiotensin system, while phentolamine, ist,  was used to  continously output  infused  into  activity.  a-adrenergic pentobarbital  (CO) and the d i s t r i b u t i o n  groups of prior  abolish  a non-selective a-adrenergic  of  These  blockers  anaesthetized  rats.  BF were determined  rats by the use of the radioactively  effects  of  AVP,  [d(CH ) Tyr(Me)AVP] 2  in  were  Cardiac the  three  labelled microspheres  to and following the adminstration of a s p e c i f i c  pressor  antagon-  antagonist  (Kruszynski  5  et  of  al_.,  1980; Pang and Leighton, 1981; Manning and Sawyer, 1982).  of  The second set of experiments  investigates  the  vasculature.  in  a-adrenoceptors  a-adrenoceptors  were shown to co-exist  and they contribute  and McGrath,  Kalman et  al.,1984;  1980;  a.- and  vasculature  a -adrenoceptors 9  Elliot  and  Kobinger and P i c h l e r ,  However, the physiological on the  at  Two  role  sub-classes  the post-junctional  of  level,  i n d i v i d u a l l y to vascular tone (Drew et a l . , 1979;  Flanvahan  tors  the  the physiological  significance of is  not  operate  clear. by  Ried,  1983;  Hick's,  1984;  1982; Steen et a l . , 1984). antagonism of these recepIt  has  different  been  shown that  mechanisms  in  the situ,  20 (Van Zwieten et al.,  1981).  receptor  a l . , 1982;  Thus,  types  there remains  a  Pedrinelli  simultaneous  may cause another  additive  and T a r a z i , activation  of  vasconstrictor  possibility  of  that  1985; the  Van Meel two  effects.  an uneven  et  separate However,  distribution  of  the receptors may exist throughout the vasculature (T'orneberbrandt et al.,  1985).  class  of  Hence, the r e l a t i v e contribution of the appropriate  adrenoceptors  density of  these  on vascular  receptors  in  tone may depend on the  the vessel.  sub-  relative  In vivo experiments  were  undertaken to examine the r e l a t i v e contributions of the sub-classes of a-adrenoceptors  to the d i s t r i b u t i o n  of halothane anaesthetised r a t s .  prazosin,  rauwolscine  and  different  The effect  tor antagonists on MAP, CO and i t s ing  of CO in  of selected  vascular  beds  a-adrenocep-  d i s t r i b u t i o n were investigated us-  phentolamine  as  a^,  a^  and  non-  selective a-adrenoceptor antagonists, respectively. 1.4.2 tone.  Actions  of  AVP,  Ag II  and a-adrenergic  agonist  on venous  Over the past twenty years i t has become evident that veins are  as important as arteries in the control of the peripheral c i r c u l a t i o n . It  has been estimated that  volume is  in veins.  by venous tone,  approximately  As w e l l , i t  provided that  70 to  80 percent  is recognized that CO is  the heart  is  not  of  blood  determined  in f a i l u r e .  Experi-  ments were carried out to investigate the actions of various vasoconstrictor  agents on the capacitance vessels in conscious  method for the estimation of the total mine the mean c i r c u l a t o r y 1980).  filling  animals.  body venous tone is  pressure  (MCFP)  to  One  deter-  (Yamamoto et  al.,  MCFP is the pressure that would occur throughout the c i r c u l a -  21 tion i f one would instantaneously bring a l l  the pressures in the  cir-  culation to an equilibrium (Guyton et a l . , 1973; Caldini et a l • , 1974). The MCFP has been shown to r e f l e c t CO (Guyton et a l . , 1973). that  blood volume remains constant,  an increase  Provided  in MCFP indicates  an  increase in the tone of the capacitance vessels. The effect gated  of  a number of  in conscious rats  i b l e for  agents  the venoconstrictor  that  were  ( a j - a g o n i s t ) , B-HT 920 ( a - a g o n i s t ) , 2  2  drugs  on MCFP was  investi-  in order to determine the receptors respons-  the mediation of  vasoconstrictor  vasoactive  studied  response in v i v o .  include  NA,  The  methoxamine  Ag II and AVP.  MATERIALS AND METHODS  2.1  Surgical preparation of rats 2.1.1  Microsphere  anaesthetized (1.5% in with  a  with  air).  studies. sodium  These  two-inch  rats  mid-line  heparinized saline  Sprague-Dawley rats  pentobarbital were  (60  subjected  incision.  to  mg/kg)  into  or  a standard  Cannulae  (25 IU) were inserted  (375-500 g) were  (PE  50)  the l e f t  haothane laparotomy  filled  with  ventricle  via  the right carotid artery, with the help of the a r t e r i a l pressure t r a c ing, the  for  the  caudal  and the  withdrawal, halothane level  injection  of  iliac  microspheres arteries,  and into the femoral  anaesthetized r a t s ,  into  for  vein for  after  the  abdominal  recording infusion  of  MAP  and  of drugs.  the completion of  via  blood In the  surgery,  of anaesthesia was maintained by reducing the flow of  ture so as to preserve some eyelid or limb r e f l e x e s .  aorta  a low  gas mix-  22 2.1.2  The  selectivity  of  a ^ , receptors.  and  Sprague-Dawley rats iliac  artery  Model  79D, Mass.)  and rauwolscine  Pentobarbital  for  anaesthetized  blocking  (60  mg/kg)  (450-500 g) were subjected to cannulation  and femoral  veins  arterial  Gould Statham, C a l i f . ) tively.  prazosin  The effect  for  the  recording  (Grass  pressure by a pressure  of  the  Polygraph,  tranducer  (P23I0,  and the injection or infusion of drugs, respec-  of rauwolscine,  prazosin and phentolamine  on MAP  and CO was investigated. 2.1.3 pressin (1980)  The effects  of methoxamine,  and angiotensin was  used  to  B-HT  II on MCFP.  determine  920,  noradrenaline,  The method of  MCFP.  vaso-  Yamamoto et  A balloon-tipped  catheter  al. was  inserted into the right atrium through the right external jugular vein of  halothane  proper  anaesthetized  location  of  the  Sprague-Dawley  balloon  was  rats  indicated  (350-450  g).  The  by a simultaneous  crease in venous pressure and a decrease in a r t e r i a l  pressure to less  than 25 mmHg, when a small volume of normal saline was injected the balloon.  Cannulae were also  the measurement of a r t e r i a l infusions  of drugs,  vein  the  for  transducer  pressure,  and into  measurement  of  the  inferior  the  iliac  and tunnelled  pressure All  for  veins for  the  by  a  femoral pressure  cannulae were  subcutaneously  to  into  artery  vena cava via the  venous  Calif.).  the neck, exteriorized and secured.  into  into the femoral  central  (P23DB, Gould Statham,  with heparinized saline  inserted  in-  the  filled back  of  The rats were allowed to recover  for 24 hr before the measurements of pressures were made.  23 2.2  Microspheres CO and the  sample  distribution  method  microspheres  (Malik  et  of  BF were determined  aj_.,  (15 um diameter,  1976),  using  New England  by the  reference  radioactively-labelled  Nuclear).  Ten  sec  before  the injection of microspheres, blood was withdrawn at 0.35 ml/min with a withdrawal  pump (Harvard Apparatus) from the i l i a c  into a heparinized syringe for 1 min. at  a constant  speed,  a 200 yl  arterial  cannula  During the withdrawal of blood  sample of  a vigorously-vortexed  pre-  counted microsphere suspension (containing 20,000-30,000 microspheres, cy  labelled  with  either  1  Co  1  or  o  Sn)  vii saline) over 10 sec into the l e f t i t y of a variation topes,  in half  before  ^Sn,  All  counting.  injected  ventricle.  and flushed  in the d i s t r i b u t i o n between the two different 57  while  in the other  half  of  the  (200  To avoid a p o s s i b i l -  of the experiments each group of  injected f i r s t . sected.  was  rats  Co was given  experiments  At the end of the experiments,  iso-  *^Sn was  whole rats were d i s -  organs were removed, weighed and loaded  into  vials  for  In rare instances (less than 5%), where BF to the l e f t  and  right kidney d i f f e r s by more than 20%, the experiment was rejected as it  was  assumed  Blood samples,  that tissue  the  mixing  samples,  of  test  microspheres tubes  was  and syringes  not  adequate.  used for  the  injection of microspheres and the c o l l e c t i o n of blood were counted for radioactivity 95-165  kev  (Beckman  and  320-460  8000 kev  Gamma for  57  Counter) Co  and  at  1 1 3  Sn,  energy  settings  respectively.  of At  these energy settings, the s p i l l - o v e r of Co into Sn channel was n e g l i gible  (0.03%)  and  no  correction  was  made  for  Co  spillover.  The  24 spill-over  of  Sn i n t o  the  Co channel  was  16.7% and c o r r e c t i o n  of  Co  i n the presence and absence  of  counts was done by s u b t r a c t i n g Sn s p i l l - o v e r from Co c o u n t s . 2.3  Experimental 2.3.1  protocol  V a s c u l a r r o l e of  influence  from  vasopressin  angiotensin  or  d i s t r i b u t i o n were determined  alpha-adrenergic  in  all  groups  of r a d i o a c t i v e l y - l a b e l l e d microspheres to  and f o l l o w i n g  the  [d(CH ) Tyr(Me)AVP] 2  L e i g h t o n , 1981; was i n f u s e d rats The  s t a r t of  ug/kg)  et  (0.08 ml/min/kg) 30 min a f t e r  injection saline  of  microspheres  infusion.  i n j e c t e d i n t o the l e f t  left  was  of  1980;  Pang  10 m i n ,  microspheres  i n j e c t e d i n t o the l e f t  the end of conducted  infusion saline.  of  saralasin  The i n f u s i o n  with  Group II  (10 ug/min/kg) of  at  the  10 min  after  the  AVP a n t a g o n i s t  was  iv  injection  a different  isotope  ml/min/kg  a continuous  at  blocked  completely  Ag II  (1 y g / k g ) .  saralasin  The p r e s s o r e f f e c t s  responses  this to  rate iv  of  for  show10 min  injections  of Ag II was t e s t e d  iv  injection  ed t h a t  the p r e s s o r  was  instead  Preliminary results  (10C%).  After  r a t s were s u b j e c t e d t o 0.08  of  infusions  of the m i c r o s p h e r e s and the AVP a n t a g o n i s t . of  the  experiment.  s a r a l a s i n was c o n t i n u e d d u r i n g t h e  infusion  and  saline  (Pang and L e i g h t o n , 1 9 8 1 ) .  labelled  ventricle.  AVP,  p r e p a r a t i o n of  4 yg/kg o f t h i s a n t a g o n i s t prevented p r e s s o r responses t o i v  another  prior  antagonist  We have shown t h a t  of supramaximal doses o f AVP i n r a t s  its  injections  In Group I , normal  Ten minutes a f t e r w a r d s ,  ventricle.  and  ventricles  al.,  surgical  until  CO  by t h e  a specific  (Kruszynski  was c o n t i n u e d  rats  the  Manning and Sawyer, 1 9 8 2 ) .  and the i n f u s i o n first  into  a d m i n i s t r a t i o n of (5  5  of  system.  in a l l  of rats  25 prior to the infusion of saralasin and after the second injection microspheres.  In  all  cases,  saralasin  responses to iv injections of Ag I I . infusion of phentolamine min p r i o r to the f i r s t the injections  completely  Group III was subjected to  i.v.  injection of microspheres and continued during  of AVP antagonist and the microspheres. of  phentolamine  completely blocked pressor responses to i . v . (Sigma, 250 yg/kg), BHT 933 (1 mg/kg) obtained  pressor  (0.5 mg/kg/min) at 0.08 ml/min/kg started 10  viously found that 10 min infusion  recordings  blocked  of  during  the  at the  and  same rate  injections of methoxamine  and clonidine  first  We have pre-  the  (5 ug/kg).  second  microspheres were used to indicate MAP during control  MAP  injections  of  and drug t r e a t -  ment period, respectively. 2.3.2  Selectivity  methoxamine  of  prazosin  (0.25 mg/kg)  and B-HT  and 933  rauwolscine. (1 mg/kg) were  In  two  i.v.  rats,  injected  prior to and following the infusion of rauwolscine (1 mg/kg infused at 0.044 ml/min over a 15-min i n t e r v a l ) .  In another two r a t s ,  doses of methoxamine and B-HT 933 were i . v .  the same  injected prior to and f o l -  lowing the infusion of prazosin (1 mg/kg infused at the same rate and time interval as for rauwolscine). 2.3.3 and i t s  Effects of rauwolscine, prazosin and phentolamine on BP, CO distribution.  (n = 10 each  group).  Rats were randomly In the  first  divided  group,  the  microspheres was conducted 30 min after surgery.  into first  three  groups  injection  of  Afterwards, rauwols-  cine was infused (1 mg/kg infused at 0.044 ml/min over a 15-min i n t e r val) into the r a t s .  A second injection of microspheres labeled with a  26 different  isotope was done 15 min after the start of the infusion of  rauwolscine. similar  The second and third groups of rats were subjected to a  protocol,  except  that  instead  of  rauwolscine,  (1 mg/kg) and phentolamine (7 mg/kg), respectively, at  the  same rate  obtained  and over  during the f i r s t  were used to  the  same  and the  time  were i . v .  interval.  second  MAP  injections  indicate MAP during control  prazosin  of  infused  recordings  microspheres  and drug treatment  periods,  respectively. 2.3.4 Effects of methoxamine, B-HT 920, noradrenaline, II  and vasopressin on MCFP.  MCFP was determined  in  angiotensin  conscious  rats.  This was accomplished by stopping the c i r c u l a t i o n of the rats via the injection of  a small volume of f l u i d  into  the balloon  that  was pre-  viously inserted into the right atrium.  Within 5 s following the i n -  flation  and  of  the  balloon,  MAP  increased simultaneously. following  the  decreased  central  venous  Central venous pressure measured within 5 s  cessation  of  circulation  was  referred  to  plateau pressure (VPP).  MAP and VPP were measured in rats  each drug or n = 6 for  normal  infusion  of  10" -4.8 10  x  10" II  normal x  10"  moles/kg/min),  8  (9.7  x 10  - 1 1  -2.8  saline  saline)  (at 7-26  NA  (3.0  x 10~  9  x  10  prior t o ,  x 10  moles/kg/min),  9  pressure  venous  (n = 8 for  and after  a 10-min,  ml/min), methoxamine  B-HT - 1 0  as  -8  920 x  moles/kg/min)  (3.5  10~ or  9  AVP  x  (1.6  10" -11.2 9  moles/kg/min), (4.5  x  10  _ 1 1  x Ag  -1.4  -9 x  10  moles/kg/min).  each agonist.  Dose-response  curves  were  carried  The rats subjected to NA infusion were f i r s t  with propranolol  (8 x I0~^moles/kg i . v .  bolus  injection  out  for  pretreated followed  by  27 3.4  x  10"  moles/kg/min  continuous  stimulation of 8-adrenoceptors  i.v.  by NA.  infusion)  to  prevent  In the determination  the  of  dose-  response curves for Ag I I , each dose of Ag II was infused for  5 min  followed by a recovery period of 12 min to tachyphylaxis to the drug. the  2-hr  infusion  avoid the development  of  The maximum volume of f l u i d infused during  period  varied  between  0.9  ml  for  saline  and NA  groups, 0.3 ml for Ag II group and 0.6 ml for the rest of the groups. 2.4  Drugs All  drugs  were  rauwolscine HC1  Co.,  London),  933 HC1  B-HT  920 HC1  up  fresh  (Carl Roth GmbH and Co.,  Pharmaceutical B-HT  made  Summit,  d(CH ) Tyr(Me)AVP, 2  Ingelheim  (Boroughs  Canada  Ingelheim Canada L t d . ) ,  in  normal  saline;  Ltd.,  Wellcome, Ontario),  NA (Sigma Chemical  Co. Mu. U.S.A.), AVP (Calbiochem. La J o l l a U.S.A.), Canada) and propranolol  5  NY), phentolamine HC1 (CIBA  NJ), methoxamine HC1  (Boehringer  (Boehringer  daily.  Ag II  (Ciba-Geigy  (Sigma Chemical Co. Mo. U.S.A.) were dissolved  prazosin  HC1  (Pfizer  Central  Research,  Sandwich,  England) was dissolved in 5% glucose s o l u t i o n . 2.5  Calculations TPR was calculated by dividing MAP (mm Hg) by CO (ml/min).  and % d i s t r i b u t i o n  of  CO  to  different  organs  were  CO, BF  calculated  as  follows:  CO (ml/min)  Rate of withdrawal of blood (ml/min) x total injected cpm cpm in withdrawn blood  Tissue BF (ml/min) =  Rate of withdrawal of blood (ml/min) x tissue cpm cpm in withdrawn blood ~  % CO  Tissue cpm x 100 total injected cpm  28 Total tracting  amount of r a d i o a c t i v i t y the  amount  of  (cpm) injected was obtained by sub-  radioactivity  left  in  the  tube,  injecting  syringe and flushing syringe from the amount of r a d i o a c t i v i t y a l l y present  in the tube.  Radioactivity  origin-  (cpm) in blood was obtained  by adding the amount of r a d i o a c t i v i t y in the blood sample, in the cannula and syringe used for c o l l e c t i n g blood. MCFP was calculated using the equation of Samar and Coleman (1978) and a value of 1/60 for arterial-to-venous  compliance r a t i o  (Yamamoto  et a l . , 1980).  MCFP = VPP^- + (FAP - VPP) FAP represents the f i n a l  arterial  pressure  (mmHg) obtained  within  5 s following c i r c u l a t o r y arrest. 2.6  Statistical Analysis  data  of  obtained  analyses  variance with during  the  repeated measures was used to  first  and  second  determinations  compare of  CO.  Analysis of variance, complete random design, was used to compare data between different  groups of  rats.  Duncan's  multiple  range  test was  used to compare group means of MAP, CO and TPR while Tukey's multiple range test was used to compare group means of tissue  BF where a more  s t r i c t test was desired for multiple comparisons of data.  A probabil-  i t y or error of less than 0.05 was pre-selected as the c r i t e r i o n statistical  significance.  for  29 3  RESULTS  3.1  Effect of antagonisms of pressor systems on MAP, CO and TPR Table 1 shows control  values  of  MAP prior  to  and following  infusion of saline or drugs in the various groups of r a t s . infusion of saline did not a l t e r MAP in rats of  saralasin  respectively.  and phentolamine  decreased  MAP  A 10-min  from Group I. in  Groups  the  Infusion  II  and  III,  However, a comparison of results between Group I and II  during infusions of saline and s a r a l a s i n , respectively, shows that the infusion of saralasin in Group II did not cause any s i g n i f i c a n t change in MAP, CO or TPR from the corresponding values Therefore,  in Group I (Table 1).  unlike comparisons of MAP within the same animal, we were  unable to detect a s i g n i f i c a n t decrease of MAP during the infusion of saralasin in Group II compared to MAP during the infusion of saline in Group I.  There was also  no difference  in CO and TPR following  the  infusion of saline and saralasin between Groups I and 11^ respectively. Comparisons of values between Groups III and I show that MAP and CO in Group III Group  were s i g n i f i c a n t l y  I following  the  lower than  infusions  of  the  corresponding  phentolamine  values  and s a l i n e ,  in  respec-  tively.  There was no difference in TPR between Groups I and I I I .  3.2  Effect of AVP antagonist on MAP, CO and TPR The injections of AVP antagonist decreased MAP and TPR, but not CO  in a l l  Groups of rats  (Fig. 1).  CO are normalized as % control the AVP antagonist  In Table 2,  results of MAP, TPR and  to allow comparisons of the effects  in the different  Groups.  of  The antagonist caused a  greater decrease of % control MAP in Group II than in Group I.  30 TABLE 1.  Control values of MAP, CO and TPR in Groups I, I I , and III  Group I  Group II  Group III  MAP (mmHg)  103 ± 17  106 ± 14  95 ± 13  MAP (mmHg)  103 ± 17  91 ± 17  105 ± 26  90 ± 20  69 ± 20  1.04 ± 0.29  1.03 ± 0.15  1.20 ± 0.37  3  b  CO (ml/min)  b  TPR (mmHg min/ml)  b  A l l values denote mean ± SD. a  h  c  79 ± 1 0  c d  d  n = 8 in each group.  Denotes MAP readings prior to drug (saline) infusion. Denotes readings of MAP, CO or TPR during the f i r s t  determination  of CO, at 10 min following the infusions of s a l i n e ,  saralasin or  phentolamine in Groups I, II and I I I , respectively. c  S i g n i f i c a n t l y different from MAP prior to the infusions of drug or saline within the same group (p < 0.05).  d  S i g n i f i c a n t l y d i f f e r e n t from corresponding values in Group I (p < 0.05).  31  F i g . 1.  E f f e c t of AVP a n t a g o n i s t on MAP, CO and TPR i n a n a e s t h e t i z e d ,  surgically  stressed  rats:  saralasin-pretreated III).  intact  (Group  CO was determined t w i c e  II)  and and  saline-pretreated  phentolamine-pretreated  i n each group o f r a t s .  was g i v e n t o each group between the f i r s t • CO.  significant  difference  d e t e r m i n a t i o n (p < 0 . 0 5 ) .  from  (Group  AVP  I),  (Group  antagonist  and second d e t e r m i n a t i o n s  values  obtained  from  the  of  first  mean + SD n = 8 \ \ \ \ \ \  1  150  i n each group  n  _  1.5  l  --^ c  \ \  100  \ \ \ \  H  E  \ \  S  \ \ \ \  \  50  £  \  \  \  \  \ ni GROUPS  i  i.o cn  III  GROUPS  0.5  \ \ \ \ \ \ \  i  JbL II  GROUPS  I III  33  Fig.  2.  Effect  of AVP antagonist  on regional  rats from Group I (saline-pretreated). the determination  of  BF.  All  values  distribution  the  first  and second  in each r a t . determinations  BF  Whole rats were dissected represent  BF to entire  Glands include thyroid, parathyroid, salivary and adrenal was determined twice  of  AVP antagonist of  BF.  in for  organs.  glands.  BF  was given between  significant  from BF obtained from the f i r s t determination (p < 0.05).  difference  34  BLOOO FLOW (ml/min) O  _1  LUNGS  HEART  ZZZ3—•  LIVER  STOMACH  INTESTINE CAECUM & COLON  //////////<  z z z 3=  KIDNEYS  SPLEEN  3:  MUSCLE  SKIN  n2  o  O cr  3 •4-  TESTES  OA  3  o . II  CD  BRAIN  GLANDS BONE  35  TABLE 2.  Effects of AVP antagonist on MAP, CO and TPR in Groups I, II and III Group I  Group II  % of control MAP  87 ±12  % of control CO  105 ± 17  106 ± 22  118 ± 30  % of control TPR  85 ±18  73 ± 15  61 ± 2 1  A l l values denote mean ± SD.  75 ± 1 0  Group III 71 ± 1 3  a  n = 8 in each group.  a  a  Values of MAP, CO  and TPR obtained during the second determination of CO following  the  administration of AVP antagonist were expressed as a % of the corresponding values  obtained during the f i r s t  various groups of rats: sin-treated); a  determination  Group I (saline-treated);  Group III (phentolamine-treated).  S i g n i f i c a n t l y different from Group I (p < 0.05).  of  CO in  Group II  the  (sarala-  36  Fig.  3.  Effect  of AVP antagonist  on regional  rats from Group II (saralasin-pretreated). for the determination of BF.  distribution  the  first  and second  in  BF in  Whole rats were dissected  A l l values represent BF to entire organs.  Glands include thyroid, parathyroid, salivary and adrenal was determined twice  of  each r a t .  determinations  AVP antagonist of  BF.  glands.  BF  was given between  significant  from BF obtained from the f i r s t determination (p < 0.05).  difference  30 -  25 -  O  cc  ui  3-  1  Z  <;  UJ  •—• >  Ho  U  - J  l/>  Z  rr> _l  / J  1  0 U  <; O  0 J  2 O  • «  : Q  >-. ^  UJ  <j  —>  V O  a.  r  2;  t—  z  D  » «  ^  </>  u  l/>  i  I—  .  <  x  2:  _ C O  j  < < O  Ul Z  o C Q  38 Although the AVP antagonist caused a greater decrease in % control TPR in Group II than in Group I, the decrease was not s t a t i s t i c a l l y ficant.  The  AVP  antagonist  caused  significantly  greater  of % control MAP and TPR in Group III than in Group I. onist  did not cause any d i f f e r e n t i a l  Group I and Groups II or I I I . exerts  greater  depressor  effects  The results  effects  in  rats  with  decreases  The AVP antag-  on % control show that  signi-  CO between  AVP antagonist  antagonisms  of  the  renin-angiotensin or a-adrenergic system than in intact r a t s . 3.3  Effect of AVP antagonist on the d i s t r i b u t i o n of BF In intact rats  (Group I ) , the AVP antagonist  stomach and skin ( F i g . 2), but did not alter This  indicates  that  AVP plays  the  greatest  increased BF to the  BF to any other organs. vasoconstrictor  influence  in the area of the stomach and skin.  During the infusion of saralasin  (Group I I ) , AVP antagonist  BF to muscles  increased  creased BF to the lungs and l i v e r ( F i g . 3).  and skin  and de-  Therefore, in the absence  of influence from Ag I I , AVP has the greatest vasoconstrictor in vascular beds in the muscles and s k i n . sion  of  phentolamine  (Group  III),  (Fig. 4).  During a continuous  AVP antagonist  muscle BF and decreased BF to the l i v e r ,  effects  markedly  infu-  increased  i n t e s t i n e , kidneys and testes  Thus, in the absence of the a-adrenergic system, AVP plays  the greatest influence in BF to the muscle.  1  39  Fig.  4.  Effect  rats from Group  of AVP antagonist III  on regional  (phentolamine-pretreated).  sected for the determination of BF. organs. glands.  Glands  include  thyroid,  the f i r s t  and second  Whole rats  of  BF  in  were d i s -  A l l values represent BF to entire parathyroid,  BF was determined twice in each r a t .  en between  distribution  salivary  and  adrenal  AVP antagonist was giv-  determinations  of  BF.  Significant  difference from BF obtained from the f i r s t determination (p < 0.05).  DLOOD FLOW (ml/min)  o  O  O  O  LUNGS  HEART  LIVER  STOMACH  INTESTINE CAECUM & COLON KIDNEYS  SPLEEN  MUSCLE  A/[/\AAAAAyy\yyy  SKIN  TESTES CD  BRAIN  GLANDS  2 ro  o  O c  D II CO  BONE  O  41  3.4  S e l e c t i v i t y of prazosin and rauwolscine In  two experiments,  the  infusion  of  p l e t e l y block pressor responses to i . v . not that of B-HT 933. ment. block  prazosin  was found  to com-  injections of methoxamine, but  F i g . 5a shows the tracing of a typical  experi-  In another two experiments, the infusion of rauwolscine did not the  pressor  responses  to  i.v.  injections  of  methoxamine,  antagonized (> 80%) pressor responses (as increases of s y s t o l i c i a l pressure) to i . v . ing of a typical 3.5  injections of B-HT 933.  but  arter-  F i g . 5b shows the t r a c -  experiment.  Effects of rauwolscine, prazosin and phentolamine on BP, CO,  TPR and the d i s t r i b u t i o n of CO A  reduction  of  MAP  was  obtained  following  the  injection  of  rauwolscine, prazosin or phentolamine into each group of rats ( F i g . 6 ) . The reductions  of  MAP in rats  treated with  amine were associated with reductions lated TPR. ing  with  rauwolscine  and  and phentol-  of CO, but no change in calcu-  CO was decreased to 82% and 67% of control  treatments  contrast,  rauwolscine  phentolamine,  values  follow-  respectively.  In  the decrease of MAP in prazosin-treated rats was associated  with a decrease of TPR (80% of control values), but no change of CO. Following the infusion of rauwolscine or phentolamine, the d i s t r i bution of BF to many organs was reduced as a r e s u l t of a decrease CO. the  Significant infusion  of  reductions of BF to most organs were detected rauwolscine,  except  muscle where BF was not changed  in the  ( F i g . 7).  lungs,  liver,  The infusion  in  after  spleen and of  phentol-  amine caused reductions of BF to most organs, except the lungs, l i v e r  B-HT 933  Methoxamine  Rauwolscine  Methoxamine  B-HT 933  F i g . 5. Tracings of two typical experiments showing the s e l e c t i v i t y of prazosin (a) and rauwolscine  (b) in antagonizing pressor responses  B-HT 933 in pentobarbital anaesthetized r a t s .  to iv injections  of methoxamine and  n = 10 in each group mean + SD  RAUWOLSCINE E3  P R A Z O S I N  H  P H E N T O L A M I N E  100 -  <0  Ol I E E  c E I E E  a E E o.s -  O  o  cc  a.  Fig.  < 2  6.  Effect  of rauwolscine,  anaesthetized r a t s . Group of r a t s .  *Significant  phentolamine and prazosin on MAP, CO and TPR in  halothane  difference from control .values (p < 0.05). n = 10 in each  C  C O N T R O L  S  R A U W O L S C I N E  mean + SD n = 10  LUNCS  HEART  LIVER  STOMACH  INTESTINE CAECUM  IC I ONE Y S  COLON  Fig.  7.  SPLEEN  MUSCLE <30j>  SKIN  TESTES  OL  <30gJ  Effect of rauwolscine on regional distribution of BF in anaesthetized rats (  •Significant difference from control values (p < 0.05).  45 and muscle where BF was not changed ( F i g . 8 ) .  Treatment with prazo-  s i n , on the other hand, only decreased BF to the skin and increased BF to the lungs ( F i g . 9). The r e l a t i v e administration and 12).  of  distribution rauwolscine,  of  CO was changed  phentolamine  similarly  or prazosin  after  the  ( F i g . 10, 11  After the infusion of rauwolscine, the % d i s t r i b u t i o n  of CO  was reduced in the heart, i n t e s t i n e , caecum and colon, kidneys, glands and brain, but increased in the lungs and muscle ( F i g . 10).  After the  infusion  of  of  prazosin  and phentolamine,  the % d i s t r i b u t i o n  CO was  reduced in the heart, caecum and colon, kidneys, skin and glands, but increased in the lungs and muscle ( F i g . 11,12). 3.6  Effects  of  methoxamine,  B-HT  920 noradrenaline,  angiotensin  II and vasopressin on MCFP Table 3 shows the control  values  of  MAP before  infusions  of  values of MAP, MCFP and HR prior  to  saline and the various vasoconstrictor agents. was no difference  in the control  the infusion of any drugs or s a l i n e . a l t e r MAP ( F i g . 13). various drugs on MAP. and Ag II a l l  the  There  The infusion of  saline did not  Figure 14 shows the effects of infusions of the The infusions of B-HT 920, methoxamine, NA, AVP  caused dose-dependent  obtained during the continuous  increase in MAP above the values  infusion  of  saline.  AVP, methoxamine  and B-HT 920 caused s i g n i f i c a n t increases of MAP at doses equal to and higher than the t h i r d infused dose (p < 0.05, F i g . 14).  NA and Ag II  caused s i g n i f i c a n t increases of MAP at doses equal to and higher than the second infused dose (p < 0.05, F i g . 14).  LUNCS  HEART  LIVER  STOMACH  INTESTINE CAECUM  KIDNEYS  COLON  F i g . 8.  SPLEEN  MUSCLE  SKIN  TESTES  Effect of phentolamine on regional distribution of BF in anaesthetized rats  •Significant difference from control values (p < 0.05).  GLANDS  BRAIN  (3095  (n = 10).  c E \  LZ1  C O N T R O L  S  P R A Z O S I N  S ...  mean + SD  o  ri = 10  ^  ,  0  1  J  Q O O _i  a i  LUNGS  HEART  ii LIVER  1  i  3  r ^ STOMACH  INTESTINE  CAECUM  I MONEYS  COLON  Fig.  9.  Effect of prazosin on regional  Ffa SPLEEN  MUSCLE ' <>Og>  *«<"  fit  TESTES  1RA.N  9  distribution of BF in anaesthetized rats  •Significant difference from control values (p < 0.05).  GLANDS  (i0 )  (n = 10),  O  LUNGS  HEART  LIVER  STOMACH  INTESTINE  CAECUM  KIDNEYS  SPLEEN  COLON  F i g . 10.  MUSCLE C30g>  C O N T R O L  SKIN  TESTES  Effect of rauwolscine on % distribution of CO in anaesthetized rats  •Significant difference from control values (p < 0.05).  GLANDS  •»  CJO»l  (n = 10).  Cl  «3-  :o  ,D  C O N T R O L P H E N T O L A M I N E  mean + SO O  n = 10  O I  4 LUNGS  F i g . 11.  1  HEART  LIVER  STOMACH  I  I  INTESTINE CAECUM COLON  i KIOHEYS S P L E E N  4  •=1 * MUSCLE <10g)  I  SKIN <10 )  TESTES  GLANDS  BRAIN  a  Effect of phentolamine on % distribution of CO in anaesthetized rats (n = 10).  •Significant difference from control values (p < 0.05).  LUNGS  Fig.  12.  HEART  Effect  LIVER  STOMACH  INTESTINE  CAECUM COLON  KIDNEYS  of prazosin on % distribution  SPLEEN  MUSCLE C30g>  SKIN <30g>  TESTES  of CO in anaesthetized rats  •Significant difference from control values (p < 0.05).  GLANDS  (n = 10).  51  TABLE 3. Methoxamine  Control vaules of MAP, MCFP and HR B-HT 920  AVP  Ag II  NA  Saline  MAP  115±3  116±2  108±2  111±3  106±2  111±4  MCFP  5.9±0.10  5.8±0.10  6.2±0.20  6.0±0.02  5.7±0.20  6.0±0.02  HR  413±9  386±14  404±7  402±10  380±15  377±8  All  values denote mean ± SE.  where n = 6.  n = 8 in each group except  for normal  saline  Values of MAP (mmHg), MCFP (mmHg) and HR (beats/min) were ob-  tained prior to the admininstration of drugs or normal s a l i n e .  52 S a I \ n Q  I 6  (N-6>  n  200  150  100  < 1  so-  7 -  01 I E E  r  f — i  CL U.  u  1 500 -  c E  i  430  N U  jj  400  0 a  5  330  or I  300 230 -  t  20  —\  40  60  Time ( m i n ) F i g . 13.  eo  i  oo  MAP, HR and MCFP d u r i n g the i n f u s i o n of normal s a l i n e at  r a t e s (7-26 x 10  m l / m i n / r a t ) over a 100 m i n . p e r i o d (mean ± S E ) .  different  53  Fig.  14.  Dose-respones curves of MAP for methoxamine,  AVP and Ag I I .  The rats subjected to NA infusion were f i r s t  ed with propranolol NA.  B-HT 920, NA,  to prevent the stimulation  of  pretreat-  e-adrenoceptors  by  In the determination of dose-response curves for Ag I I , each dose  of Ag II was infused for 5 min followed by a recovery period of 12 min to avoid the development of tachyphylaxis to the drug (n=8 mean ± SE).  54  250-1  ( O ) C •) C A) T )  (  C -• )  NA Mathaxqmino B-HT 920 AVP Ag I I  200H  CD I  E E ISO Q_ < 2 100  50 -11  i  i—i" i i i n i  -10  r~—i—III  111.|  1—i—i~r i tiii  -9  Moles/Kg/min  -8  1—i—II i r  111  -7  55 HR was not changed during the infusion ( F i g . 15)  of  all  the  compared  to  infusion of  vasoactive  agents  control  obtained  HR  saline  produced before  ( F i g . 13).  decreases the  The  in  HR  infusions  of  these drugs (Table 3). MCFP readings were not changed during the infusion of saline ( F i g . 13). MCFP obtained  during  the  infusions  of  various  doses  of  methoxamine  ( F i g . 16) were not s i g n i f i c a n t l y different from the control MCFP prior to  drug  increased  infusion during  (Table 3 ) . the  MCFP was  infusions  B-HT 920 caused s i g n i f i c a n t  of  the  slightly, highest  but three  increased MCFP at doses equal (p < 0.05,  Fig.  16).  doses  increases of MCFP at doses equal  higher than, the second infused dose, while NA and Ag II  dose  significantly,  to,  of to,  of  the  and  significantly  and higher than, the t h i r d  The order  AVP.  effectivness  infused of  these  vasoconstrictors to increase MCFP was: Ag II > NA = B-HT 920 > AVP.  56  Fig.  15.  Dose-respones curves of HR for methoxamine,  AVP and Ag I I .  The rats subjected to NA infusion were f i r s t  ed with propranolol NA.  B-HT 920, NA,  to prevent the stimulation  of  pretreat-  e-adrenoceptors  by  In the determination of dose-response curves for Ag I I , each dose  of Ag II was infused for 5 min followed by a recovery period of 12 min to avoid the development of tachyphylaxis to the drug (n=8 mean ± SE) •significant (p < 0.05).  difference from HR obtained from the f i r s t  determination  57  CO) C • 5  500 n  <  A  <  T )  )  C • 5  NA H o t h Q x cxm i n a  B-HT 920 AVP Ag II  450H  2  0  0  "1 -)]  1 — I i I Mll|  - ] •  1 — I I I I 111 j  1 — I I I I III |  - 9  Moles/kg/min  - 8  1 — I I I I III]  - 7  58  Fig.  16.  Dose-response curves of MCFP for methoxamine,  AVP and Ag I I .  The rats subjected to NA infusion were f i r s t  ed with propranolol NA.  B-HT 920, NA,  to prevent the stimulation  of  pretreat-  e-adrenoceptors  by  In the determination of dose-response curves for Ag I I , each dose  of Ag II was infused for 5 min followed by a recovery period of 12 min to avoid the development of tachyphylaxis to the drug (n=8 mean ± SE).  59  12-1 11  H  co)  NA  ( •) C A ) C r) < •)  MethQxqminQ B-HT 9 2 0 AVP Ag I I  i c H  /^\ ui I  E QL  8-j  LL  U  2  7-)  6H 1  11  I  1—I 'I I i i :  -10  T  l  i  i i i i i i  l  I  I  l l l 111  -9  Mo 1 Q s / k g / m i n  -8  l  1 — i i 1III]  -7  60 4  DISCUSSION It has been shown that large amounts of AVP are released following  surgery in different  species of  animals  (Moran et  and Malvin, 1970; Ishihara et a l . , 1978). onist  in  halothane  shown to  decrease  expected that  anaesthetized  the  1964;  Bonjour  The i n j e c t i o n of AVP antag-  surgically  MAP by the reduction  al.,  of  stressed  TPR  rats  has  (Pang, 1983).  depressor response following  the  been It  injection  is  of AVP  antagonist would result in reflex activation of other endogenous pressor systems, thereby masking the vascular effects of the antagonism of AVP.  The f i r s t  released  AVP  endogenous  in  study the  pressor  investigates presence  systems,  and  vascular absence  namely,  the  effects  of  of  influences  endogenously from  renin-angiotensin  other  or  the  a-adrenergic systems. The injection of the AVP antagonist decreased MAP and TPR, but did not a l t e r CO in a l l groups of r a t s .  The AVP antagonist caused a s i g -  n i f i c a n t l y greater decrease of % control MAP in Groups II and III than in Group I.  As w e l l , the AVP antagonist caused a s l i g h t , but not s i g -  n i f i c a n t l y greater than in Group I, decrease of % control TPR in Group I I , and a s i g n i f i c a n t l y greater decrease of % control TPR in Group III than in Group I.  The results  strictor  influences  systems,  endogenously  control  of  from  the  released  MAP and vascular  stressed r a t s .  show that,  in  the  renin-angiotensin AVP  exerts  resistance  in  absence of or  greater  the  a-adrenergic  influence  anaesthetized,  vasocon-  in  the  surgically-  61 The  administration  tized,  of  AVP  antagonist  surgically-stressed and intact rats  in  pentobarbital  in Group I increased BF to  the stomach and skin, but not the other organs. lar  to those previously reported  in  our  anaesthe-  The results are s i m i -  laboratory,  using  halothane  Surgery has been shown to increase plasma renin a c t i v i t y  (McKenzie  anaesthetized surgically-stressed rats (Pang, 1983).  et  al.,  tized,  1967).  It  has been  shown previously  in  halothane-anaesthe-  surgically-stressed rats that the infusion of saralasin caused  a decrease of MAP and TPR but no change in CO (Pang, 1983). study,  the infusion of saralasin  in Group II also resulted  crease of MAP within the same group of animals. II  rats  subjected  to  the  infusion  of  In this in  a de-  Although MAP in Group  saralasin  was  less  than MAP  values in Group I given saline infusion, the decrease was not s t a t i s tically  significant.  This  was probably  due  to  difficulties  in  detection of small differences between animals due to biological ations.  The administration of the AVP antagonist  the vari-  in Group II caused  an increase of BF to the skin and muscle and a decrease of BF to the lungs and l i v e r .  Therefore, in the absence of vasomotor tone from the  renin-angiotensin  system, AVP plays  the greatest  vasoconstrictor  in-  fluence in the areas of the muscle and skin and the least in the lungs and l i v e r . infusion  of  It should be emphasized that a depressor response from the saralasin would be expected  nervous system.  Therefore,  to  activate  the  sympathetic  one should not expect to obtain the same  effects from the injection of the AVP antagonist which have d i f f e r e n t endogenous vasomotor tones.  in Groups I and I I ,  62 The  infusion  reduction  of  of  CO,  phentolamine  but  not  TPR.  in  Group  The  III  decrease  decreased of  CO was  r e s u l t of reduced venous return due to the blockade of (see later)  receptors  in veins.  MAP by  the  probably  a  postjunctional  Administration of the AVP antag-  onist during the infusion of phentolamine markedly increased BF to the muscle and decreased BF to the l i v e r , Therefore,  in the absence of  intestine,  kidneys  and t e s t e s .  influence from the a-adrenergic  system,  AVP plays the greatest vasoconstrictor influence in the muscle and the least in the l i v e r ,  intestine,  kidneys and testes.  It has been shown  that the administration of phentolamine in rats increased plasma renin activity  (Burnier et a l . ,  1983b).  Renin release  creased by a reduction of MAP or renal Campbell, 1981).  arterial  is  known to be  pressure  in-  (Keeton and  It has been shown that endogenously released Ag II  played the greatest vasoconstrictor and skin (Pang, 1983).  influence in areas of the kidneys  Increased vasomotor tone from the renin-angio-  tensin system in rats from Group III may have overcome the  influence  of AVP antagonist on skin BF (in rats from Groups I and I I ) .  Control  skin BF in rats from Group III during the infusion of phentolamine was indeed  very  low,  3.3 ± 0.8  versus  10.6 ± 3.8  and  8.6 ± 4.0  ml/min  (mean ± SD) in Groups I and I I , respectively. The namely,  administration rauwolscine,  reductions  of  MAP  of  a£-,  prazosin showing  ay  of  a -,but 9  not  non-specific  and phentolamine,  that  both  pate in the control of blood pressure. infusion  and  a,-blockers.  ay  and  a-blockers,  respectively, a2~receptors  caused partici-  CO was decreased following the Thus,  both  rauwolscine  and  63 phentolamine  decreased  MAP by the reduction  phentolamine on CO in this  of CO.  The effect of  study was, therefore, consistent with  in Group III of the previous study.  that  The decrease in CO was probably a  r e s u l t of reduced venous return due to the blockade of postjunctional venous c^-receptors. reducing TPR, functionally  Prazosin,  on the other  but not CO. Our results more  important  ct^- and  ct^-agonists,  reported  to increase  a - | - and  o^-receptors  with  rauwolscine,  o^-receptors the control  et al_.,  suggest  the control  by  of  on the other more  of venous capacitance.  of  show  important  of  postjunctional  bed of the r a t .  hand,  were  The results  1984).  the existence  in the venous  are f u n c t i o n a l l y  in  and B-HT 9 2 0 , r e s p e c t i v e l y ,  CO (Kalkman  et a l . , therefore,  MAP  In pithed r a t s , the injections of both  methoxamine  Kalkman  decreased  suggest that ct^-receptors are  o^-receptors  than  venous capacitance in the r a t .  hand,  Our results  that  post-junctional  than  a^-receptors in  It is of interest  that  treatment  of hypertensive patients with prazosin was reported to decrease blood pressure by reducing TPR, prazosin reflex  selectively  increase  but not CO (deLeeuw et a l . ,  blocks  c^-receptors,  in the release  caused by prazosin  could  it  is  of NA following  stimulate  o^-receptors  1980).  expected  that the  a depressor in veins  Since  response  to enhance  venous return to maintain CO. As a r e s u l t of the reduction of CO by rauwolscine or phentolamine, the d i s t r i b u t i o n of BF to most organs was decreased. sion of rauwolscine, s i g n i f i c a n t heart,  stomach,  intestine,  After the i n f u -  decreases of BF were detected in the  caecum and colon,  kidneys,  skin,  testes,  64  glands  and  decreases and  brain.  in  colon,  other  the  BF w e r e  amine  spleen,  of  the  % distribution  or  in  resistance  prazosin,  kidneys,  cantly  reduced  the  reduced brain the in  the  in and  resistance  heart,  contrast,  blood  previous  thane-anaesthetized, the  greatest  while  Ag  II  (Pang,  that  vascular  plays  1983).  the  vessels  intestine,  exerts  and  caecum  studies  the  and  muscle.  the SNS  in  the  and  rat.  vasoconstrictor greatest  a - j - and  Furthermore,  our  lungs  and  muscle  this  influence  in in  muscle.  of  CO  was  glands  and  indicate  results  with  vasoconstrictor  and  skin  have  s i g n i f i -  and  the  and  laboratory  rats  influence  not  heart,  a2~adrenoceptors  greatest  in  phentol-  the  results  the  conducted  in  kidneys, Our  kidneys,  suggests  of  but  exerts  colon,  skin.  following  distribution  postjunctional in  infusion  the lungs  and c o l o n ,  surgically-stressed  the  in  the  the  (^-postjunctional  slightly,  and i n c r e a s e d  lungs,  the  beds  the  On  This  CO w a s r e d u c e d  glands,  caecum  BF t o  altered  and  caecum  brain.  a-blockers.  After of  and  similarly  significant  intestine,  reduced  ay  rauwolscine,  functional  suggest  in  vessels.  skin  of  in  was  functional  intestine,  increased  phentolamine  the  infusion  of  CO  only  different  intestine,  the heart,  presence  influence  in  three  stomach, glands  prazosin  the % distribution  and c o l o n ,  phentolamine,  testes,  of  blood  caecum  Following  of  of  with  the heart,  skin,  distributions  administration  receptors  in  the administration  relative  similar  treatment  observed  kidneys,  hand,  The  After  least  glands. using  shown  the  stomach  the  kidneys  that and and  in In  haloAVP skin, skin  65 It  was  unexpected  to  find  that,  while  caused similar reductions of MAP and similar tribution  the  various  a-blockers  alterations  in the d i s -  of CO, there was a decrease of TPR only after  the admini-  stration of prazosin.  One possible explanation  is that  the depressor  response produced by phentolamine or rauwolscine caused the release of greater amounts of vasoconstrictor agents, such as AVP and Ag I I , than the depressor response produced by prazosin. quantities role  of  of  the  these  vasoconstrictor  renin-angiotensin  agents  system in  The release of then  maintain  the maintenance  peripheral vascular resistance is well-established.  TPR. of  The  MAP and  Renin release has  been shown to be increased after a reduction of MAP or renal pressure (Keeton and Campbell, 1981).  greater  Normotensive rats  arterial  subjected to  the administration of phentolamine were reported to have 19 times the PRA of control rats  (Burnier et a l . , 1983b).  treated with prazosin was elevated rats (Waeber et a l . , 1983).  In contrast, PRA of rats  to 4 times  the  value  sure (Share, 1976; Rocha e Silva et a l . , 1978). quently, stimulation of l e f t a t r i a l  i.v.  it  is  logical  et  al.  (1983b)  reported  to expect  administration  that,  following  infusion of phentolamine, plasma AVP levels were elevated to 18.5  times the level onist  Burnier  pres-  Since CO and, conse-  that AVP release may be greatly enhanced following the blockers.  atrial  receptors were decreased following  the infusion of rauwolscine and phentolamine,  these  control  AVP release has been shown to be increased  following either a decrease of MAP or a decrease of l e f t  of  of  of  the  in control r a t s .  vasopressor effect  Moreover, the injection of an antagof  AVP was found to cause  a marked  66 decrease  of  MAP  in  rats  subjected  (Burnier et a l . , 1983b). reported  that,  although  to  On the other the  injection  the  infusion  of  phentolamine  hand, the same laboratory has of  prazosin  in  rats  caused a  similar decrease of MAP and a 7 x increase in the plasma level of AVP, the  injection  with  prazosin  of  AVP antagonist  (Waeber  et  al.,  did  not  1983).  reduce  Thus,  that endogenously-released AVP plays a role and  peripheral  vascular  resistance  MAP of  their  rats  treated  results  indicate  in the maintenance of MAP  following  the  administration  of  phentolamine, but not prazosin. Further experiments were conducted to determine the of  a ^ - and  ctg-receptors  in  the  control  of  venous  participations tone  Experiments were conducted to determine the p a r t i c i p a t i o n  in  of  rats.  vasoact-  ive agents in the control of MCFP in r a t s .  It has been reported that  MCFP  therefore,  is  (Guyton  a primary et  al.,  Yamamoto et a l . ,  determinant  1973;  Caldini  of et  CO and, al.,  1974).  Using  venous the  return  method  of  (1980), we were able to obtain reproducible readings  of MCFP in conscious r a t s .  The values of  MCFP that we have obtained  in conscious rats are similar to those from other laboratories  (Samar  and Coleman, 1978, 1979; Yamamoto et a l . , 1980). It ephrine caused 1984;).  has (an  been  shown  that  ct^-agonist)  increases  in  MCFP  in  i.v.  administrations  anaesthetized  (Yamamoto  et  al_.,  and  of  NA and  conscious  1980;  Hirakawa  phenylanimals et  al.,  Our results show that the infusion of methoxamine, a s p e c i f i c  ct^-agonist,  increased MAP, but did not change MCFP.  B-HT 920 (a s p e c i f i c  The infusion  c^-agonist) and NA (a non-selective  a  of  agonist)  67  increased a ^ - are  MAP,  more  as  well  as  important  MCFP.  than  Therefore,  -receptors  in  our  results  show  the  control  of  that  venous  tone in the r a t . The results obtained is by Kalkman et_al_., (1984).  in contradication with the data presented However Kalkman's  experiments  were  carried  out in pithed Wistar r a t s , while we used conscious Sprague-Dawley rats .  It is possible that the discrepancy was due to the use of a d i f f e r -  ent strain of rats or different  preparations of animals.  Pithed rats  have very low pressures due to the absence of sympathetic nervous activity  and,  expected Moreover,  therefore,  to  have  both  arterioles  supernormal  and  veins  of  responsiveness  a-^- and c^-adrenoceptors  of  to  pithed  these  animals  vasoactive animals  are  drugs.  were  not  activated due to the absence of endogenously released NA. It was shown that in anaesthetized Sprague-Dawley rats the administration selective  of  rauwolscine  a-blockers,  administration CO.  of  and  phentolamine,  respectively,  prazosin,  a  caused  specific  a-^  selective  a - and 2  a reduction blocker,  of  did  CO. not  nonThe alter  The results of selective a-adrenergic agonist are, therefore con-  sistent  with  those  a -adrenoceptors 2  of  are  the  more  previous  study  important  than  and  they  suggest  a^-adrenoceptors  in  that the  control of CO in r a t s . It has been show that continuous  infusion of Ag II caused an i n -  crease of MAP (by about 20-30 mmHg) and an increase in MCFP (2-3 mmHg) of anaesthetized dogs.  In this  dose-dependent  in MAP as well  increase  study,  the infusion of Ag II caused a as MCFP.  On the other hand,  68 the infusion of high doses of AVP increased MAP, but i t a very small increase in MCFP.  produced only  The results show that receptors for Ag  I I , but not AVP are important in the control of venous tone pressure. 4.1  Summary  • We have found that endogenously-released AVP plays a vascular in the control of MAP and vascular resistance. a greater  pressor role  in  the absence of  AVP was shown to play  influences  angiotensin or the sympathetic nervous systems. constrictor varies,  influence  by  AVP  in  from the  The extent  different  renin-  of  vaso-  vascular  beds  depending on endogenous vasomotor tone from Ag II or a-adren-  ergic system. tensin  exerted  role  In the absence of vasomotor tone from the renin-angio-  system,  vascular  AVP  beds  in  plays  the  the  skin  greatest  vasoconstrictor  and muscle.  In the  absence  influence of  on  influence  from the SNS, AVP plays the greatest vasoconstrictor influence on vascular beds in the muscle. We have obtained similar decreases of MAP with acute blockades of a  l ' -  a  2~  results  a s  did  a^-receptors  w e  ^  a s  not  show  th  a  any  l~  a n c  '  a  2  - r e c e  functional  administrations  found  to  cause  similar  and a^-receptors  al c i r c u l a t i o n .  of  rauwolscine,  important  in  Therefore,  inhibition prazosin  redistributions  are  Ptors.  significance  in the negative feedback  acute  aj-  b o  of the  CO,  of  of  our  prejunctional  NA release.  The  and phentolamine  were  suggesting  control  of  the  that  both  peripher-  The % d i s t r i b u t i o n of CO to the lungs and muscle were  increased following the administrations  of prazosin, rauwaloscine and  phentolamine.  the  Thus,  the  SNS  exerts  greatest  vasoconstrictor  69 influence  on vascular  beds  in  the  lungs  and muscle.  Since  CO was  reduced after treatment with phentolamine and rauwolscine but not with prazosin,  our  results  indicate  that  a r e  c^-receptors  m o r e  important  than ct^-receptors in the control of venous capacitance. The B-HT  stimulations  920,  show that ial  respectively, both  resistance.  found  to  a - ^ - and  of  a - ^ - and  caused  MCFP.  of  These  responsible for the control rat.  increases  o^-receptors  The infusion  increase  o^-receptors  of  B-HT  are  in  MAP.  but  show  methoxamine The  present  920,  results  by  to  results control  that  These results from the administration of s p e c i f i c  the  rat.  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