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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 Tabrizchi, 1986 I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by t h e h e a d o f my d e p a r t m e n t o r by h i s o r h e r r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Reza Tabrizchi D e p a r t m e n t o f Pharmacology & Therapeutics The U n i v e r s i t y o f B r i t i s h C o l u m b i a 1956 Main Mall V a n c o u v e r , Canada v. V6T 1Y3 D a t e 15 A p r i l 1986 > E - 6 ( 3 / 8 1 ) - i i -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 peripher-al 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 effect of AVP in the pres-ence and absence of influence from angiotensin II (Ag II) or a-adrenergic system was investigated in pentobarbital anaesthetized rats. Cardiac output (CO) and the distribution of blood flow (BF) were determined by the micro-spheres technique prior to and following the injection of an AVP pressor antagonist [d(CH2)gTyr(Me)AVP] in three Groups of rats: saline-treated (I) , saralasin-treated (II) and phentolamine-treated (III) . The AVP antag-onist decreased MAP and TPR in al l Groups and i t caused a greater depressor effect in Groups II and III than in I. In Group I, AVP antagonist increased BF to the stomach and skin. In Group II, AVP antagonist increased BF to the muscle and skin. In Group III, AVP antagonist markedly increased BF to the muscle. The second set of experiments investigates the physiological role of the a-adrenoceptors in the vasculature. The effects of prazosin (a-^-blocker), rauwolscine (c^-blocker) and phentolamine (nonselective a-blocker) on MAP, CO and i ts distribution were investigated in halothane anaesthetized rats. Al l three a-antagonists caused similar decreases of MAP and al l increased of % distribution of CO to the lungs and muscle. During the infusion of prazo-s in , TPR was decreased but CO was not changed. In contrast, CO was de-creased but TPR was not altered during the infusions of rauwolscine and phentolamine. Since CO was reduced after the blockade of (*2 but not a-^ receptors, i t appears that receptors are responsible for the control of venous capacitance. A f inal set of experiments were carried out to investigate the actions of various vasoconstrictor agents on the capacitance vessels of conscious rats. We investigated the dose-response relationships of methoxamine (a^-agonist), B-HT 920 (c^-agonist), noradrenaline (NA, non-selective a-agonist), AVP and Ag II on MAP, mean circulatory f i l l i n g pressure (MCFP) and heart rate (HR) in conscious rats. The infusions of a l l the agonists, but not sal ine, caused dose-dependent increases in MAP and decreases in HR. The infusions of saline and methoxamine did not affect MCFP while the infu-sions of B-HT 920, NA and Ag II increased MCFP. Therefore, receptors for <*2 adrenergic agonists and Ag II are involved in the control of venous tone. -iv -TABLE OF CONTENTS CHAPTER Page 1 INTRODUCTION 1 1.1 Renin-angiotensin system 2 1.2 Vasopressin 8 1.3 Sympathetic Nervous System 14 1.4 Nature of the problem 18 2 MATERIALS AND METHODS 21 2.1 Surgical preparation of rats 21 2.2 Microspheres 23 2.3 Experimental protocol 24 2.4 Drugs 27 2.5 Calculations 27 2.6 Stat ist ica l analyses 28 3 RESULTS 29 3.1 Effect of antagonisms of pressor systems on MAP, CO and TPR 29 3.2 Effect of AVP antagonist on MAP, CO and TPR 29 3.3 Effect of AVP antagonist on the distribution of BF 38 3.4 Select iv ity of prazosin and rauwolscine 41 3.5 Effects of rauwolscine, prazosin and phentolamine on 43 BP, CO, TPR and the distribution of CO 3.6 Effects of methoxamine, B-HT 920 noradrenaline, 45 angiotensin II and vasopressin on MCFP 4 DISCUSSION 60 4.1 Summary 68 5 REFERENCES 70 - V -LIST OF TABLES TABLE Page 1 Control values of mean arterial pressure, cardiac output 30 and total peripheral resistance in Group I, II and III. 2 Effect of vasopressin antagonist on mean arterial pressure, 35 cardiac output and total peripheral resistance in Groups I, II and III. 3 Control of mean arterial pressure, mean circulatory f i l l i n g 51 pressure and heart rate. - vi -LIST OF FIGURES FIGURE Page 1 Effect of AVP antagonist on MAP, CO and TPR in anaes- 31 thetized, surgical ly stressed rats: intact and sal ine-pretreated (Group I) , saralasin-pretreated (Group II) and phentolamine-pretreated (Group III) . 2 Effect of AVP antagonist on regional distribution of BF 33 in rats from Group I (saline-pretreated). 3 Effect of AVP antagonist on regional distribution of BF in 36 rats from Group II (saralasin-pretreated). 4 Effect of AVP antagonist on regional distribution of BF 39 in rats from Group III (phentolamine-pretreated). 5 Tracings of two typical experiments showing the se lect iv i ty 42 of prazosin (a) and rauwolscine (b) in antagonizing pressor responses to iv injections of methoxamine and B-HT 933 in pentobarbital anaesthetized rats. 6 Effect of rauwolscine, phentolamine and prazosin on MAP, CO 43 and TPR in halothane anaesthetized rats. 7 Effect of rauwolscine on regional distribution of BF in 44 anaesthetized rats 8 Effect of phentolamine on regional distribution of BF in 46 anaesthetized rats. 9 Effect of prazosin on regional distribution of BF in anaes- 47 thetized rats. 10 Effect of rauwolscine on % distribution of CO in anaesthe- 48 tized rats . 11 Effect of phentolamine on % distribution of CO in anaesthe- 49 tized rats. 12 Effect of prazosin on % distribution of CO in anaesthetized 50 rats. - v i i -FIGURE Page 13 MAP, HR and MCFP during the infusion of normal saline at 52 different rates. 14 Dose-respones curves of MAP for methoxamine, B-HT 920, NA, 53 AVP and Ag II. 15 Dose-respones curves of HR for methoxamine, B-HT 920, NA, 56 AVP and Ag II. 16 Dose-response curves of MCFP for methoxamine, B-HT 920, NA, 58 AVP and Ag II. - v i i i -ABBREVIATIONS Angiotensin = Ag Arginine Vasopressin = AVP Blood Flow = BF Cardiac Output = CO Final Arterial Pressure = FAP Heart Rate = HR Mean Arterial Pressure = MAP Mean Circulatory F i l l i ng Pressure = MCFP Noradrenaline = NA Plasma Renin Act iv i ty = PRA Total Amount of Radioactivity = cpm Total Peripheral Resistance = TPR Venous Plateau Pressure = VPP - ix -ACKNOWLEDGEMENTS The author wishes to thank Dr. Catherine Cheuk Ying Pang for her excellent advice, supervision and guidance. The contributions 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 advice and guidance, Ms. Elaine L. Jan for secretarial assistance and Mr. Glenn Coll ins for s tat is t ica l analysis. While this work was carried out, the author was a recipient of a Brit ish Columbia Heart Foundation Research Traineeship, and would l ike to thank the BCHF for their financial 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 for the tissue; the "milieu interieur" as Claude Bernard (1885-86) characterized i t , is the primary function of the cardiovascular system. The supply of nutrient, oxygen, the removal of waste products, bulk transport between organs, maintenance of a normal tissue f lu id volume and fac i l i ta t ion of food absorption are among a number of functions ascribed to the c i rculat ion. A number of factors control the calibre of the blood vessels and, hence, the circulation of blood through the tissues which i t supplies. Nervous, thermal, hormonal, metabolic and myogenic influences consti-tute the most important of these factors and blood vessels may be affected by any, or a l l , of these stimuli in varying degrees in d i f -ferent circumstances; the ultimate stimulus to which the smooth muscle of the vessel responds, however, is a chemical one. Three systems that have been reported to participate in the maintenance of vascular tone are: the renin-angiotensin, arginine vasopressin (AVP) and sympa-thetic 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 rudi-mentary stage and, to say the least, 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 renal fa i lure (Hofbauer, et al 1977), hemorrhage (Arnauld et al_., 1977; Cousineau et al_., 1973; Fyhrquist et al_., 1981), adrenal insufficiency (Ishikawa and Schrier, 1984; Schwartz, et a l . , 1983) and congestive heart fa i lure (Uretsky, et a l . , 1985). Cer-ta in ly , derangements of multiple systems in addition to vasopressin occur in these conditions. The aim of my research was to consider the vascular roles of AVP and sympathetic nervous systems in the peripheral c irculat ion. How-ever, i t may be appropriate to discuss the vascular roles of these three vasopressor systems, and consider the conditions that alter the act iv i t ies of these systems. 1.1 Renin-angiotensin system The f i r s t group of people who caught the attention of modern investigators of a pressor role for the renin-angiotensin system was Goldblatt and his co-workers in 1934. The description given at that time by these investigators was in essence the existence of an endo-genous pressor substance released from the renal system; i f the renal artery was to be constricted, i t subsequently produced persistent hypertension. Ear l ier , Tigerstedt and Bergman (1898) had described a substance of renal origin which caused the elevation of blood pressure and i t was later realized that the substance of renal origin was actually an enzyme, "renin", which activated the formation of an endo-genous 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 catalysis of a blood protein in v i tro by renin would lead to the for-mation of a potent pressor agent which was also found in the venous effluent blood of the ischemic kidneys. This substance was later named angiotensin (Ag) (Braun, Menendez and Page, 1958). In order to determine the Ag levels in the blood, one t rad i t iona l -ly measures the plasma renin concentration or act iv i ty . Renin is released from the juxtaglomerular (JG) apparatus, a structure which can be divided into four dist inct parts: 1) granular ce l l s , 2) macula densa ce l l s , 3) agranular ce l ls and 4) mesangial cel ls (Barajas, 1964; Barajas and Lata, 1963). The ce l ls which are responsible for the syn-thesis and the storage of renin are the granular JG ce l l s , which are basical ly smooth muscle cel ls found in the media of the renal afferent arterioles. Lying close to granular JG cel ls are the macula densa ce l l s , which are either columnar or cuboidal. The ce l ls of agranular JG are composed of the walls of afferent and efferent arterioles and in some areas, the agranular JG ce l l s completely replace vascular smooth muscle cel ls lying in close contact with the macula densa ce l l s . The cel ls of the JG apparatus which form the extension to the glomeru-lus are the mesangial cel ls (Barajas, 1964; Barajas and Lata, 1963; Biava and West, 1966). Renin, an enzyme of approximately 40,000 molecular weight, is released into the circulation from the granular JG cel ls that l ine the afferent glomerular arterioles. It cleaves the leu-leu bond of angio-tensinogen to form Ag I, a decapeptide. Angiotensinogen, an o^-glo-bulin which is synthesized in the l i ver , is largely present in blood 4 and other extracellular space. The carboxyl terminal His-Leu of Ag I is cleaved by Ag converting enzyme (kininase II) to yield Ag II, an octapeptide. This reaction takes place in the vascular endothelium and the catalysis has been shown to be retarded by low pH and lack of calcium ions. Ag I has limited pharmacological properties. Ag II is acted upon by another enzyme, angiotensinase A, to form Ag III, a heptapeptide which has been shown to be physiologically and pharmaco-logical ly less active as a vasoconstrictor than Ag II (McCaa, 1978; Toda et a l . , 1978). However, Ag III and II are equi-effective in stimulating the secretion of aldosterone. Ag II has a ha l f - l i f e of 30 sec in the blood and i ts synthesis is dependent on the amount of c irculat ing renin. It is important to understand the mechanisms which affect renin release, since the level of c irculating Ag II is primarily dependent upon plasma renin levels. There are a number of physiological factors which control the plasma concentration of renin. These can be divided into three main classes. Primarily, there are the internal baroreceptors located in the affer-ent arter io les. Tobian et a l . (1959) showed that mean renal perfusion pressure controls the release of renin. Later, Blaine et a l . (1970) showed that hemorrhage and suprarenal aortic constriction in conscious dogs (with non-functional macula densa system) lead to an increase in plasma renin act iv i ty (PRA). The latter authors have also shown that i f the renal afferent arterioles are dilated by papaverine, haemorr-hage-induced renin secretion is prevented. Later, the level of pros-taglandins was shown to affect the baroreceptor-mediated renin release: 5 blockade of renal prostaglandins synthesis by indomethacin was shown to prevent baroreceptor-mediated increase in renin secretion (Blackshear et a l . , 1979). Overall, there appears to be two mechan-isms by which baroreceptors-mediate the release of renin: ( i) physi-cal change in afferent arterioles (Tobian, 1962) and ( i i ) a change in the amount of renal prostaglandins (Blackshear and Wathen, 1978). Secondly, the autonomic nervous system has been shown to affect renin release. Noradrenergic innervation is present in the walls of the afferent arteriole near the granular JG cel ls (Barajas, 1964; Barajas et a l . , 1977; Barajas and Muller, 1973). The stimulation of renal nerves has been shown to cause the release of renin into the circulation (Vander, 1965). It has been shown that renin release, as a result of renal nerve stimulation, can be inhibited by the B-adreno-ceptor antagonist propranolol (Loeffler et a l . , 1972). Noradrenaline (NA) infusion into anaesthetized dogs has been shown to increase PRA (Ueda et a l . , 1970). This action was prevented by propranolol, but not by the a-adrenoceptor antagonist, dibenamine. Two other systems have been implicated as influencing the release of renin via altera-tion of act iv i t ies of the autonomic nervous system: (i) the baro-receptors in the carotid sinus area (Cunningham et a l . , 1973) where acute carotid sinus hypotension was shown to produce an increase in PRA, and ( i i ) the le f t atr ia l low-pressure receptors, which respond to volume changes (Zehr, 1976). In this case, an increase in blood vo l -ume which resulted in mechanical distension of the le 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 bi lateral cervi-cal vagotomy. Thus, renin release can be modified by afferent vagal fibres arising from the cardiopulmonary region. These afferent sen-sory fibres constitute the afferent limb of a reflex arc that affects renin release via efferent sympathetic nerve fibres (Thames et a l . , 1978). Acetylcholine has been shown to have no effect on renin release from rat renal s l ice in vitro (DeVito et a l . 1970). However, acetylcholine may affect renin release indirectly by changing sodium excretion (Itskovitz and Campbell, 1976) or adrenergic neural act iv i ty (Loffelholz and Munscholl, 1969). The f inal mechanism that affects renin release involves the macula densa segment. Brown et a l . (1963) observed that sodium depletion leads to the elevation of PRA in man. This observation led Vander and Luciano (1967) to suggest that a decrease in tubular sodium concentra-tion in the region of the macula densa stimulates renin secretion. Other investigators have also shown that renin release is inversely related to sodium transport at the macula densa area (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 irbar i , 1972). In many of these studies loop diuretics (furosemide or ethacrynic acid) were used to increase the transport of sodium to the macula densa area. Since renin release was increased by these diuret ics, i t was concluded that renin release was related to the concentration of sodium present at the macula densa area. How-7 ever, i t has been shown that both these diuretics inhibit ionic trans-port at the macula densa ce l ls (Schnerman et a l . , 1976) and, there-fore, these drugs could have prevented the generation of the ionic signaling mechanism of the macula densa ce l l s . It is not clear whether sodium is the only ion sensed by the macula densa ce l l s ; i t seems that there are species differences in the signaling mechanism. In rats, for example, i t appears that chloride ions are involved in the release of renin by the macula densa cel ls (Galla et a l . 1977; Kotchen et a l . , 1976). The most important by-product of renin's act iv i ty is Ag II. Ag II has a very short ha l f - l i f e (30 sec) in the blood (Ferreira and Vane, 1967) and i ts continued prodution is dependent on the presence and, hence, the release of renin. Ag II has diverse physiological and pharmacological actions. The most important of which include vaso-constriction of the arterioles to maintain arterial pressure, stimula-tion of the adrenal cortex to enhance the synthesis and secretion of aldosterone, a mineralocortcoid, and stimulation of JG cel ls to modul-ate renal hemodynamics and renin secretion. Ag II also has a direct vasoconstrictor action on the resistance blood vessels and an indirect effect on arterioles by the stimulation of NA release (Zimmerman, et a l . , 1972). Stimulation of the synthesis and release of aldosterone enhances the reabsorption of sodium ions and the excretion of potas-sium and hydrogen ions by the distal renal tubule. Therefore, by the stimulation of aldosterone release, Ag II plays an indirect role in the control of sodium balance and blood volume. Ag II also increases 8 cardiac contract i l i ty (Blumberg et a l . , 1975; Koch-Weser 1965) direct-ly and indirect ly by the enhancement of NA release (Blumberg et a l . , 1975; Starke, 1970). The actions of Ag II on the venous bed has not been defined, to this end controversies appear to exist . In vivo experiments have shown that i .v . or intra-arter ial administration of Ag II has negligible effect on small and large veins of the limb and splanchnic area (Folkow et a l . , 1961; Rose, 1962). On the contrary, Ag II has been shown to cause contractions on isolated veins (Sutter, 1965; Somylyo and Somlyo, 1966). 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 antidiuretic hormone, was f i r s t described by Verney (1947) to be in the conservation of water in the body. AVP is synthesized primarily in the supraoptic, paraventri-cular and suprachiasmatic nuclei of the hypothalmus (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 in the specif ic hypothalamic nuclei . Their axons which traverse to the supraoptic hypophyseal tract terminate in the median eminence and pars nervosa of the neurohypophysis. The hypothalamo-hypophyseal system has become a useful model for the study of secretory mechanisms for the release of hormones. Four phases have been defined: synthesis of the molecule, packaging into neurosecretory granules, transport to the site of release and subse-9 quent release (Pickering, 1978). Most of the evidence concerning the mechanism of AVP release has come from studies of cultured neurons (Pearson, 1977). Vasopressin and neurophysin are synthesized simul-taneously possibly from precursors (Brownstein et a l . , 1977, Brown-stein and Gainer, 1977) and their release is calcium-dependent (Thorn et a l . , 1978) and probably involves exocytosis (Thorn, et a l . , 1978). Impulses coming from "osmoreceptors" 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 into two major categories: (i) osmotic and ( i i ) non-osmotic. The normal plasma level of AVP in man is about 0.5 to 5 pg/ml (Robertson et al_.,1976). The secretion of AVP is affected by changes in plasma osmolality (Landgraf and Gunther, 1983; Szsczepanska-Sadowska, 1972; Woods and Johnstone, 1983). However, in pathophysiological 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. His description of the mechanism for the release of AVP was that of an osmoreceptor which responded to changes in osmolality ( i . e . , tonicity) of the extracellu-lar f l u i d . The osmoreceptor hypothesis put forward by Verney was accepted for over three decades. However, a signif icant number of 10 observations involving intracarotid and/or intracerebro-ventricular administrations of hypo- or hypertonic solutions to animals during antidiuresis or water diuresis were inconsistent with the osmoreceptor hypothesis proposed by Verney. In 1978, Anderson postulated a new mechanism: the release of the hormone was controlled by a juxta-ven-tr icu lar sodium sensitive system. Bie (1978) produced evidence con-sistent with both hypotheses of receptors sensitive to osmolality or concentration of sodium. 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 is lacking such as the sub-fornical organs and supraoptic crest. The sodium sensitive receptors, on the other hand, are located within tfie blood-brain-barrier. The concept of the osmol-a l i ty sensing mechanism is by no means clear. The non-osmotic factors that affect the release of AVP include changes in blood pressure, blood volume and hormonal levels, hypoxia, surgical stress, etc. Reyden and Verney (1938) have shown that AVP is released during hemorrhage. Hypotensive hemorrhage (Cousineau, et j H . , 1984; Fyhrquist, et a l . , 1981; Landgraf and Gunther, 1983,) and non-hypotensive hemorrhage (Claybaugh and Share, 1973; Szczepanska-Sadowska, 1972) have both been shown to cause the release of large amounts of AVP. Both a f a l l in blood pressure and/or blood volume were reported to increase the release of AVP by the activation of carotid sinus baroreceptors and/or left atr ia l receptors (Rocha e Si lva, Jr . and Rosenberg, 1969; Share, 1976). Severe and mild hypoxia 11 have been shown to cause an increase in plasma AVP levels in fetal sheep (Stark et a l . , 1984) and dogs (Wang et a l . , 1984). Several hor-mones have also been implicated 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 hyper-tension. The vascular action of AVP has been studied both in vitro and in s i tu . AVP has been shown to be a potent vasopressor agent (Altura and Altura, 1977). It has been reported that, in the rat mesenteric artery, the amplitude of response to AVP was reduced in the presence of the prostaglandin inhibitor indomethacin (Manku and Horrobin, 1977). AVP was shown to potentiate the constrictor effect of NA, Ag II and potassium in isolated mesenteric artery preparation of the rat (Karmazyn et a l . , 1978). The effect of AVP in isolated veins appears to be negligible (Sutter, 1965; 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 doses of AVP were shown to cause constriction of splenic and intestinal beds, but dilatations of hepatic arterial beds in anaesthetizied cats (Cohen e_t a l . , 1970). Vasopressin was reported to have greater vasoconstrictor effect in grac i l i s muscle than that in mesenteric beds which, in turn, 12 is greater than that in renal beds of anaesthetized dogs (Schmid e_t a l . , 1974). Other investigators have also reported dif ferential effects of infusions of AVP on different 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 levels of AVP (amounts released during hemorrhage or surgery) were found to be pressor in conscious dogs (Szczepanska-Sadowska, 1973). In anaesthetized surgically-stressed dogs, infusions of similar levels of AVP were pressor only after inactivation of sino-aortic baroreceptor reflexes (Rocha e Silva and Rosenberg, 1969). It has also been shown that, although an infusion of pathophysiological levels of AVP did not increase the arterial pressure of anaesthetized surgically-stressed cats, i t caused a small decrease of superior mesenteric arterial conductance. An infusion of the dose of AVP following the removal of influence from endogenous AVP and Ag II resulted in an increase in arterial pressure and a much greater decrease in superior mesenteric arterial conductance (Pang et a l . , 1979). Infusion of low doses of AVP (two to f ive times physiol-ogical levels) into conscious dogs was reported to cause signif icant increases of pressure after baroreceptor denervation (Cowley et a l . , 1974; Montani et a l . , 1980) and after total pharmacological autonomic blockade (Pullan et al •, 1980). It has been shown by Mohring et a l . (1978a) that hypertension induced by the administration of deoxycor-ticosterone and sodium chloride salt (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 of a specif ic AVP anti-serum. Hypertension produced as a result of daily injections of lysine AVP was found to persist several months after the cessation of lysine AVP injections. This hypertension was associated with an increase in the act iv i ty 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 effects of AVP is to inactivate the AVP system. Cowley et a l . (1980) have shown that, in the absence of the arterial baroreceptor reflex and the renin-angio-tensin system, AVP released during a hypotensive hemorrhage was responsible for the compensation of arterial pressure following hemorrhage since the injection of a specif ic antagonist of AVP, dPVDAVP, completely prevented the compensation of arterial pressure following hemorrhage. Laycock et a l . (1979) showed that a small loss of blood (1 percent of body weight) was nonhypotensive in control rats. However, this amount of blood loss was hypotensive in Brattleboro rats with diabetes insipidus. Schwartz and Reid (1981) have shown that in conscious dogs, mild hemorrhage (15 ml/kg) did not change arterial pressure. However, the same hemorrhage s ignif icant ly decreased arter-ial pressure following the injection of a specif ic antagonist of AVP. It has been shown that the injection of a specif ic antagonist of the vasopressor effect of AVP in halothane-anaesthetized rats subjected to hypotensive hemorrhage caused a decrease of arterial pressure due to 14 the reduction of total peripheral resistance and a signif icant increase in the distribution of blood flow (BF) to the stomach, cae-cum, colon and skin (Pang, 1983). This suggests that following hypo-tensive hemorrhage, endogenously-released AVP contributed to the main-tenance of arterial pressure and peripheral vascular resistance. The injections of an AVP antagonist in conscious, water-deprived rats (Aisenbrey et a l . , 1981) and anaesthetized rats with glycerol-induced acute renal fa i lure (Hofbauer et a l . , 1981) were shown to cause a marked f a l l in arterial pressure suggesting a vascular role of AVP in these pathophsiological states. The administration of a specif ic antagonist of AVP in waterdeprived anaesthetized rats (Andrews and Brenner, 1981), conscious DOCA/salt hypertensive rats (Burnier et a l . , 1983a) and control conscious rats (Burnier et a l . , 1983a) were shown to cause a greater f a l l in arterial pressure following the inactiva-tion of other cardiovascular reflex systems. Thus, there is a lot of evidence to indicate a vascular role for AVP in physiological 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 supra-renal extracts. This observation led to the discovery of adrenaline by Abel in 1899 (Hartung, 1931). Cannon and Uridi l (1921) reported that stimulation of the sympathetic hepatic nerves resulted in the release of an adrenaline-like substance that increased blood pressure and heart rate (HR). 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 peripheral nerves that release NA. Euler, in 1946, showed that the sypathomimetic substance in purified extracts of sym-pathetic nerves and effector organs resembled NA. Burn and Rand (1959) postulated that sympathetic nerves release acetylcholine at the pre-ganglionic fibers which lead to the release of NA at the postjunc-tional f ibers . The anatomy of noradrenergic nerves did not become clear until the use of histochemical techniques for direct v isual iza-tion of NA (Falk et a l . , 1962). The morphological evidence, together with the electrophysiological evidence presented by Bennett and co-workers (1966), precipitated a model for the autonomic neuromuscu-lar junction, which suggests that NA (synthesized from tyrosine through a number of steps (Blaschko, 1939)) is stored in the granules (Burnstock and Robinson, 1967), and is subsequently released upon nerve stimulation. The transmitter released, hence, acts upon the appropriate receptor located on the effector c e l l . It has become clear over the past eighty years that adrenergic receptors are not homogeneous. The division of adrenergic receptors was init iated by Dale (1906), who made signif icant use of receptor concept in relation to the SNS. His work with the ergot alkaloids was probably the f i r s t , in terms of receptor antagonism, and this was part ia l ly responsible for the discovery of adrenoceptors. ' It was Alquist (1948) who studied the actions of NA, adrenaline and isopro-16 pylnoradrenaline and distinguished the sensit iv i ty of different t i s -sues to the mentioned agonists. This led to the division of adreno-ceptors into a- and ^-adrenoceptors and further subdivison of the e receptors were into and ^-adrenoceptors (Alquist 1948). The receptors that predominantly mediate the actions of the SNS in vascular smooth muscles are the a-adrenoceptors (Burnstock, 1961); they are responsible for the maintenance of tone in the vasculature. In recent years i t has become evident that the a-adrenoceptors are not of a single population. As early as 1956-57, Brown and Gi l lespie showed that dibenamine and phenoxybenzamine increased the stimulation evoked overflow of NA from the cat spleen. 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 reject-ed by Kirpekar and Cervoni (1963). This concept gained support later as more evidence was gathered (Hedquist 1969, 1970; Farnebo and Hamerger 1970, 1971; Stark et a l . , 1971). Langer et a l . (1970, 1971) investigated the effects of phenoxy-benzamine on NA release, metabolism and uptake in the cat n ict i tat ing membrane. He found that, even though phenoxybenzamine inhibited the metabolism and uptake of NA, this inhibition could not fu l l y account for the increase in the amount of NA released in the presence of phenoxybenzamine. As well, not only phenoxybenzamine, but also phen-tolamine, 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 direct ly increase the release of the transmitter per impulse by some negative feedback mechanisms on the nerve terminal. In 1970, two a-adrenoceptor agonists, namely, xylasin and clonidine, were found to reduce the stimlated evoked over-flow 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 of the effector c e l l , whereby stimulation of the nerve terminal would inhibit the release of NA, antagonism would attenuate NA release. Langer (1971) also postulated that the increase in the overflow of NA in the presence of a-adrenoceptor antagonists was due to a presynaptic effect . This ultimately resulted in the subdivision of a-adrenoceptors by Langer (1974). Langer proposed that the post-junctional a-adrenocep-tors be known as a^, and the pre-junctional a-adrenoceptors as a^. This hypothesis of Langer (1974) assumed a homogeneous population of a-adrenoceptors at the post-junctional level . Bentley and co-workers (1977) reported that the existence of a sub-population of a-adrenocep-tors mediating vasoconstriction in the vasculature of the cat and rat and that the vasoconstriction mediated through these receptors could not be abolished by a selective a-adrenoceptor antagonist, prazosin. A similar observation, that the contraction induced by NA involved two dist inct sets of a-adrenoceptors was reported in human arteries in  vitro by Moulds et a l . (1977). Despite these observations, post-junc-tional a-adrenoceptors were not c lass i f ied until 1979. 18 Drew e t a l . (1979) showed the ex i s t ence of two sub-c l asses of a-adrenoceptors at the p o s t - j un c t i o na l s i t e in the anaes the t i zed cat and p i thed r a t . The pressor e f f e c t induced by pheny lephr ine cou ld on ly be p a r t i a l l y antagonized by e i t h e r p razos in or yohimbine, but the e f f e c t cou ld be t o t a l l y abo l i shed i f both antagon i s t s were given s imu l t aneous l y . Th is led to the s u b - c l a s s i f i c a t i o n of p o s t - j un c t i o na l a-adrenoceptors i n to a^ and a2~adrenoceptors. S ince then i t has been shown that the p o s t - j un c t i o na l a^-adrenoceptor can cause both v a s o c o n s t r i c t i o n (Flanvhan and MaGrath 1980; Timmermans and Van Zweiten 1980; Kobinger and P i c h l e r 1980a,b; E l l i o t and Reid 1983; Van Meel et a l . 1983; Hickes et a l . 1984) and v eno con s t r i c t i o n (Schumann and Lues 1983; Sho j i et a l . 1983; Kalkman et a l . 1984; Steen et a l . 1984) in response to nerve s t i m u l a t i o n or NA i n f u s i o n . 1.4 Nature of the problem The aim of the i n v e s t i g a t i o n was, f i r s t l y , to cons ider the r e l a -t i v e i n f l u ence of the AVP and the SNS in the c on t r o l of pe r i phe ra l r e s i s t an ce and, second ly , to examine the c o n s t r i c t o r ac t i ons of v a r i -ous pressor agents in the capac i tance v e s s e l s . 1.4.1 In f luence of vasopress in and sympathet ic nervous system in  the con t ro l of vascu l a r r e s i s t a n c e . In the f i r s t set of exper iments, the vascu l a r r o l e of endogenous ly-re leased AVP dur ing s u r g i c a l s t r e s s in pen toba rb i t a l anaesthet i zed r a t s was examined. Large amounts of AVP were shown to be re leased dur ing surgery (Moran et a l . , 1964; Bonjour and Ma l v i n , 1970). AVP re l eased dur ing surgery has been shown to p a r t i c i p a t e in the con t ro l of mean a r t e r i a l pressure (MAP) and 19 peripheral resistance (McNeill and Pang, 1982; Pang, 1983). The vas-cular role of endogeously-released AVP was shown to be attenuated in the presence of opposing reflexes from the renin-angiotensin and/or the SNS (Burnier et a l . , 1983a; Waeber et a l . , 1984; Dipette et a l . , 1984). The study was designed to investigate the vascular role of AVP in the presence and absence of influences from the renin-angiotensin system or the a-adrenergic system. Saralasin, a competitive antagon-ist of Ag II, was used to remove the influence of the renin-angioten-sin system, while phentolamine, a non-selective a-adrenergic antagon-i s t , was used to abolish a-adrenergic act iv i ty . These blockers were continously infused into pentobarbital anaesthetized rats. Cardiac output (CO) and the distribution of BF were determined in the three groups of rats by the use of the radioactively labelled microspheres prior to and following the adminstration of a specif ic antagonist of pressor effects of AVP, [d(CH2)5Tyr(Me)AVP] (Kruszynski et al_., 1980; Pang and Leighton, 1981; Manning and Sawyer, 1982). The second set of experiments investigates the physiological role of the a-adrenoceptors in the vasculature. Two sub-classes of a-adrenoceptors were shown to co-exist at the post-junctional level , and they contribute individually to vascular tone (Drew et a l . , 1979; Flanvahan and McGrath, 1980; E l l i o t and Ried, 1983; Hick's, 1984; Kalman et al.,1984; Kobinger and Pichler, 1982; Steen et a l . , 1984). However, the physiological significance of antagonism of these recep-tors on the vasculature is not clear. It has been shown that the a.- and a 9-adrenoceptors operate by different mechanisms in s i tu , 20 (Van Zwieten et a l . , 1982; Pedrinell i and Tarazi, 1985; Van Meel et a l . , 1981). Thus, a simultaneous activation of the two separate receptor types may cause additive vasconstrictor effects. However, there remains another poss ib i l i ty of that an uneven distribution of the receptors may exist throughout the vasculature (T'orneberbrandt et a l . , 1985). Hence, the relative contribution of the appropriate sub-class of adrenoceptors on vascular tone may depend on the relative density of these receptors in the vessel. In vivo experiments were undertaken to examine the relative contributions of the sub-classes of a-adrenoceptors to the distribution of CO in different vascular beds of halothane anaesthetised rats. The effect of selected a-adrenocep-tor antagonists on MAP, CO and i ts distribution were investigated us-ing prazosin, rauwolscine and phentolamine as a^, a^ and non-selective a-adrenoceptor antagonists, respectively. 1.4.2 Actions of AVP, Ag II and a-adrenergic agonist on venous  tone. 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 rculat ion. It has been estimated that approximately 70 to 80 percent of blood volume is in veins. As well , i t is recognized that CO is determined by venous tone, provided that the heart is not in fa i lure . Experi-ments were carried out to investigate the actions of various vasocon-str ictor agents on the capacitance vessels in conscious animals. One method for the estimation of the total body venous tone is to deter-mine the mean circulatory f i l l i n g pressure (MCFP) (Yamamoto et a l . , 1980). MCFP is the pressure that would occur throughout the c i rcu la-21 tion i f one would instantaneously bring al l the pressures in the c i r -culation to an equilibrium (Guyton et a l . , 1973; Caldini et a l• , 1974). The MCFP has been shown to ref lect CO (Guyton et a l . , 1973). Provided that blood volume remains constant, an increase in MCFP indicates an increase in the tone of the capacitance vessels. The effect of a number of vasoactive drugs on MCFP was invest i-gated in conscious rats in order to determine the receptors respons-ible for the mediation of the venoconstrictor response in vivo. The vasoconstrictor agents that were studied include NA, methoxamine (aj - a g o n i s t ) , B-HT 920 (a 2 -agon is t ) , Ag II and AVP. 2 MATERIALS AND METHODS 2.1 Surgical preparation of rats 2.1.1 Microsphere studies. Sprague-Dawley rats (375-500 g) were anaesthetized with sodium pentobarbital (60 mg/kg) or haothane (1.5% in a i r ) . These rats were subjected to a standard laparotomy with a two-inch mid-line incis ion. Cannulae (PE 50) f i l l e d with heparinized saline (25 IU) were inserted into the le f t ventricle via the right carotid artery, with the help of the arterial pressure trac-ing, for the injection of microspheres into the abdominal aorta via the caudal and the i l i a c arteries, for recording of MAP and blood withdrawal, and into the femoral vein for infusion of drugs. In the halothane anaesthetized rats, after the completion of surgery, a low level of anaesthesia was maintained by reducing the flow of gas mix-ture so as to preserve some eyelid or limb reflexes. 22 2.1.2 The se lect iv i ty of prazosin and rauwolscine for blocking  and a ^ , receptors. Pentobarbital anaesthetized (60 mg/kg) Sprague-Dawley rats (450-500 g) were subjected to cannulation of the i l i a c artery and femoral veins for the recording (Grass Polygraph, Model 79D, Mass.) arterial pressure by a pressure tranducer (P23I0, Gould Statham, Ca l i f . ) and the injection or infusion of drugs, respec-t ive ly . The effect of rauwolscine, prazosin and phentolamine on MAP and CO was investigated. 2.1.3 The effects of methoxamine, B-HT 920, noradrenaline, vaso-pressin and angiotensin II on MCFP. The method of Yamamoto et a l . (1980) was used to determine MCFP. A balloon-tipped catheter was inserted into the right atrium through the right external jugular vein of halothane anaesthetized Sprague-Dawley rats (350-450 g). The proper location of the balloon was indicated by a simultaneous in-crease in venous pressure and a decrease in arterial pressure to less than 25 mmHg, when a small volume of normal saline was injected into the balloon. Cannulae were also inserted into the i l i a c artery for the measurement of arterial pressure, into the femoral veins for the infusions of drugs, and into the inferior vena cava via the femoral vein for the measurement of central venous pressure by a pressure transducer (P23DB, Gould Statham, C a l i f . ) . Al l cannulae were f i l l e d with heparinized saline and tunnelled subcutaneously to the back of the neck, exteriorized and secured. The rats were allowed to recover for 24 hr before the measurements of pressures were made. 23 2.2 Microspheres CO and the distribution of BF were determined by the reference sample method (Malik et aj_., 1976), using radioactively-labelled microspheres (15 um diameter, New England 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 arterial cannula into a heparinized syringe for 1 min. During the withdrawal of blood at a constant speed, a 200 yl sample of a vigorously-vortexed pre-counted microsphere suspension (containing 20,000-30,000 microspheres, c y 1 1 o labelled with either Co or Sn) was injected and flushed (200 vii saline) over 10 sec into the le f t ventric le. To avoid a poss ib i l -i ty of a variation in the distribution between the two different iso-57 topes, in half of the experiments each group of rats Co was given before ^ S n , while in the other half of the experiments *^Sn was injected f i r s t . At the end of the experiments, whole rats were d is-sected. Al l organs were removed, weighed and loaded into vials for counting. In rare instances (less than 5%), where BF to the le f t and right kidney dif fers by more than 20%, the experiment was rejected as i t was assumed that the mixing of microspheres was not adequate. Blood samples, tissue samples, test tubes and syringes used for the injection of microspheres and the collection of blood were counted for radioactivity (Beckman 8000 Gamma Counter) at energy settings of 95-165 kev and 320-460 kev for 5 7 Co and 1 1 3 S n , respectively. At these energy settings, the spi l l -over of Co into Sn channel was negl i-gible (0.03%) and no correction was made for Co spi l lover. The 24 s p i l l - o v e r of Sn i n to the Co channel was 16.7% and c o r r e c t i o n of Co counts was done by sub t r a c t i ng Sn s p i l l - o v e r from Co counts . 2.3 Exper imental p ro toco l 2.3.1 Vascu la r r o l e of vasopress in in the presence and absence of  i n f l u en ce from ang io tens in or a lpha-adrenerg i c system. CO and i t s d i s t r i b u t i o n were determined in a l l groups of r a t s by the i n j e c t i o n s of r a d i o a c t i v e l y - l a b e l l e d microspheres i n to the l e f t v e n t r i c l e s p r i o r to and f o l l ow i n g the adm in i s t r a t i on of a s p e c i f i c antagon is t of AVP, [d(CH 2 ) 5 Tyr(Me)AVP] (5 ug/kg) (Kruszynsk i et a l . , 1980; Pang and Le igh ton , 1981; Manning and Sawyer, 1982). In Group I , normal s a l i n e was in fused (0.08 ml/min/kg) 30 min a f t e r s u r g i c a l p repara t i on of the r a t s and the i n f u s i o n was cont inued u n t i l the end of the exper iment. The f i r s t i n j e c t i o n of microspheres was conducted 10 min a f t e r the s t a r t of s a l i n e i n f u s i o n . Ten minutes a f te rwards , AVP antagon is t was i n j e c t ed i n to the l e f t v e n t r i c l e . We have shown tha t i v i n j e c t i o n of 4 yg/kg of t h i s antagon is t prevented pressor responses to iv i n f u s i on s of supramaximal doses of AVP in r a t s (Pang and Le i gh ton , 1981). A f t e r another 10 min, microspheres l a b e l l e d w i th a d i f f e r e n t i so tope was i n j e c t ed i n t o the l e f t v e n t r i c l e . Group II r a t s were subjected to i v i n f u s i o n of s a r a l a s i n (10 ug/min/kg) at 0.08 ml/min/kg ins tead of s a l i n e . The i n f u s i o n of s a r a l a s i n was cont inued dur ing the i n j e c t i o n of the microspheres and the AVP an tagon i s t . P r e l im i na r y r e s u l t s show-ed tha t a cont inuous i n f u s i on of s a r a l a s i n at t h i s r a t e f o r 10 min b locked complete ly (10C%). the pressor responses to iv i n j e c t i o n s of Ag II (1 yg / kg ) . The pressor e f f e c t s of Ag II was t e s ted in a l l r a t s 25 prior to the infusion of saralasin and after the second injection of microspheres. In a l l cases, saralasin completely blocked pressor responses to iv injections of Ag II. Group III was subjected to i .v . infusion of phentolamine (0.5 mg/kg/min) at 0.08 ml/min/kg started 10 min prior to the f i r s t injection of microspheres and continued during the injections of AVP antagonist and the microspheres. We have pre-viously found that 10 min infusion of phentolamine at the same rate completely blocked pressor responses to i .v. injections of methoxamine (Sigma, 250 yg/kg), BHT 933 (1 mg/kg) and clonidine (5 ug/kg). MAP recordings obtained during the f i r s t and the second injections of microspheres were used to indicate MAP during control and drug treat-ment period, respectively. 2.3.2 Select ivity of prazosin and rauwolscine. In two rats, methoxamine (0.25 mg/kg) and B-HT 933 (1 mg/kg) were i .v . injected prior to and following the infusion of rauwolscine (1 mg/kg infused at 0.044 ml/min over a 15-min interval). In another two rats, the same doses of methoxamine and B-HT 933 were i .v. 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 Effects of rauwolscine, prazosin and phentolamine on BP, CO  and i ts distr ibut ion. Rats were randomly divided into three groups (n = 10 each group). In the f i r s t group, the f i r s t injection of microspheres was conducted 30 min after surgery. Afterwards, rauwols-cine was infused (1 mg/kg infused at 0.044 ml/min over a 15-min inter-val) into the rats. A second injection of microspheres labeled with a 26 different isotope was done 15 min after the start of the infusion of rauwolscine. The second and third groups of rats were subjected to a similar protocol, except that instead of rauwolscine, prazosin (1 mg/kg) and phentolamine (7 mg/kg), respectively, were i .v . infused at the same rate and over the same time interval . MAP recordings obtained during the f i r s t and the second injections of microspheres were used to indicate MAP during control and drug treatment periods, respectively. 2.3.4 Effects of methoxamine, B-HT 920, noradrenaline, angiotensin  II and vasopressin on MCFP. MCFP was determined in conscious rats. This was accomplished by stopping the circulation of the rats via the injection of a small volume of f lu id into the balloon that was pre-viously inserted into the right atrium. Within 5 s following the in-f lat ion of the balloon, MAP decreased and central venous pressure increased simultaneously. Central venous pressure measured within 5 s following the cessation of circulation was referred to as venous plateau pressure (VPP). MAP and VPP were measured in rats (n = 8 for each drug or n = 6 for normal saline) prior to, and after a 10-min, infusion of normal saline (at 7-26 x 10 ml/min), methoxamine (1.6 x 10" 1 0 -4.8 x 10" 9 moles/kg/min), B-HT 920 (3.5 x 10"9-11.2 x 10" 8 moles/kg/min), NA (3.0 x 1 0 - 1 0 - 8 x 10~9 moles/kg/min), Ag II (9.7 x 1 0 - 1 1 - 2 . 8 x 10~9 moles/kg/min) or AVP (4.5 x 10 _ 1 1 -1 .4 -9 x 10 moles/kg/min). Dose-response curves were carried out for each agonist. The rats subjected to NA infusion were f i r s t pretreated with propranolol (8 x I0~^moles/kg i .v. bolus injection followed by 27 3.4 x 10" moles/kg/min continuous i .v. infusion) to prevent the stimulation of 8-adrenoceptors by NA. In the determination of dose-response curves for Ag II, 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. The maximum volume of f lu id infused during the 2-hr infusion 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 Al l drugs were made up fresh dai ly. d(CH2)5Tyr(Me)AVP, rauwolscine HC1 (Carl Roth GmbH and Co., NY), phentolamine HC1 (CIBA Pharmaceutical Co., Summit, NJ), methoxamine HC1 (Boroughs Wellcome, London), B-HT 933 HC1 (Boehringer Ingelheim Canada Ltd . , Ontario), B-HT 920 HC1 (Boehringer Ingelheim Canada Ltd.) , NA (Sigma Chemical Co. Mu. U.S.A.), AVP (Calbiochem. La Jol la U.S.A.), Ag II (Ciba-Geigy Canada) and propranolol (Sigma Chemical Co. Mo. U.S.A.) were dissolved in normal saline; prazosin HC1 (Pfizer Central Research, Sandwich, England) was dissolved in 5% glucose solution. 2.5 Calculations TPR was calculated by dividing MAP (mm Hg) by CO (ml/min). CO, BF and % distribution of CO to different organs were 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 amount of radioactivity (cpm) injected was obtained by sub-tracting the amount of radioactivity le f t in the tube, injecting syringe and flushing syringe from the amount of radioactivity or ig in-a l ly present in the tube. Radioactivity (cpm) in blood was obtained by adding the amount of radioactivity in the blood sample, in the can-nula and syringe used for collecting blood. MCFP was calculated using the equation of Samar and Coleman (1978) and a value of 1/60 for arterial-to-venous compliance ratio (Yamamoto et a l . , 1980). MCFP = VPP^- + (FAP - VPP) FAP represents the f inal arterial pressure (mmHg) obtained within 5 s following circulatory arrest. 2.6 Stat ist ica l analyses Analysis of variance with repeated measures was used to compare data obtained during the f i r s t and second determinations 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 ty or error of less than 0.05 was pre-selected as the cr iter ion for s tat is t ica l significance. 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 the infusion of saline or drugs in the various groups of rats. A 10-min infusion of saline did not alter MAP in rats from Group I. Infusion of saralasin and phentolamine decreased MAP in Groups II and III, respectively. However, a comparison of results between Group I and II during infusions of saline and saralasin, respectively, shows that the infusion of saralasin in Group II did not cause any signif icant change in MAP, CO or TPR from the corresponding values in Group I (Table 1). Therefore, unlike comparisons of MAP within the same animal, we were unable to detect a signif icant 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 were s ignif icant ly lower than the corresponding values in Group I following the infusions of phentolamine and sal ine, respec-t ive ly . There was no difference in TPR between Groups I and III. 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). In Table 2, results of MAP, TPR and CO are normalized as % control to allow comparisons of the effects of the AVP antagonist in the different Groups. 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, II, and III Group I Group II Group III MAP (mmHg)3 103 ± 17 106 ± 14 95 ± 13 MAP (mmHg)b 103 ± 17 91 ± 17 c 79 ± 1 0 c d CO (ml/min)b 105 ± 26 90 ± 20 69 ± 20 d TPR (mmHg min/ml)b 1.04 ± 0.29 1.03 ± 0.15 1.20 ± 0.37 Al l values denote mean ± SD. n = 8 in each group. a Denotes MAP readings prior to drug (saline) infusion. h Denotes readings of MAP, CO or TPR during the f i r s t determination of CO, at 10 min following the infusions of sal ine, saralasin or phentolamine in Groups I, II and III, respectively. c Signif icantly different from MAP prior to the infusions of drug or saline within the same group (p < 0.05). d Signif icantly different from corresponding values in Group I (p < 0.05). 31 F i g . 1. E f f e c t of AVP antagon is t on MAP, CO and TPR in anaes the t i z ed , s u r g i c a l l y s t r e s sed r a t s : i n t a c t and s a l i n e - p r e t r e a t e d (Group I ) , s a r a l a s i n - p r e t r e a t e d (Group I I ) and phento lamine-pret reated (Group I I I ) . CO was determined twice in each group of r a t s . AVP antagon is t was given to each group between the f i r s t and second determinat ions of • CO. s i g n i f i c a n t d i f f e r en ce from va lues obta ined from the f i r s t determinat ion (p < 0 .05) . \ \ \ \ \ \ \ \ \ \ \ \ \ 1 150 n 100 H E S 50 mean + SD n = 8 i n e a c h g r o u p \ \ \ \ \ \ \ \ \ \ \ _ 1.5 l --^ c i.o cn £ 0.5 ni \ \ \ \ \ \ \ JbL i i III I I I III GROUPS GROUPS GROUPS 33 Fig. 2. Effect of AVP antagonist on regional distribution of BF in rats from Group I (saline-pretreated). Whole rats were dissected for the determination of BF. Al l values represent BF to entire organs. Glands include thyroid, parathyroid, salivary and adrenal glands. BF was determined twice in each rat . AVP antagonist was given between the f i r s t and second determinations of BF. signif icant difference from BF obtained from the f i r s t determination (p < 0.05). 34 BLOOO FLOW (ml/min) LUNGS HEART LIVER STOMACH INTESTINE CAECUM & COLON KIDNEYS SPLEEN MUSCLE SKIN TESTES BRAIN GLANDS BONE //////////< z z z _1 O ZZZ3—• 3= 3: o 2 O n c r 3 •4-OA 3 o . II C D 35 TABLE 2. Effects of AVP antagonist on MAP, CO and TPR in Groups I, II and III Group I Group II Group III % of control MAP 87 ±12 75 ± 10 a 71 ± 13 a % of control CO 105 ± 17 106 ± 22 118 ± 30 % of control TPR 85 ±18 73 ± 15 61 ± 21 a All values denote mean ± SD. n = 8 in each group. 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 corres-ponding values obtained during the f i r s t determination of CO in the various groups of rats: Group I (saline-treated); Group II (sarala-sin-treated); Group III (phentolamine-treated). a Signif icantly different from Group I (p < 0.05). 36 Fig. 3. Effect of AVP antagonist on regional distribution of BF in rats from Group II (saralasin-pretreated). Whole rats were dissected for the determination of BF. Al l values represent BF to entire organs. Glands include thyroid, parathyroid, salivary and adrenal glands. BF was determined twice in each rat. AVP antagonist was given between the f i r s t and second determinations of BF. signif icant difference from BF obtained from the f i r s t determination (p < 0.05). 30 -25 -O cc ui 3 - 1 / 1 0 0 2 : U J <j z t— . 2 : U l Z <; > o U J U J O Q —> V O »-« l/> << Z rr> U J •—• H - < ; >- . a. r D ^ u i < x _ j o _ l - J l/> Z O • « ^ 2 ; </> I— C O 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 ta t i s t i ca l l y s igni -f icant . The AVP antagonist caused signif icantly greater decreases of % control MAP and TPR in Group III than in Group I. The AVP antag-onist did not cause any dif ferential effects on % control CO between Group I and Groups II or III . The results show that AVP antagonist exerts greater depressor effects in rats with antagonisms of the renin-angiotensin or a-adrenergic system than in intact rats. 3.3 Effect of AVP antagonist on the distribution of BF In intact rats (Group I) , the AVP antagonist increased BF to the stomach and skin (Fig. 2), but did not alter BF to any other organs. This indicates that AVP plays the greatest vasoconstrictor influence in the area of the stomach and skin. During the infusion of saralasin (Group II) , AVP antagonist increased BF to muscles and skin and de-creased BF to the lungs and l iver (Fig. 3). Therefore, in the absence of influence from Ag II, AVP has the greatest vasoconstrictor effects in vascular beds in the muscles and skin. During a continuous infu-sion of phentolamine (Group III) , AVP antagonist markedly increased muscle BF and decreased BF to the l i ver , intestine, kidneys and testes (Fig. 4) . Thus, in the absence of the a-adrenergic system, AVP plays the greatest influence in BF to the muscle. 1 39 Fig. 4. Effect of AVP antagonist on regional distribution of BF in rats from Group III (phentolamine-pretreated). Whole rats were dis-sected for the determination of BF. A l l values represent BF to entire organs. Glands include thyroid, parathyroid, salivary and adrenal glands. BF was determined twice in each rat . AVP antagonist was giv-en between the f i r s t and second determinations of BF. S i g n i f i c a n t difference from BF obtained from the f i r s t determination (p < 0.05). DLOOD FLOW (ml/min) LUNGS HEART LIVER STOMACH INTESTINE CAECUM & COLON KIDNEYS SPLEEN MUSCLE SKIN TESTES BRAIN GLANDS BONE o O O O O A/[/\AAAAAyy\yyy CD 2 O ro c o D II CO 41 3.4 Select ivity of prazosin and rauwolscine In two experiments, the infusion of prazosin was found to com-pletely block pressor responses to i .v . injections of methoxamine, but not that of B-HT 933. F ig . 5a shows the tracing of a typical experi-ment. In another two experiments, the infusion of rauwolscine did not block the pressor responses to i .v. injections of methoxamine, but antagonized (> 80%) pressor responses (as increases of systol ic arter-ial pressure) to i .v. injections of B-HT 933. F ig . 5b shows the trac-ing of a typical experiment. 3.5 Effects of rauwolscine, prazosin and phentolamine on BP, CO,  TPR and the distribution of CO A reduction of MAP was obtained following the injection of rauwolscine, prazosin or phentolamine into each group of rats (Fig. 6). The reductions of MAP in rats treated with rauwolscine and phentol-amine were associated with reductions of CO, but no change in calcu-lated TPR. CO was decreased to 82% and 67% of control values follow-ing treatments with rauwolscine and phentolamine, respectively. In contrast, 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 result of a decrease in CO. Significant reductions of BF to most organs were detected after the infusion of rauwolscine, except in the lungs, l i ver , spleen and muscle where BF was not changed (Fig. 7). The infusion of phentol-amine caused reductions of BF to most organs, except the lungs, l iver B-HT 933 Methoxamine Rauwolscine Methoxamine B-HT 933 Fig. 5. Tracings of two typical experiments showing the se lect iv i ty of prazosin (a) and rauwolscine (b) in antagonizing pressor responses to iv injections of methoxamine and B-HT 933 in pentobarbital anaesthetized rats. n = 10 in each group mean + SD c E I E E cc a. o.s -E E O o R A U W O L S C I N E 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 a < 2 Fig. 6. Effect of rauwolscine, phentolamine and prazosin on MAP, CO and TPR in halothane anaesthetized rats. *Significant difference from control .values (p < 0.05). n = 10 in each Group of rats. C C O N T R O L S R A U W O L S C I N E mean + SD n = 10 L U N C S H E A R T L I V E R S T O M A C H I N T E S T I N E C A E C U M IC I ONE Y S S P L E E N M U S C L E S K I N T E S T E S OL C O L O N <30j> <30gJ Fig. 7. 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 (Fig. 8). Treatment with prazo-sin, on the other hand, only decreased BF to the skin and increased BF to the lungs (Fig. 9). The relative distribution of CO was changed similarly after the administration of rauwolscine, phentolamine or prazosin (Fig. 10, 11 and 12). After the infusion of rauwolscine, the % distribution of CO was reduced in the heart, intestine, caecum and colon, kidneys, glands and brain, but increased in the lungs and muscle (Fig. 10). After the infusion of prazosin and phentolamine, the % distribution of CO was reduced in the heart, caecum and colon, kidneys, skin and glands, but increased in the lungs and muscle (Fig. 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 the infusions of saline and the various vasoconstrictor agents. There was no difference in the control values of MAP, MCFP and HR prior to the infusion of any drugs or sal ine. The infusion of saline did not alter MAP (Fig. 13). Figure 14 shows the effects of infusions of the various drugs on MAP. The infusions of B-HT 920, methoxamine, NA, AVP and Ag II al l caused dose-dependent increase in MAP above the values obtained during the continuous infusion of sal ine. AVP, methoxamine and B-HT 920 caused signif icant increases of MAP at doses equal to and higher than the third infused dose (p < 0.05, F ig . 14). NA and Ag II caused signif icant increases of MAP at doses equal to and higher than the second infused dose (p < 0.05, F ig . 14). LUNCS HEART LIVER STOMACH INTESTINE CAECUM KIDNEYS SPLEEN MUSCLE SKIN TESTES GLANDS BRAIN COLON (3095 Fig . 8. Effect of phentolamine on regional distribution of BF in anaesthetized rats (n = 10). •Significant difference from control values (p < 0.05). c E \ S ... o ^ , 0 J Q O O _ i a i L U N G S H E A R T i i r 3 ^ 1 i LZ1 C O N T R O L S P R A Z O S I N mean + SD ri = 10 1 I Ffa f i t L I V E R S T O M A C H I N T E S T I N E C A E C U M M O N E Y S S P L E E N M U S C L E * « < " T E S T E S G L A N D S 1 R A . N C O L O N ' <>Og> (i09) Fig . 9. Effect of prazosin on regional distribution of BF in anaesthetized rats (n = 10), •Significant difference from control values (p < 0.05). O C O N T R O L LUNGS HEART LIVER STOMACH INTESTINE CAECUM KIDNEYS SPLEEN MUSCLE SKIN TESTES GLANDS •» C O L O N C30g> CJO » l Fig . 10. Effect of rauwolscine on % distribution of CO in anaesthetized rats (n = 10). •Significant difference from control values (p < 0.05). C l «3-: o O O 4 1 I I I i ,D C O N T R O L P H E N T O L A M I N E mean + SO n = 10 •=1 * 4 I LUNGS HEART LIVER STOMACH INTESTINE CAECUM KIOHEYS SPLEEN MUSCLE SKIN TESTES GLANDS BRAIN COLON <10g) <10a) Fig . 11. Effect of phentolamine on % distribution of CO in anaesthetized rats (n = 10). •Significant difference from control values (p < 0.05). LUNGS HEART LIVER STOMACH INTESTINE CAECUM KIDNEYS SPLEEN MUSCLE SKIN TESTES GLANDS COLON C30g> <30g> Fig . 12. Effect of prazosin on % distribution of CO in anaesthetized rats (n = 10). •Significant difference from control values (p < 0.05). 51 TABLE 3. Control vaules of MAP, MCFP and HR Methoxamine 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. n = 8 in each group except for normal saline where n = 6. Values of MAP (mmHg), MCFP (mmHg) and HR (beats/min) were ob-tained prior to the admininstration of drugs or normal sal ine. 52 200 n I 1 5 0 6 < 1 1 0 0 so-S a I \ n Q ( N - 6 > 01 I E E CL U. u 7 -1 f — i r 5 0 0 i c - 4 3 0 E N U jj 4 0 0 0 a 5 3 3 0 or I 3 0 0 2 3 0 -t 2 0 4 0 6 0 Time ( m i n ) eo — \ i oo F i g . 13. MAP, HR and MCFP dur ing the i n f u s i on of normal s a l i n e at d i f f e r e n t r a te s (7-26 x 10 ml /min/ ra t ) over a 100 min. pe r i od (mean ± SE) . 53 Fig. 14. Dose-respones curves of MAP for methoxamine, B-HT 920, NA, AVP and Ag II. The rats subjected to NA infusion were f i r s t pretreat-ed with propranolol to prevent the stimulation of e-adrenoceptors by NA. In the determination of dose-response curves for Ag II, 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 2 5 0 - 1 ( O ) NA C • ) M a t h a x q m i n o C A ) B - H T 9 2 0 ( T ) A V P C -• ) A g I I 2 0 0 H CD I E E ISO Q_ < 2 1 0 0 5 0 i i—i" i i i n i r~—i—III 1 1 1 . | 1 — i — i ~ r i t i i i 1—i— I I i r 1 1 1 -11 - 1 0 - 9 - 8 - 7 M o l e s / K g / m i n 55 HR was not changed during the infusion of saline (Fig. 13). The infusion of a l l the vasoactive agents produced decreases in HR (Fig. 15) compared to control HR obtained before the infusions of these drugs (Table 3). MCFP readings were not changed during the infusion of saline (Fig. 13). MCFP obtained during the infusions of various doses of methoxamine (Fig. 16) were not s ignif icant ly different from the control MCFP prior to drug infusion (Table 3). MCFP was s l ight ly , but s igni f icant ly , increased during the infusions of the highest three doses of AVP. B-HT 920 caused signif icant increases of MCFP at doses equal to, and higher than, the second infused dose, while NA and Ag II s ignif icant ly increased MCFP at doses equal to, and higher than, the third infused dose (p < 0.05, F ig. 16). The order of the effectivness of these vasoconstrictors to increase MCFP was: Ag II > NA = B-HT 920 > AVP. 56 Fig. 15. Dose-respones curves of HR for methoxamine, B-HT 920, NA, AVP and Ag II. The rats subjected to NA infusion were f i r s t pretreat-ed with propranolol to prevent the stimulation of e-adrenoceptors by NA. In the determination of dose-response curves for Ag II, 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 difference from HR obtained from the f i r s t determination (p < 0.05). 57 500 n C O ) NA C • 5 H o t h Q x cxm i n a < A ) B-HT 920 < T ) A V P C • 5 A g I I 450H 2 0 0 "1 1 — I i I Mll| 1 — I I I I 111 j 1 — I I I I III | 1 — I I I I III] - ) ] - ] • - 9 - 8 - 7 M o l e s / k g / m i n 58 F ig . 16. Dose-response curves of MCFP for methoxamine, B-HT 920, NA, AVP and Ag II. The rats subjected to NA infusion were f i r s t pretreat-ed with propranolol to prevent the stimulation of e-adrenoceptors by NA. In the determination of dose-response curves for Ag II, 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 i c H /^\ ui I E Q L 8-j LL U 2 7-) 6H c o ) N A ( • ) MethQxqminQ C A ) B-HT 920 C r ) AVP < • ) Ag I I 1 1 1 I 1 — I ' I I i i : T l i i i i i i i l I I l l l 111 l 1 — i i 1 I I I ] -10 -9 -8 Mo 1 Q s / k g / m i n - 7 60 4 DISCUSSION It has been shown that large amounts of AVP are released following surgery in different species of animals (Moran et a l . , 1964; Bonjour and Malvin, 1970; Ishihara et a l . , 1978). The injection of AVP antag-onist in halothane anaesthetized surgically stressed rats has been shown to decrease MAP by the reduction of TPR (Pang, 1983). It is expected that the depressor response following the injection of AVP antagonist would result in reflex activation of other endogenous pres-sor systems, thereby masking the vascular effects of the antagonism of AVP. The f i r s t study investigates vascular effects of endogenously released AVP in the presence and absence of influences from other endogenous pressor systems, namely, the renin-angiotensin or the a-adrenergic systems. The injection of the AVP antagonist decreased MAP and TPR, but did not alter CO in al l groups of rats. The AVP antagonist caused a s ig -ni f icant ly greater decrease of % control MAP in Groups II and III than in Group I. As well , the AVP antagonist caused a s l ight , but not s ig-ni f icant ly greater than in Group I, decrease of % control TPR in Group II, and a s igni f icant ly greater decrease of % control TPR in Group III than in Group I. The results show that, in the absence of vasocon-str ictor influences from the renin-angiotensin or the a-adrenergic systems, endogenously released AVP exerts greater influence in the control of MAP and vascular resistance in anaesthetized, surgical ly-stressed rats. 61 The administration of AVP antagonist in pentobarbital anaesthe-t ized, surgically-stressed and intact rats in Group I increased BF to the stomach and skin, but not the other organs. The results are simi-lar to those previously reported in our laboratory, using halothane anaesthetized surgically-stressed rats (Pang, 1983). Surgery has been shown to increase plasma renin act iv i ty (McKenzie et a l . , 1967). It has been shown previously in halothane-anaesthe-t ized, surgically-stressed rats that the infusion of saralasin caused a decrease of MAP and TPR but no change in CO (Pang, 1983). In this study, the infusion of saralasin in Group II also resulted in a de-crease of MAP within the same group of animals. Although MAP in Group II rats subjected to the infusion of saralasin was less than MAP values in Group I given saline infusion, the decrease was not s tat i s -t i c a l l y s igni f icant. This was probably due to d i f f i cu l t i es in the detection of small differences between animals due to biological var i -ations. The administration of the AVP antagonist in Group II caused an increase of BF to the skin and muscle and a decrease of BF to the lungs and l i ver . 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 ver . It should be emphasized that a depressor response from the infusion of saralasin would be expected to activate the sympathetic nervous system. Therefore, one should not expect to obtain the same effects from the injection of the AVP antagonist in Groups I and II, which have different endogenous vasomotor tones. 62 The infusion of phentolamine in Group III decreased MAP by the reduction of CO, but not TPR. The decrease of CO was probably a result of reduced venous return due to the blockade of postjunctional (see later) receptors in veins. Administration of the AVP antag-onist during the infusion of phentolamine markedly increased BF to the muscle and decreased BF to the l i ver , intestine, kidneys and testes. Therefore, in the absence of influence from the a-adrenergic system, AVP plays the greatest vasoconstrictor influence in the muscle and the least in the l iver , intestine, kidneys and testes. It has been shown that the administration of phentolamine in rats increased plasma renin act iv ity (Burnier et a l . , 1983b). Renin release is known to be in-creased by a reduction of MAP or renal arterial pressure (Keeton and Campbell, 1981). It has been shown that endogenously released Ag II played the greatest vasoconstrictor influence in areas of the kidneys and skin (Pang, 1983). 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 II) . 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 II, respectively. The administration of a£-, ay and non-specific a-blockers, namely, rauwolscine, prazosin and phentolamine, respectively, caused reductions of MAP showing that both ay and a2~receptors par t i c i -pate in the control of blood pressure. CO was decreased following the infusion of a 9 - ,but not a,-blockers. Thus, both rauwolscine and 63 phentolamine decreased MAP by the reduction of CO. The effect of phentolamine on CO in this study was, therefore, consistent with that in Group III of the previous study. The decrease in CO was probably a result of reduced venous return due to the blockade of postjunctional venous c^-receptors. Prazosin, on the other hand, decreased MAP by reducing TPR, but not CO. Our results suggest that ct^-receptors are functionally more important than o^-receptors in the control of venous capacitance in the rat. In pithed rats, the injections of both ct^- and ct^-agonists, methoxamine and B-HT 9 2 0 , respectively, were reported to increase CO (Kalkman et al_., 1 9 8 4 ) . The results of Kalkman et a l . , therefore, suggest the existence of postjunctional a - | - and o^-receptors in the venous bed of the rat . Our results with rauwolscine, on the other hand, show that post-junctional o^-receptors are functionally more important than a^-receptors in the control of venous capacitance. It is of interest that treatment of hypertensive patients with prazosin was reported to decrease blood pressure by reducing TPR, but not CO (deLeeuw et a l . , 1 9 8 0 ) . Since prazosin selectively blocks c^-receptors, i t is expected that the reflex increase in the release of NA following a depressor response caused by prazosin could stimulate o^-receptors in veins to enhance venous return to maintain CO. As a result of the reduction of CO by rauwolscine or phentolamine, the distribution of BF to most organs was decreased. After the infu-sion of rauwolscine, signif icant decreases of BF were detected in the heart, stomach, intestine, caecum and colon, kidneys, skin, testes, 6 4 g l a n d s a n d b r a i n . A f t e r t r e a t m e n t w i t h p h e n t o l a m i n e , s i g n i f i c a n t d e c r e a s e s i n BF w e r e o b s e r v e d i n t h e h e a r t , s t o m a c h , i n t e s t i n e , c a e c u m a n d c o l o n , k i d n e y s , s p l e e n , s k i n , t e s t e s , g l a n d s a n d b r a i n . On t h e o t h e r h a n d , t h e a d m i n i s t r a t i o n o f p r a z o s i n o n l y r e d u c e d BF t o t h e s k i n . T h e r e l a t i v e d i s t r i b u t i o n s o f CO w a s s i m i l a r l y a l t e r e d f o l l o w i n g t h e a d m i n i s t r a t i o n o f t h e t h r e e d i f f e r e n t a - b l o c k e r s . T h i s s u g g e s t s s i m i l a r % d i s t r i b u t i o n o f f u n c t i o n a l ay a n d ( ^ - p o s t j u n c t i o n a l r e c e p t o r s i n r e s i s t a n c e b l o o d v e s s e l s . A f t e r t h e i n f u s i o n o f p h e n t o l -a m i n e o r p r a z o s i n , t h e % d i s t r i b u t i o n o f CO w a s r e d u c e d i n t h e h e a r t , c a e c u m a n d c o l o n , k i d n e y s , s k i n a n d g l a n d s , s l i g h t l y , b u t n o t s i g n i f i -c a n t l y r e d u c e d i n t h e i n t e s t i n e , a n d i n c r e a s e d i n t h e l u n g s a n d m u s c l e . F o l l o w i n g t h e i n f u s i o n o f r a u w o l s c i n e , t h e d i s t r i b u t i o n o f CO was r e d u c e d i n t h e h e a r t , i n t e s t i n e , c a e c u m a n d c o l o n , k i d n e y s , g l a n d s a n d b r a i n a n d i n c r e a s e d i n t h e l u n g s , a n d m u s c l e . O u r r e s u l t s i n d i c a t e t h e p r e s e n c e o f f u n c t i o n a l p o s t j u n c t i o n a l a - j - a n d a 2 ~ a d r e n o c e p t o r s i n r e s i s t a n c e b l o o d v e s s e l s i n t h e r a t . F u r t h e r m o r e , o u r r e s u l t s w i t h p h e n t o l a m i n e s u g g e s t t h a t t h e SNS e x e r t s t h e g r e a t e s t v a s o c o n s t r i c t o r i n f l u e n c e i n v a s c u l a r b e d s i n t h e l u n g s a n d m u s c l e a n d t h e l e a s t i n t h e h e a r t , i n t e s t i n e , c a e c u m a n d c o l o n , k i d n e y s , s k i n a n d g l a n d s . I n c o n t r a s t , p r e v i o u s s t u d i e s c o n d u c t e d i n t h i s l a b o r a t o r y u s i n g h a l o -t h a n e - a n a e s t h e t i z e d , s u r g i c a l l y - s t r e s s e d r a t s h a v e s h o w n t h a t AVP p l a y s t h e g r e a t e s t v a s o c o n s t r i c t o r i n f l u e n c e i n t h e s t o m a c h a n d s k i n , w h i l e A g I I e x e r t s t h e g r e a t e s t i n f l u e n c e i n t h e k i d n e y s a n d s k i n ( P a n g , 1 9 8 3 ) . 65 It was unexpected to find that, while the various a-blockers caused similar reductions of MAP and similar alterations in the dis-tribution 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 II, than the depressor response produced by prazosin. The release of greater quantities of these vasoconstrictor agents then maintain TPR. The role of the renin-angiotensin system in the maintenance of MAP and peripheral vascular resistance is well-established. Renin release has been shown to be increased after a reduction of MAP or renal arterial pressure (Keeton and Campbell, 1981). Normotensive rats subjected to the administration of phentolamine were reported to have 19 times the PRA of control rats (Burnier et a l . , 1983b). In contrast, PRA of rats treated with prazosin was elevated to 4 times the value of control rats (Waeber et a l . , 1983). AVP release has been shown to be increased following either a decrease of MAP or a decrease of le f t atr ia l pres-sure (Share, 1976; Rocha e Silva et a l . , 1978). Since CO and, conse-quently, stimulation of le f t atr ia l receptors were decreased following the infusion of rauwolscine and phentolamine, i t is logical to expect that AVP release may be greatly enhanced following the administration of these blockers. Burnier et a l . (1983b) reported that, following i .v . infusion of phentolamine, plasma AVP levels were elevated to 18.5 times the level in control rats. Moreover, the injection of an antag-onist of the vasopressor effect of AVP was found to cause a marked 66 decrease of MAP in rats subjected to the infusion of phentolamine (Burnier et a l . , 1983b). On the other hand, the same laboratory has reported that, although the injection of prazosin in rats caused a similar decrease of MAP and a 7 x increase in the plasma level of AVP, the injection of AVP antagonist did not reduce MAP of rats treated with prazosin (Waeber et a l . , 1983). Thus, their results indicate that endogenously-released AVP plays a role in the maintenance of MAP and peripheral vascular resistance following the administration of phentolamine, but not prazosin. Further experiments were conducted to determine the participations of a ^ - and ctg-receptors in the control of venous tone in rats. Experiments were conducted to determine the participation of vasoact-ive agents in the control of MCFP in rats. It has been reported that MCFP is a primary determinant of CO and, therefore, venous return (Guyton et a l . , 1973; Caldini et a l . , 1974). Using the method of Yamamoto et a l . , (1980), we were able to obtain reproducible readings of MCFP in conscious rats. 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 has been shown that i .v. administrations of NA and phenyl-ephrine (an ct^-agonist) in anaesthetized and conscious animals caused increases in MCFP (Yamamoto et al_., 1980; Hirakawa et a l . , 1984;). Our results show that the infusion of methoxamine, a specif ic ct^-agonist, increased MAP, but did not change MCFP. The infusion of B-HT 920 (a specif ic c^-agonist) and NA (a non-selective a agonist) 67 increased MAP, as well as MCFP. Therefore, our results show that a ^ - are more important than -receptors in the control of venous tone in the rat . The results obtained is in contradication with the data presented by Kalkman et_al_., (1984). However Kalkman's experiments were carried out in pithed Wistar rats, while we used conscious Sprague-Dawley rats . It is possible that the discrepancy was due to the use of a d i f fer -ent strain of rats or different preparations of animals. Pithed rats have very low pressures due to the absence of sympathetic nervous act-iv i ty and, therefore, arterioles and veins of these animals are expected to have supernormal responsiveness to vasoactive drugs. Moreover, both a-^- and c^-adrenoceptors of pithed animals were not activated due to the absence of endogenously released NA. It was shown that in anaesthetized Sprague-Dawley rats the admini-stration of rauwolscine and phentolamine, selective a 2 - and non-selective a-blockers, respectively, caused a reduction of CO. The administration of prazosin, a specif ic a-^ blocker, did not alter CO. The results of selective a-adrenergic agonist are, therefore con-sistent with those of the previous study and they suggest that a 2-adrenoceptors are more important than a^-adrenoceptors in the control of CO in rats. It has been show that continuous infusion of Ag II caused an in -crease of MAP (by about 20-30 mmHg) and an increase in MCFP (2-3 mmHg) of anaesthetized dogs. In this study, the infusion of Ag II caused a dose-dependent increase in MAP as well as MCFP. On the other hand, 68 the infusion of high doses of AVP increased MAP, but i t produced only a very small increase in MCFP. The results show that receptors for Ag II, 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 role in the control of MAP and vascular resistance. AVP was shown to play a greater pressor role in the absence of influences from the renin-angiotensin or the sympathetic nervous systems. The extent of vaso-constrictor influence exerted by AVP in different vascular beds varies, depending on endogenous vasomotor tone from Ag II or a-adren-ergic system. In the absence of vasomotor tone from the renin-angio-tensin system, AVP plays the greatest vasoconstrictor influence on vascular beds in the skin and muscle. In the absence of influence from the SNS, AVP plays the greatest vasoconstrictor influence on vas-cular beds in the muscle. We have obtained similar decreases of MAP with acute blockades of a l - ' a 2 ~ a s w e ^ a s b o t h a l ~ a n c ' a 2 - r e c e P t o r s . Therefore, our results did not show any functional significance of prejunctional a^-receptors in the negative feedback inhibition of NA release. The acute administrations of rauwolscine, prazosin and phentolamine were found to cause similar redistributions of CO, suggesting that both aj- and a^-receptors are important in the control of the peripher-al c i rculat ion. The % distribution of CO to the lungs and muscle were increased following the administrations of prazosin, rauwaloscine and phentolamine. Thus, the SNS exerts the 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 c^-receptors a r e m o r e important than ct^-receptors in the control of venous capacitance. The stimulations of a - ^ - and o^-receptors by methoxamine and B-HT 920, respectively, caused increases in MAP. The results again show that both a - ^ - and o^-receptors are present to control arter-ia l resistance. The infusion of B-HT 920, but not methoxamine, was found to increase MCFP. These results show that c^-receptors are responsible for the control of venous tone and, therefore, CO in the rat . These results from the administration of specif ic agonists fur-ther support the results from the administrations of specif ic blockers that o^-receptors are responsible for the control of venous tone and CO in the rat . 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