Arginine Vasopressin Antagonist Research Articles

The role of vasopressin in the pressor response to bilateral carotid occlusion

Exogenous arginine vasopressin (AVP) has been shown to interact with the arterial baroreflex control of renal sympathetic nerve activity. In addition, we have shown that both AVP and the sympathetic nervous system (SNS) contribute to the pressor response to interruption of cardiopulmonary vagal afferents. This study examined the role and interaction of AVP and the SNS in the pressor response to a reduction of carotid sinus afferent activity by bilateral carotid occlusion (BCO). In addition the role of the area postrema (AP) in mediating the interaction between AVP and the SNS was examined. In aortic denervated conscious dogs, BCO increased mean arterial pressure 51.7 ± 3.1 mm Hg. Specific vascular (V 1) AVP antagonist d(CH 2) 5Tyr(Me)AVP did not alter the response to BCO ( Δ 50.8 ± 7.9 mm Hg). Subsequent ganglionic blockade abolished the response to BCO ( Δ−10 ± 3.8). When ganglionic blockade was induced in the absence of AVP antagonist, BCO increased MAP 25.0 ± 2.8 mm Hg. AVP antagonist following ganglionic blockade eliminated the pressor response to BCO ( Δ −6.7 ± 5.1) There was an interaction between AVP and the SNS such that the contribution of one system to the hemodynamic response was greater in the absence of the other system. Ablation of the AP abolished the interaction between reflexly released AVP and the SNS which was observed in intact dogs. These data demonstrate that both AVP and the SNS contribute to the pressor response to BCO. Reflexly released AVP appears to limit the reflex activation of the SNS. The interaction of endogenous AVP and the arterial baroreflex involves the AP. The results are consistent with the hypothesis that vasopressin interacts centrally to limit a reflex increase in sympathetic outflow and thus modulate the pressor response to BCO.

Arginine vasopressin mediates cardiovascular responses to hypoxemia in fetal sheep

Acute hypoxemia results in hypertension, bradycardia, and cardiac output redistribution in fetal sheep. The blood flow redistribution is produced by differential changes in vascular resistance of various fetal organs. alpha-Adrenergic activity is one of the few vasoconstrictor mechanisms thus far identified in the hypoxemic fetal sheep. Arginine vasopressin (AVP) is a potent vasoconstrictor in adults. Since AVP administration to the normoxic fetus mimics some of the fetal cardiovascular responses to hypoxemia and fetal plasma AVP levels increase with hypoxemia, we examined the hypothesis that AVP modifies the fetal cardiovascular response to hypoxemia by changing the vascular resistance of some fetal vascular beds. To test this we determined fetal systemic arterial pressure and fetal cardiac output and its distribution during hypoxemia with and without the V1 AVP antagonist d(CH2)5-Tyr(Me)AVP. Fourteen fetal sheep (0.79-0.90 of gestation) were chronically catheterized. Five days after surgery fetal hypoxemia was induced by introducing a mixture of 95% N2-5% CO2 (10-20 l/min) into a maternal tracheal catheter. The hypoxemia was maintained for 40 min. Fetal heart rate, systemic arterial blood pressure, and combined ventricular output and its distribution (radiolabeled microspheres) were measured before hypoxemia, at 20 min of hypoxemia alone, and at 20 min of hypoxemia plus either AVP antagonist (n = 5) or NaCl 0.9% (n = 5, controls). Fetal hypertension and bradycardia were partially reversed after the AVP antagonist administration during hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional hemodynamic changes following hypovolemia in conscious rats.

Regional hemodynamic responses to subcutaneous injection of hyperoncotic polyethylene glycol (PEG) were assessed in Long-Evans (i.e., normal) and Brattleboro [i.e., arginine vasopressin (AVP)-deficient] rats with chronically implanted, pulsed Doppler probes. The results were compared with saline-injected time controls. PEG injection elicited an early (30 min) selective mesenteric vasoconstriction in Long-Evans rats; 4-5 h after PEG the mesenteric vasoconstriction was greater in Long-Evans than in Brattleboro rats, but the renal and hindquarters vasoconstrictions were similar in both strains. There was a transient mesenteric vasodilatation [with no change in blood pressure (BP)] in Long-Evans rats given an antagonist of the V1-receptor actions of AVP 5 h after PEG. In the presence of the AVP antagonist, Long-Evans rats showed a marked dependence on the vasoconstrictor actions of the renin-angiotensin system for the maintenance of BP, similar to Brattleboro rats. Both strains also showed marked hypotensive responses to inhibition of sympathoadrenal activity (with pentolinium). Hence, AVP has clear-cut hemodynamic effects after PEG administration, but its role is not indispensable.

The interaction of arginine vasopressin and oxytocin with bovine adrenal medulla cells

Binding of [3H]arginine vasopressin (AVP) and [3H]oxytocin to primary monolayer cultures of bovine adrenal chromaffin cells was time-dependent, and the binding sites for each peptide were specific and saturable. Studies with the V1 AVP antagonist d(CH2)5Tyr(Me)2-AVP, the V2 agonist 1-deamino-8-D-AVP and the V2 antagonist d(CH2)5D-Leu2,Val4-AVP indicated that the AVP receptor was V1 in specificity. Scatchard plots showed that each ligand interacted with a single high-affinity, low-capacity binding site: oxytocin dissociation constant (Kd) 0.29 +/- 0.02 nmol/l, maximum binding capacity (Bmax) 7.6 +/- 0.2 fmol/10(6) cells (or 4500 +/- 102 sites/cell) (n = 3); AVP Kd 0.09 +/- 0.02 nmol/l, Bmax 5.1 +/- 0.63 fmol/10(6) cells (or 3050 +/- 318 sites/cell) (n = 3). Although forskolin in concentrations from 1 nmol/l to 1 mmol/l stimulated cyclic AMP (cAMP) production in isolated chromaffin cells, this did not result in detectable catecholamine release. Neither AVP nor oxytocin in concentrations between 10 pmol/l and 10 mumols/l stimulated cAMP production in these cells. Vasopressin in concentrations as low as 10 pmol/l stimulated a sixfold increase in total inositol phosphates; the dose-response curve was triphasic. Oxytocin had little effect on total inositol phosphate accumulation at low concentrations, but concentrations above micromolar stimulated total inositol phosphate production approximately fourfold. There was no measurable release of catecholamines in response to either peptide. The physiological consequences of these AVP-induced changes in inositol phosphate concentrations remain to be elucidated.

Sodium salicylate: alternate mechanism of central antipyretic action in the rat.

Infusion of sodium salicylate (50.0 or 100.0 micrograms/microliters) into the ventral septal area (VSA) of the rat brain suppressed Prostaglandin-E1-induced hyperthermia. Infusion of artificial cerebrospinal fluid (aCSF) or 10.0 micrograms doses of salicylate did not. The suppression of intracerebroventricularly-induced (icv) Prostaglandin E1 (PGE1) hyperthermia was not due to a hypothermic action of salicylate since salicylate infusions given during cold exposure (10.0 degrees C) did not lower core body temperatures. A possible interaction between salicylate and endogenous arginine vasopressin (AVP) was investigated. Infusion of both salicylate (50.0 micrograms/microliters) and either AVP antiserum or AVP antagonist into the VSA resulted in PGE hyperthermias occurring at levels which were not different from control levels as opposed to enhanced hyperthermia (antiserum or antagonist alone) or suppressed hyperthermia (salicylate alone). These results are consistent with the notion that sodium salicylate infusions within the VSA enhance AVP action and thus bring about the attenuation of PGE-induced hyperthermia.

Effects of chronic icv infusion of vasopressin on sleep-waking cycle of rats

The effect of arginine vasopressin (AVP) on the duration and the relative proportion of sleeping and wakeful periods has been investigated. Vigilance states were determined by visual scoring of polygraphic recordings from unrestrained rats. Animals were implanted with a cannula into the third ventricle through which AVP or related drugs, dissolved in artificial cerebrospinal fluid, were infused at a constant rate by an osmotic pump. Polygraphic data were collected 24 h/day from day 4 to day 9. Recordings were continued for 3 additional days during AVP recovery. AVP infusions significantly increased the amount of time spent in waking compared with control or recovery periods (12%). This effect was mimicked by an AVP agonist (2-phenylalanine, 8-ornithine oxytocin). Oxytocin, a peptide structurally close to AVP, induced a mild change in waking time. The infusion of an AVP antagonist, 1-desaminopenicillamine-2-(O-methyl)tyrosine-arginine vasopressin (dPTyr(Me)AVP), or of anti-AVP antibodies significantly decreased duration of waking. The infusion of antioxytocin antibodies did not modify the duration of waking. The effects of structural analogues of AVP relatively specific for each type of peripheral AVP receptor indicated the participation of a V1-like AVP receptor in the action of AVP on waking time. During infusion of anti-AVP antibodies and dPTyr(Me)AVP and during the first days of recovery from AVP infusion, the ultradian rhythmic distribution of sleep and wakefulness was still present, but the amplitude of the circadian rhythm was reduced.

Activation of renal sympathetic outflow by intracisternal hypertonic NaCl in dogs.

The neurohormonal and sympathetic nervous system responses to injection of hypertonic NaCl (1.5 M) into the cisterna magna were investigated in morphine-pentobarbital-anesthetized dogs (n = 8). Mean arterial blood pressure (MAP), heart rate (HR), and integrated efferent renal sympathetic nerve activity (ERSNA) were recorded, and blood samples were taken for the determination of plasma concentrations of epinephrine (Epi), norepinephrine (NE), arginine vasopressin (AVP), osmolality, plasma renin activity (PRA), and serum sodium and potassium. By 2 min after injection of hypertonic NaCl into the cisterna magna, significant increases were observed for MAP (+47 +/- 5 mmHg, P less than 0.01), HR (+59 +/- 11 beats/min, P less than 0.01), and ERSNA (+47 +/- 16%, P less than 0.01) above base line. The increased activity of the sympathetic nervous system was not accompanied by changes in PRA, Epi, NE, or AVP. Hypertonic NaCl was injected into the cisterna magna of six dogs before and after intravenous administration of the AVP antagonist [d(CH2)5Tyr(Me)]AVP. The time course for increases in MAP, HR, and ERSNA was not affected by AVP blockade. Subsequent administration of hexamethonium chloride abolished the pressor, tachycardic, and ERSNA responses elicited by cisterna magna injection of hypertonic NaCl. These experiments indicate that hypertonic NaCl acts at the lower brain stem to activate the sympathetic nervous system. Further, the pressor and tachycardic responses evoked by hypertonic NaCl acting at the lower brain stem do not appear to involve the hypothalamic-hypophysial-adrenal axis.

Synergism of intraventricular NaCl infusion and subpressor angiotensins in rats.

The effect of selective salt infusion to the central nervous system on the blood pressure (BP) regulation was examined in male Wistar rats. Hypertonic NaCl (0.8 M, 1 microliter/h) was infused into the lateral ventricle concomitantly with intravenous infusion of a subpressor dose (5.4 pmol.kg-1.min-1) of angiotensin II (ANG II) or its analogues for 7 days using osmotic minipumps. The BP was not increased by intracerebroventricular infusion of NaCl alone at this dose but was significantly and consistently increased by concomitant intravenous infusion of ANG II or its analogues. The increases in the BP over the base-line values on day 7 in groups on infusions of ANG II, ANG III, and pentasarcosyl-ANG II [(Sar)5ANG II] were 29 +/- 5 mmHg (n = 9, P less than 0.05), 8 +/- 2 mmHg (n = 8, P less than 0.05), and 19 +/- 3 mmHg (n = 6, P less than 0.05), respectively. The responses to hexamethonium, prazosin, and antagonists of arginine vasopressin and ANG II were examined in separate sets of conscious and unrestrained animals that had received intracerebroventricular infusion of NaCl and intravenous infusion of ANG II for the preceding 6 days. These animals showed significantly greater depressor responses only to hexamethonium and prazosin than control. These results indicate that the pressor effect of continuous and concomitant administration of intracerebroventricular NaCl and intravenous ANG II is mainly due to activation of the sympathetic nerve function. Synergism of the effects of selective central sodium administration and a subpressor dose of ANG II in the central nervous system is suggested.

Neonatal vasopressin antagonist treatment facilitates adult copulatory behavior in female rats and increases hypothalamic vasopressin content

This study confirms that i.c.v. administration of Arg-vasopressin (AVP, 20 ng) inhibits copulatory behavior in female rats (lordosis response, LR) and demonstrates that this inhibitory effect is blocked by the vasopressin antagonist (3-mercapto-3-methylbutyryl-Tyr-[Me])arginine vasopressin (dPTyr(Me)AVP, 20 ng, i.c.v.). The effects of neonatal AVP antagonist treatment on adult female copulatory behavior, hypothalamic content of AVP and AVP-like immunoreactive (AVP-ir) neurons were examined. dPTyr(Me)AVP was given to female rats 1 μg/animal/day s.c. from day 1 through to day 7 (day 0 = day of birth). The females were ovariectomized as adults and sexual receptivity activated by submaximal doses of estradiol plus progesterone. The LR was significantly facilitated in the neonatally dPTyr(Me) AVP treated females who also showed a higher content and an increased number of AVP-ir neurons in the suprachiasmatic nucleus compared to saline controls. Functional, biochemical and immunocytochemical evidence is provided that neonatal exposure to an AVP antagonist induces persistent changes in central vasopressinergic neuronal mechanisms.

Neurogenic and humoral factors maintaining arterial pressure in conscious dogs

This study examined the contribution of each primary pressor system to resting arterial pressure and the ability of each to maintain pressure in the absence of the other systems in conscious dogs. In dogs with intact carotid sinus baroreflexes, ganglionic blockade (GB) reduced blood pressure by 13 +/- 3 mmHg, whereas blockade of the renin-angiotensin (RAS) and arginine vasopressin (AVP) systems did not significantly alter arterial pressure. After removal of the other two systems, the depressor response to blockade of the sympathetic nervous system (SNS) with hexamethonium and atropine was significantly augmented (-33 +/- 3 mmHg), whereas captopril (CAP) blockade of the RAS reduced pressure 14 +/- 4 mmHg, and AVP blockade decreased pressure 12 +/- 2 mmHg. In sinoaortic-denervated (SAD) dogs, the SNS exhibited a greater contribution (28 +/- 4 mmHg) to resting pressure compared with intact, and the role of the RAS (10 +/- 2 mmHg) was also augmented, whereas the effects of AVP blockade were unaltered. Effects of GB and CAP were unaltered after blockade of the other systems in SAD animals, whereas the depressor response to AVP antagonist (-13 +/- 2 mmHg) was significantly augmented. Results indicate the SNS is the primary pressor system in resting intact or SAD conscious dogs, whereas the RAS also contributes to resting blood pressure in SAD animals. The ability of the SNS alone to maintain arterial pressure after acute removal of the other systems is also significantly greater than that of AVP or the RAS.

The role of vasopressin as an antipyretic in the ventral septal area and its possible involvement in convulsive disorders

Perfusion of the peptide, arginine vasopressin (AVP), within the ventral septal area (VSA) of the brain of a number of species reduces fever but not normal body temperature. This antipyretic response appears to be mediated by AVP receptors of the V 1 subtype. Lesions of the VSA with kainic acid are associated with prolonged and enhanced fevers in rats. A role for endogenous AVP in fever suppression within the VSA comes from several types of experiments: (1) AVP release within the VSA is inversely correlated to fever height, (2) AVP antagonists or antiserum injected into the VSA prolong fever, (3) animals lacking endogenous AVP in the VSA (Brattleboro rat, long-term castrated rat) develop enhanced fevers. Electrical stimulation of the AVP-containing cell bodies of the bed nucleus of the stria terminalis (BST) orthodromically inhibits VSA neurons and also suppresses fever, the latter effect can be abolished with application of a V 1 antagonist to the VSA. lontophoretic studies indicate that AVP inhibits glutamatestimulated activity of thermoresponsive and other VSA neurons. AVP can also act in the VSA to cause severe motor disturbances, this action is receptor mediated and increases in severity upon sequential exposure to AVP. Because sites of action of the antipyretic and convulsive action of AVP are similar, and because animals lacking brain AVP display reduced convulsive activity, it is possible that AVP, released during fever, could be involved in the genesis of convulsive activity.

3H]AVP binding to rat renal tubular receptors during long-term treatment with an antagonist of arginine vasopressin

The interaction of an antagonist of arginine vasopressin (AVP), d(CH 2) 5-D-Tyr(Et)VAVP, with renal tubular V 2 receptors were studied in medullary membrane preparations from kidneys of Sprague-Dawley and Brattleboro rats. In both rat strains, V 2 receptors had comparable K D and B max values for binding of [ 3H]AVP. In vitro studies revealed that the V 2-antagonist was more potent than cold AVP in displacing [ 3H]AVP. In vivo treatment of Sprague-Dawley rats with the antagonist over one week resulted only in a transient state of diabetes insipidus (DI). No specific [ 3H]AVP binding was detectable throughout the period of administration. Chronic treatment of Brattleboro rats resulted in a complete normalization of water intake. This agonistic effect was also associated with undetectable [ 3H]AVP binding. After stopping the infusion of d(CH 2) 5-D-Tyr(Et)VAVP, B max values tended to rise but had still not reached base line values after 6 days. In contrast, the chronic infusion of AVP in Brattleboro rats resulted in a reduction in water intake which was accompanied by a decreased B max. [ 3H]AVP binding remained detectable during the entire treatment period. Thereafter B max was restored to base line values within 2 days of stopping the infusion. These results suggest that d(CH 2) 5-D-Tyr(Et)VAVP has a high affinity for V 2 receptors in both Sprague-Dawley and Brattleboro rats. Its rate of dissociation from the receptor appears to be much slower than that of AVP. In Brattleboro rats, the binding of d(CH 2) 5-D-Tyr(Et)VAVP leads to an antidiuretic response. In Sprague-Dawley rats, a transient diuretic response is followed by a progressive normalization in water intake. This occurs despite persistent and complete blockade of renal medullary V 2 receptors.

Osmotically released vasopressin augments cardiopulmonary reflex inhibition of the circulation.

Exogenous arginine vasopressin (AVP) has been shown to augment the inhibitory influence of arterial and cardiopulmonary baroreflexes. This study examined the influence of osmotically released AVP on the inhibitory responses to activation of cardiopulmonary receptors by administration of veratrum alkaloids. Three groups of conscious dogs, with carotid sinus intact, with prior sinoaortic denervation (SAD), and with prior lesion of the area postrema (AP), were instrumented for monitoring arterial pressure and heart rate and with left circumflex coronary artery or left atrial catheters for administration of veratrum alkaloids. Conscious dogs were administered veratridine (0.5-1.0 microgram.kg-1.min-1) under control conditions, after infusion of hypertonic saline (HS, 6% NaCl), and after HS in the presence of the AVP vascular (V1) receptor antagonist. In carotid sinus-intact dogs, veratridine reduced arterial pressure (-10 +/- 0.4 mmHg). After HS infusion, the depressor response to veratridine was significantly greater (-18 +/- 0.8 mmHg). The enhanced depressor response during HS infusion was prevented by administration of the AVP antagonist (-8 +/- 0.6 mmHg). Responses to veratrum alkaloids in SAD dogs were similar. In AP-lesioned animals, the depressor effects of veratridine (-9 +/- 0.5 mmHg) were similar to intact animals. However, the response to veratridine during HS was not altered (-9 +/- 0.8 mmHg) in AP-lesioned dogs. Results suggest that osmotically stimulated AVP augments the inhibitory effects of cardiopulmonary reflexes and that this effect is mediated through the area postrema via the V1 receptor.

Renal Vasodepressor Mechanism: Characterization by Chemical Medullectomy

The features of hypertension produced in the rat by chemical medullectomy with 2-bromoethylamine hydrobromide are described. This procedure partially prevents the fall in blood pressure that occurs when the constriction is removed from the renal artery of rats with two-kidney one-clip Goldblatt hypertension. In normal rats, chemical medullectomy causes a moderate but consistent blood pressure elevation that is dose related and associated with elevation of peripheral resistance; the venous side of the circulation is normal. The hypertension is not associated with sodium retention or with activation of the renin angiotensin system. Although vasopressin levels are elevated, the rise is only modest, and blood pressure is not reduced by a vascular AVP antagonist. It is concluded that chemical medullectomy removes the source of a humoral substance that has been shown by other workers to carry out a vasodepressor role. The chemical medullectomy model therefore offers new insights into the renomedullary vasodepressor system.

The role of vasopressin in acute cerebral vasospasm. Effect on spasm of a vasopressin antagonist or vasopressin antiserum.

An experimental model of subarachnoid hemorrhage (SAH) in the Sprague-Dawley rat induces angiographically demonstrable, reproducible biphasic vasospasm of the vertebrobasilar system. The acute vasospasm is maximum at 10 minutes and the maximum late vasospasm occurs 2 days after the SAH. Brattleboro rats, which are deficient in arginine vasopressin (AVP), do not have acute vasospasm after SAH but exhibit a degree of late vasospasm that is not significantly different from that seen in Sprague-Dawley rats. Cisternal injection of AVP induced acute vasospasm in Sprague-Dawley rats with a duration similar to that seen after cisternal blood injection; however, at 2 days, the vessel diameter was normal. Intravenous AVP antagonist or intracisternal AVP antiserum administered prior to the SAH prevented the development of acute vasospasm without affecting the late phase. The data suggest that an increased release of AVP in the cerebrospinal fluid is involved in the development of acute cerebral vasospasm.

Specificity of arginine vasopressin and angiotensin II for microvessels in the hamster cheek pouch after the induction of renovascular hypertension

The present study was undertaken to determine the specificity of the vasoconstrictor activity to angiotensin II (AII) and arginine vasopressin (AVP) on the microcirculation in normal and renovascular hypertensive states. Ten to fourteen days after the induction of hypertension, Syrian hamsters were anesthetized with pentobarbital sodium, the cheek pouch was exposed, and a plastic chamber was placed in situ so the membrane could be suffused with bicarbonate-buffered Ringer's solution (5% CO 2, 95% N 2, pH 7.4). Third order arterioles (30–45 μm) were identified for study and vessel diameter was measured using a shearing device. In one group of normotensive and hypertensive hamsters, AII was microapplied to the arteriole before and after adding an AVP antagonist to the suffusate. In a second group of similar hamsters, AVP was microapplied to the arteriole before and after adding an angiotensin II blocker, saralasin acetate, to the suffusate. AVP and AII receptor blockade was documented by observing whether the vasoconstrictor effect of either AVP or AII was abolished. Dose-response curves for either peptide were not altered in the presence of the antagonist to the other peptide; however, they were shifted to the left in the RHT hamsters. Neither AVP nor AII receptor blockade altered control resting arteriolar diameters. Thus, it can be concluded that the microvascular response to both AII and AVP are potentiated in RHT and there are no interactions between either AII or AVP with the receptors of the other peptide in these microvessels in normal or RHT hamsters, indicating a high specificity for each peptide to its vascular receptor.

Vasopressin and sympathetic nervous functions both contribute to development and maintenance of hypertension in DOCA-salt rats.

We evaluated the time course of changes in the relative contribution of arginine-vasopressin (AVP) and sympathetic nervous system (SNS) during the development of DOCA-salt hypertension in rats. Intravenous administrations of an AVP antagonist (d(CH2)5Tyr(Me) AVP; AVPA) and hexamethonium (C6) were given at 3 and 7 days, and 2 and 4 weeks after the initiation of treatment with DOCA-salt to conscious and unrestrained rats. Mean arterial pressure (MAP) was higher and heart rate (HR) tended to be rapid in the rats on DOCA-salt treatment for over 1 week, compared with those of the control groups. The hypotensive effect of AVPA in the DOCA-salt treated rats was gradually enhanced with the development of hypertension and was significantly greater than in the control rats, at all stages of hypertension, including the prehypertensive phase. The depressor response to intravenous C6 following AVPA also resulted in a gradual enhancement, with time, after DOCA treatment. This decrease in MAP was greater at the hypertensive stage than that in the control rats, although the response was not significantly different among three groups on the 3rd treatment day. It was concluded that the pressor systems AVP and SNS may contribute to the initiation and development as well as maintenance of DOCA-salt hypertension in rats.

Central and peripheral mechanisms of the enhanced hypertension following long-term salt loading in spontaneously hypertensive rats.

We evaluated whether or not increased sodium (Na) concentrations of cerebrospinal fluid (CSF) and stimulated activities of brain renin-angiotensin system (RAS) contribute to an enhanced hypertension by salt overload in spontaneously hypertensive rats (SHR). Long-term salt loading (1% NaCl solution as drinking fluid) accelerated the development of hypertension in SHR, but did not alter the blood pressure (BP) in normotensive Wistar-Kyoto rats (WKY). CSF Na concentration was elevated in uninephrectomized (Nx) group as compared to that in control SHR, while in WKY CSF Na was not influenced by the treatment. A fall in BP by intravenous AVP antagonist or hexamethonium was greater in salt-loaded SHR than in controls. This hypotensive response to the combined blockade of AVP and SNS correlated with CSF Na in SHR but not in WKY. Plasma concentration of AVP and epinephrine tended to increase in relation to the degree of salt loading in SHR but not in WKY. Pressor responses to intracerebroventricular (ICV) angiotensin II (AII) and NaCl were greater in SHR than in WKY, although these responses were not influenced by chronic salt load in either SHR or WKY. The enhanced hypertensive action of ICV NaCl in SHR was abolished by pretreatment with ICV AII antagonist. Chronic saline drinking enhanced the depressor effect of ICV captopril in SHR but not in WKY. These observations suggest that salt overload in SHR may cause an elevated CSF Na concentration and an enhanced activity of brain RAS, which may increase activity of SNS and release of AVP, resulting in an enhanced development of hypertension.

Role of AVP in malignant DOC-salt hypertension: studies using vascular and antidiuretic antagonists.

To investigate the role of arginine vasopressin (AVP) in the maintenance of blood pressure in deoxycorticosterone (DOC)-salt hypertension, the effects of specific pressor and antidiuretic antagonists of AVP were studied in conscious, freely moving rats with established malignant DOC-salt hypertension. Plasma AVP level was significantly higher in hypertensive than in normotensive animals (4.8 +/- 1.0 vs. 2.0 +/- 0.3 fmol/ml, n = 5, P less than 0.02). Administration of d(CH2)5-d-Leu-VAVP, 10 micrograms/kg, an AVP antagonist that blocked the antidiuretic, but not the pressor effect of exogenous AVP, induced diuresis, and caused a transient fall in blood pressure from 173 +/- 3 to 167 +/- 4 mmHg (n = 8, P less than 0.01) with a concomitant slight increase in heart rate. Similar changes were observed after administration of d(CH2)5Tyr(Et)VAVP, 10 micrograms/kg, an antidiuretic plus pressor antagonist of AVP. Intravenous injection of d(CH2)5Tyr(Me)AVP, 10 micrograms/kg, a specific AVP pressor antagonist had no effect on blood pressure or heart rate, although it completely abolished the pressor response to exogenous AVP. Plasma renin activity remained suppressed following administration of all AVP antagonists. These findings suggest that if AVP should contribute to maintaining high blood pressure in malignant DOC-salt hypertension it would have to be the results of its antidiuretic and not its vasoconstrictor property.

Suprachiasmatic injection of a vasopressin antagonist modifies the circadian rhythm of food intake

To study the effect on the circadian feeding rhythm, injections of AVP and its antagonist were made into the suprachiasmatic nuclei (SCN) of rats after implanting cannulae into the bilateral SCN. Injections of arginine vasopressin (AVP) antagonist at the beginning of the light and dark phases disrupted the circadian rhythm of food intake while injections of AVP during the beginning of the light or dark phase did not disrupt the circadian rhythm. It may be concluded that endogenous vasopressin has a modulatory role in the mediation of the circadian feeding rhythm at SCN.