Renal versus hindquarter hemodynamic responses to vasopressin in conscious rats.

Experiments were performed on conscious rats to (a) compare the responsiveness of the renal and hindquarter vascular beds to infusions of exogenous arginine vasopressin (AVP), and (b) determine whether either bed demonstrates V2-vasopressinergic vasodilation when the vasoconstrictor properties of AVP are blocked. Rats were chronically instrumented with pulsed Doppler flow probes on either the left renal artery or the distal abdominal aorta as well as with femoral arterial and venous catheters. One series of experiments examined the vascular responses of these two beds to exogenous AVP infused intravenously (i.v.) at 0.2, 2.0, or 5.0 ng/min. The lowest infusion rate was associated with no detectable changes in mean arterial blood pressure (MAP), heart rate (HR), renal or hindquarter blood flow (RBF or HQBF), or vascular resistance in these beds. In contrast, the higher infusion rates caused a marked increase in MAP, a decrease in HR, and a reduction in HQBF; RBF was unaffected, however. A second series of experiments tested for the presence of a V2-vasodilatory influence during infusion of AVP at 5 ng/min by selectively blocking V1-vasopressinergic receptors or both V1- and V2-receptor types. Little evidence for V2-mediated vasodilation was found in either vascular bed, however. We conclude that although the renal vasculature appears relatively insensitive to exogenous AVP, this insensitivity probably is not due to vasodilation mediated by activation of V2-receptors.     

EFFECTS OF V2 RECEPTOR ACTIVITY ON THE PRESSOR RESPONSE TO VASOPRESSIN IN THE RAT

1. To determine the contribution of V1 and V2 receptor activity on the enhancement of reflex buffering of the pressor response to arginine-vasopressin (AVP), mean arterial pressure (MAP) and heart rate (HR) changes were examined in response to graded injections of phenylephrine, AVP, or Phe2Orn8OT, a potent, selective V1-receptor agonist in the absence and presence of Val4DArg8VP, a potent, selective V2-receptor agonist. 2. There were no significant differences in MAP responses to the V1 agonist in the absence and presence of the V2 agonist in either conscious intact or autonomic-blocked rats. 3. Autonomic blockade with methscopolamine and hexamethonium increased the pressor sensitivity to phenylephrine threefold. In contrast, the pressor sensitivities to AVP and Phe2Orn8OT were increased 14-fold and 11-fold, respectively, by autonomic blockade. 4. V2-receptor activity does not have any inherent vasocative action or synergistic vasoactive action with V1-receptor activity. 5. V2 receptors do not play a role in enhancing reflex buffering of the pressor response to AVP; V1 receptors are suggested to play the role.     

Regional haemodynamic responses to the cannabinoid agonist, WIN 55212-2, in conscious, normotensive rats, and in hypertensive, transgenic rats

Regional haemodynamic responses to the cannabinoid agonist, WIN 55212-2 (5 - 250 microg kg(-1) i.v.) were assessed in conscious, normotensive, Hannover, Sprague-Dawley (HSD) rats, and in hypertensive, transgenic ((mRen-2)27) (abbreviated to TG) rats. In HSD rats, WIN 55212-2 caused pressor, and renal and mesenteric vasoconstrictor effects, with a hindquarters vasodilator effect occurring only at the highest dose. In TG rats, the effects of the cannabinoid agonist were qualitatively similar to those seen in HSD rats, except there was no hindquarters vasodilatation. In both strains of rat, in the presence of losartan, pentolinium and a vasopressin (V1-receptor) antagonist, the pressor and vasoconstrictor effects of WIN 55212-2 were abolished, but the hindquarters vasodilator response was enhanced (HSD rats) or was seen only in that circumstance (TG rats). Under these conditions, both strains of rat showed a modest fall in blood pressure, together with mesenteric vasodilatation. In additional experiments in normotensive SD rats from Charles River (CRSD), it was shown that, in the presence of the V1-receptor antagonist alone, or losartan alone, or the two antagonists together, the cardiovascular effects of WIN 55212-2 (50 or 150 microg kg(-1)) were not attenuated. Hence, the effects described above were likely due to pentolinium. There were no consistent differences between HSD and TG rats in their haemodynamic responses to methoxamine or noradrenaline, indicating the two strains were not likely to differ markedly in their responsiveness to any putative sympathetic activation induced by WIN 55212-2. Collectively, the results indicate that the predominant cardiovascular effects of WIN 55212-2 in conscious HSD and TG rats (i.e., pressor and vasoconstrictor actions) can be attributed largely to indirect, pentolinium-sensitive mechanisms, which appear to differ little in the normotensive and hypertensive state, at least in conscious animals. Under the conditions of our experiments, signs of cannabinoid-induced vasodilatation were modest.     

Dopamine preferentially stimulates postsynaptic alpha 2-adrenoceptors in the femoral vascular bed, but alpha 1-adrenoceptors in the renal vascular bed of the anaesthetised dog

The decrease in blood flow in response to dopamine (DA) injected intraarterially (i.a.) into the femoral or renal vascular beds was examined in the anaesthetised dog. DA or noradrenaline (NA) were 10 times more potent as vasoconstrictor agents in the femoral than in the renal vasculature. In the femoral bed, the DA induced vasoconstriction was completely resistant to antagonism by prazosin (30-300 micrograms/kg i.v.), but was dose-dependently blocked by the alpha 2-receptor antagonist idazoxan (30-300 micrograms/kg i.v.). In the renal bed the vasoconstrictor effects of DA were resistant to blockade by idazoxan, but were prazosin sensitive indicating that alpha 1-adrenoceptors were involved in this response. The alpha-receptor agonist profile for DA was not modified in the femoral bed after blockade of dilatory D1-receptors with SCH 23390 (0.5 mg/kg i.v. and 0.1 mg/kg per h i.v.). However, this antagonist significantly increased the vasoconstrictor potency for DA in the renal bed. The decrease in femoral blood flow induced by an injection of DA, appears to be mediated by alpha 2-adrenoceptors. In the renal vascular bed where the predominant alpha-adrenoceptor corresponds to the alpha 1-subtype and there are few postsynaptic alpha 2-receptors subserving vasoconstriction, DA can stimulate alpha 1-receptors but this action requires higher doses of agonist than those needed for alpha 2-adrenoceptor stimulation.     

Role of endothelin and vasopressin in DOCA-salt hypertension

1. The relative roles of endothelin (ET) and vasopressin (AVP) in the regulation of blood pressure (BP), cardiac output (CO) and total peripheral resistance (TPR) were investigated in the early stages (24 - 31 days) of development of hypertension in the conscious deoxycorticosterone acetate (DOCA)-salt hypertensive rat model. 2. BP was recorded with radiotelemetry devices and CO with ultrasonic transit-time probes. TPR was calculated from the BP and CO recordings. The contributions of endogenous ET and AVP were studied by infusing [d(CH(2))(5)(1),O-Me_Tyr(2),Arg(8)]-vasopressin, a V(1)-receptor antagonist, and bosentan, a mixed ET(A)/ET(B) receptor antagonist (Study 1). Vascular responsiveness was estimated from the changes in TPR evoked by i.v. infusions of ET-1 and AVP (Study 2). 3. In study 1, infusion of bosentan reduced TPR and BP dramatically in DOCA-salt hypertensive rats but not in SHAM control rats, and this effect was greater when the AVP system had been blocked. In contrast, the V(1) receptor antagonist alone failed to change TPR and BP in DOCA-salt hypertensive rats. However, subsequent infusion of the V(1) receptor antagonist during the plateau phase of the response in bosentan pretreated DOCA-salt hypertensive rats led to significant decreases in both BP and TPR. 4. In study 2, TPR and BP responses to ET-1, but not AVP, were greater in DOCA-salt rats than in control rats. CO responses to ET-1 or AVP were similar in the two groups. 5. The results suggest that both ET and AVP play a role in the maintenance of TPR and BP; when one system is blocked the other compensates. However, the magnitude of the contribution to the hypertensive state appears greater for ET than for AVP. Enhanced vascular responses to ET appear to contribute to this greater role.     

Vasopressin-induced facilitation of adrenergic responses in the rat mesenteric artery is V1-receptor dependent

1. The present study was designed to analyse the possible involvement of V1- and V2-receptors in vasopressin (AVP)-induced facilitation of the sympathetic nervous system. Furthermore, we aimed to determine whether the site of facilitation by AVP is located pre- or postsynaptically. 2. Electrical field stimulation (EFS) was applied on the rat mesteric artery to activate the sympathetic nervous system. In addition, we evaluated the direct vascular effects of AVP. The postsynaptic effect of AVP on the sympathetic nervous system was investigated by exposing the vessels to exogenous noradrenaline. These experiments were performed in the absence or presence of selective V1 and V2 receptor antagonists SR 49059 and SR 121463, respectively. Desmopressin was applied as a selective V2 agonist. 3. The direct vasoconstrictor effect of AVP was antagonized by SR 49059 and not by SR 121463. Desmopressin neither showed any direct vasoconstrictor effect nor produced vasodilatation after a precontraction induced by noradrenaline (10 microM). The EFS-induced rise in vascular tone could be increased by a sub-pressor concentration of AVP. This fascilitation could be antagonized by SR 49059, but not by SR 121463. Desmopressin did not influence the increase in vascular tone during EFS. Vasoconstriction induced by exogenous noradrenaline could be facilitated by a sub-pressor concentration of AVP and this selective postsynaptic effect could be antagonized by V1-receptor blockade. 4. In conclusion, the AVP-induced facilitation of the sympathetic nervous system is completely V1-receptor dependent and at least partly postsynaptically mediated.     

Vascular and renal effects of vasopressin and its antagonists in conscious rats with chronic myocardial infarction; evidence for receptor shift.

Acute myocardial infarction evokes activation of, among others, the arginine-vasopressin system, resulting in vasoconstriction and fluid retention. In the present study, the vasoconstrictor and antidiuretic effects of vasopressin were examined in vivo in conscious rats with chronic myocardial infarction, in the absence or presence of the V(1a) receptor antagonist SR-49059 or the V(2) receptor antagonist OPC-31260. In sham rats, vasopressin dose-dependently increased mean arterial pressure (maximum response: 45+/-3 mm Hg), which was significantly suppressed in infarcted rats (maximum response: 32+/-3 mm Hg). SR-49059, but not OPC-31260, caused a significant rightward shift of the dose pressure response curve in sham rats, indicating V(1a) receptor mediation. This rightward shift by SR-49059 was significantly more in infarcted rats. The suppressed response to the agonist and enhanced sensitivity to the antagonist suggest a reduction of V(1a) receptor number in infarcted rats. In both sham and infarcted rats, the urine production after OPC-31260 (337+/-14 and 329+/-30 microl/min, respectively) was about twice of that in vehicle-treated rats (188+/-25 and 155+/-24 microl/min, respectively). However, the response in infarcted rats reached its peak quicker and lasted for a shorter period, resulting in a 40% lower area under the curve. Although only measurable during V(2) receptor blockade, the reduction of urine production by vasopressin was significantly more in infarcted compared to sham rats. The enhanced renal response to the agonist and reduced response to the antagonist suggest an increase in V(2) receptor number in infarcted rats. In conclusion, in chronically infarcted rats, vasopressin causes vasoconstriction and fluid retention through the V(1a) and V(2) receptors, respectively. Altered responses after infarction indicate a shift from V(1a) to V(2) receptors.     

Cardiovascular effects of irindalone, a new S2-serotonergic antagonist, in the rat

Irindalone is a new antihypertensive agent with affinity to serotonin (5-HT2) receptors and at higher concentrations also to alpha 1-adrenoceptors. The present study was designed to evaluate the relative importance of the antagonism of central and peripheral alpha 1- and 5-HT2-receptors in the blood pressure lowering properties or irindalone after acute administration. In conscious Sprague-Dawley rats intravenous irindalone (0.05-1.5 mg/kg) dose-dependently reduced the blood pressure. In the same dose-range irindalone antagonized pressor responses to phenylephrine and electrical stimulation of the spinal sympathetic outflow (SNS) in the pithed rats, indicating that the acute blood pressure lowering effect is primarily related to the blockade of alpha 1-adrenoceptors. However, the concomitant 5-HT2-receptor blockade may contribute since irindalone in a dose (0.15 mg/kg) where it had no alpha-adrenoceptor blocking properties enhanced the hypotensive response to selective alpha 1-adrenoceptor blockade by prazosin (1 micrograms/kg). We found no evidence that central mechanisms contributed to the blood pressure lowering effect of irindalone. In anaesthetized rats irindalone (1 mg/kg) did not reduce the directly recorded sympathetic nerve activity. Intracerebroventricular administration of irindalone in conscious rats (10-100 micrograms) had no consistent effects on the blood pressure and did not enhance the hypotensive response to intracerebroventricularly administered prazosin (10 micrograms). Finally, the hypotensive response to irindalone was not influenced by depletion of central serotonin stores (by PCPA). It is concluded that the blood pressure lowering effect of irindalone following acute administration is related primarily to blockade of peripheral alpha-adrenoceptors but that the concomitant blockade of 5-HT2-receptors may contribute.     

Differential effects of peroxynitrite on the function of arginine vasopressin V(1a) receptors and alpha(1)-adrenoceptors in vivo

OBJECTIVE: The aim of this study was to provide evidence that peroxynitrite may differentially affect the function of arginine vasopressin (AVP) V(1a) receptors and alpha(1)-adrenoceptors in vascular smooth muscle of the rat METHODS: The vasoconstrictor responses elicited by AVP, or the alpha(1)-adrenoceptor agonist, phenylephrine, were determined in anesthetized rats before and after injections of (i) peroxynitrite, the thiol chelator, para-hydroxymercurobenzoic acid (PHMBA), or the electron acceptor, nitroblue tetrazolium (NBT). The ability of the reducing agent, glutathione, to reverse the loss of response to phenylephrine and AVP in peroxynitrite-treated rats was also examined. RESULTS: The AVP-induced responses were suppressed 10-20 min but not 60-70 min after the administration of peroxynitrite. Glutathione reversed the above loss of response to AVP at 10-20 min. The responses elicited by phenylephrine were suppressed 10-20 min and 60-70 min after administration of peroxynitrite. Glutathione did not reverse the above losses of response to phenylephrine. In addition, the vasoconstrictor actions of AVP and phenylephrine were markedly suppressed after administration of PHMBA or nitroblue tetrazolium. CONCLUSIONS: The above findings provide evidence that exogenously administered peroxynitrite may differentially affect the function of AVP V(1a) receptors and alpha(1)-adrenoceptors in vascular smooth muscle of the rat. The possibility that peroxynitrite impairs AVP V(1a) receptor function by transient oxidation events whereas peroxynitrite impairs alpha(1)-adrenoceptor function by transient oxidation and permanent nitration events will be discussed.     

Effect of acute unilateral renal denervation on renal hemodynamics in spontaneously hypertensive rats

1 This study was undertaken to characterize the renal responses to acute unilateral renal denervation in anaesthetized spontaneously hypertensive rats (SHR) by examining the effect of acute unilateral renal denervation on the renal hemodynamic responses to a set of vasoactive agents and renal nerve stimulation. 2 Twenty-four male SHR rats underwent acute unilateral renal denervation and the denervation was confirmed by significant drop (P < 0.05) in renal vasoconstrictor response to renal nerve stimulation along with marked diuresis and natriuresis following denervation. After 7 days treatment with losartan, the overnight fasted rats were anaesthetized (sodium pentobarbitone, 60 mg kg(-1) i.p.) and renal vasoconstrictor experiments were performed. The changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine, methoxamine and angiotensin II. 3 The data showed that there was significantly (all P < 0.05) increased renal vascular responsiveness to the vasoactive agents in denervated rats compared to those with intact renal nerves. In losartan-treated denervated SHR rats, there were significant (all P < 0.05) reductions in the renal vasoconstrictor responses to neural stimuli and vasoactive agents as compared with that of untreated denervated SHR rats. 4 The data obtained in denervated rats suggested an enhanced sensitivity of the alpha(1)-adrenoceptors to adrenergic agonists and possible increase of AT(1) receptors functionality in the renal vasculature of these rats. These data also suggested a possible interaction between sympathetic nervous system and renin-angiotensin system in terms of a crosstalk relationship between renal AT(1) and alpha(1)-adrenoceptor subtypes.     

Inhibition of Ang II and renal sympathetic nerve influence dopamine-and isoprenaline-induced renal haemodynamic changes in normal Wistar-Kyoto and spontaneously hypertensive rats

1. This study was undertaken to elucidate the effects of inhibiting the renin-angiotensin system (RAS) with losartan, and acute unilateral renal denervation on renal haemodynamic responses to intrarenal administration of vasoconstrictor doses of dopamine and vasodilator doses of isoprenaline in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. Acute unilateral renal denervation of the left kidney in rats was confirmed by a drop in the renal vasoconstrictor response to renal nerve stimulation (P < 0.05) along with diuresis and natriuresis. Rats were pretreated with losartan for 7 days and thereafter animals fasted overnight were anaesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and acute renal haemodynamic responses studied. 3. Dose-response curves were constructed for dopamine and isoprenaline that induced falls or increases in renal blood flow, respectively. It was observed that renal vascular responses were greater in the denervated as compared with rats with intact renal nerves (all P < 0.05). Dopamine-induced renal vasoconstrictor responses were markedly lower in losartan-treated denervated WKY and SHR compared with their untreated counterparts (all P < 0.05). It was also observed that in losartan-treated and denervated WKY rats the vasodilatory responses to isoprenaline were markedly lower compared with untreated rats (all P < 0.05). However, in SHR, under the same conditions, there was no difference in the renal response to isoprenaline whether or not rats were treated with losartan (P > 0.05). 4. The data obtained showed that the renal vasoconstrictor effect of dopamine depends on intact renal nerves and RAS in WKY and SHR. Isoprenaline responses were likewise sensitive to renal denervation and RAS inhibition in WKY rats but not SHRs. Our observations reveal a possible relationship between renal AT(1) receptors and alpha(1)-adrenoceptors in WKY and SHR. There is also evidence to suggest an interaction between renal beta-adrenoceptors and AT(1) receptors in WKY rats.     

Vasopressin: mechanism of central cardiovascular action in conscious rats

Arginine vasopressin (AVP) and AVP binding sites have been localized in brain areas involved in cardiovascular control. To elucidate the mechanisms by which brain AVP may participate in central blood pressure regulation, we investigated the effects of central AVP receptor stimulation on mean arterial pressure (MAP), heart rate (HR), efferent splanchnic nerve (SpNA), and renal nerve activity (RNA) in conscious chronically instrumented rats. Intracerebroventricular (i.c.v.) injections of AVP (1-100 ng) produced dose-dependent increases in MAP together with marked increases in HR, SpNA, and RNA. The pressor responses were inhibited by peripheral alpha-adrenoceptor blockade with i.v. phentolamine. In contrast, the pressor responses to either i.v. or intracarotid injections of AVP were accompanied by baroreceptor reflex (BRR)-mediated decreases in HR and SpNA. Central (i.c.v.) pretreatment with d(CH2)5AVP, a V1-AVP receptor antagonist, completely abolished the responses to i.c.v. but not to i.v. AVP. The same antagonist had no effect on the responses to i.c.v. angiotensin II. Our results demonstrate that: (a) central AVP overrides the BRR by sympathetic stimulation, whereas blood-borne AVP activates the BRR; (b) specific AVP receptors in the brain probably of the V1-subtype are involved in the central pressor responses to AVP; (c) the central pressor actions of AVP are transmitted to the periphery by stimulation of the sympathetic nervous system. We conclude that brain AVP may contribute to central cardiovascular control by modulating the sympathetic outflow to the periphery.     

Effects of dexamethasone and SB 209670 on the regional haemodynamic responses to lipopolysaccharide in conscious rats.

1. Male (350-450 g) Long Evans rats were chronically instrumented to permit regional haemodynamics to be monitored in the conscious state. In the first experiment, either saline (0.4 ml h-1) or dexamethasone (3 mg kg-1, 125 micrograms kg-1 h-1) was infused continuously for 24 h, before co-infusion of lipopolysaccharide of (LPS, 150 micrograms kg-1 h-1) for 24 h. Dexamethasone prevented the delayed (5-24 h) fall in mean arterial blood pressure (MAP) and the renal and hindquarters vasodilatation seen with LPS infusion alone, but not the initial (about 2 h) fall in MAP or renal vasodilatation. However, at this dose, dexamethasone itself caused a significant rise in MAP and regional vasoconstrictions. 2. In the second experiment, dexamethasone at a lower dose (12.5 micrograms kg-1 h-1) had only slight pressor and vasoconstrictor effects. However, in its presence, infusion of LPS caused a substantial and progressive rise in MAP (maximum at 8 h, +32 +/- 3 mmHg) together with persistent mesenteric and hindquarters vasoconstriction and a transient renal vasodilatation. 3. In the third experiment, the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 h-1), blocked the slight pressor and regional vasoconstrictor effects of the lower dose of dexamethasone. Furthermore, in the presence of dexamethasone and SB 209670, infusion of LPS caused marked, but transient hypotension (nadir at 5 h, -24 +/- 2 mmHg) and renal and mesenteric vasodilatation. 4. At the end of all experimental protocols, sequential administration of the AT1-receptor antagonist, losartan, followed by the V1-receptor antagonist, (+)-(CH2)5-O-Me-Tyr, vasopressin, caused effects indicating a variable involvement of angiotensin and vasopressin in the maintenance of cardiovascular status. 5. Collectively, the results indicate that, in the conscious rat, dexamethasone interacts with vasoconstrictor and vasodilator mechanisms, and hence its influence on the haemodynamic responses to LPS cannot be attributed, simply, to inhibition of the activity of inducible nitric oxide synthase and/or cyclo-oxygenase-2.     

Cardiovascular effects of cannabinoids in conscious spontaneously hypertensive rats

BACKGROUND AND PURPOSE: In anaesthetized spontaneously hypertensive rats (SHR), there is evidence for up-regulation of cannabinoid (CB1) receptors: antagonism of CB1 receptors causes a rise in blood pressure, and administration of the endocannabinoid, anandamide, or inhibition of anandamide degradation causes hypotension. These findings have led to the suggestion that the endocannabinoid system may be a therapeutic target in hypertension. However, since the cardiovascular responses to cannabinoids are substantially influenced by anaesthesia, the purpose of this study was to assess regional haemodynamic responses to cannabinoid receptor stimulation and inhibition in conscious SHR. EXPERIMENTAL APPROACH: Cardiovascular responses to i.v. administration of anandamide, the cannabinoid receptor agonist, WIN 55212-2, and the CB(1) receptor antagonist, AM 251, were measured in male SHR, Wistar Kyoto rats and outbred Wistar rats, chronically instrumented for recording renal, mesenteric and hindquarters haemodynamics in the conscious, freely-moving state. KEY RESULTS: Hypotensive responses to anandamide and WIN 55212-2 only occurred in SHR, but these were relatively modest and not associated with CB1 receptor-mediated vasodilatation. In SHR only, anandamide caused bradycardia, which was inhibited by AM 251. Furthermore, a pressor response to CB1 receptor antagonism occurred only in SHR, but was not associated with vasoconstriction. Moreover, there was some evidence for CB1 receptor-mediated vasoconstrictor actions of anandamide in SHR, which was not seen in the normotensive strains. CONCLUSIONS AND IMPLICATIONS: The results are consistent with activation of CB1 receptors in SHR by endogenous ligands exerting an antihypertensive effect, but the findings do not indicate enhanced CB1 receptor-mediated vasodilator mechanisms in SHR.     

Taurine modulates arginine vasopressin-mediated regulation of renal function

Taurine has been implicated in the regulation of arginine vasopressin (AVP) secretion, and we have previously shown altered renal excretory function in the taurine-depleted rat. To further elucidate the role of taurine in AVP-mediated renal responses, the effects of an antagonist for renal AVP receptors were examined in four groups of conscious rats: control, taurine-supplemented, taurine-depleted, and taurine-repleted. Control and taurine-supplemented rats displayed similar and significant AVP receptor antagonist-induced elevations in fluid excretion, sodium excretion, and free water clearance but a marked reduction in urine osmolality. These effects are consistent with inhibition of endogenous AVP activity. By contrast, in the taurine-depleted rats, the magnitude and the time course of drug-induced renal excretory responses lagged behind those of the control and taurine-supplemented groups. Further, baseline urine osmolality was significantly higher in the taurine-depleted compared with the control or taurine-supplemented groups. However, after administration of the antagonist, taurine-depleted rats manifested a delayed but more marked reduction in urine osmolality, thereby eliminating the baseline differential that existed between the taurine-depleted rats and control or taurine-supplemented groups. Consistent with these observations, plasma AVP was significantly increased in the taurine-depleted compared with the control rats. Interestingly, taurine repletion shifted all responses closer to the control group. Analysis of the data suggests that the effect of the antagonist on renal excretory function is related primarily to altered tubular reabsorption activity. These observations suggest that taurine modulates renal function, and, thereby, body fluid homeostasis, through an AVP-dependent mechanism.     

Chloride anion concentration as a determinant of renal vascular responsiveness to vasoconstrictor agents.

1. The role of chloride concentration in modulating vasoconstrictor responses of the rat isolated kidney, perfused with Krebs-Henseleit solution, to angiotensin II (AII), arginine vasopressin (AVP) and phenylephrine (PE) was investigated. 2. Reduction of perfusate chloride from a high (117 mM) to low (87 mM) concentration, by substitution of sodium chloride with a mixture of sodium salts of propionate, acetate and methanesulphonate, reduced responsiveness to all three vasoconstrictors, the change for AII being most pronounced. 3. For AII, reduced vasoactivity with low chloride was evident both in terms of the threshold dose and on the linear part of the dose-response curve but not for the maximum response. This attenuating effect of low chloride on the vasoconstrictor response to AII was reversed when perfusion with high chloride was reinstituted. Continuous perfusion with high chloride progressively increased the vasoconstrictor effect of low doses of AII for successive dose-response curves. 4. In addition to reducing responses on the linear part of the dose-response curve for both AVP and PE, low chloride also reduced the maximum vasoconstrictor response to PE, whereas the threshold dose for the two agonists was unchanged. In contrast to the enhanced pressor response to AII, during continuous perfusion with high chloride, tachyphylaxis occurred with AVP and PE. 5. The ability of chloride to modify renal responsiveness to vasoconstrictor agents may contribute to the increase in renal vascular resistance and decrease in glomerular filtration rate (GFR) which occurs during infusion of hyperchloremic solutions into the renal artery and explain the need for chloride as the anion accompanying sodium in salt-sensitive hypertensive models.     

Central Vasopressin V1A Receptor Blockade Impedes Hypothalamic–Pituitary–Adrenal Habituation to Repeated Restraint Stress Exposure in Adult Male Rats

Previous studies suggest that central arginine vasopressin (AVP) signaling can inhibit the hypothalamic–pituitary–adrenal (HPA) axis. To test a role for the AVP V1A receptor in stress HPA axis habituation, adult male rats were exposed to 5 consecutive days of 3 h restraint with or without continuous intracerebroventricular infusion of the V1A receptor antagonist d(CH2)5Tyr(Me)AVP (10 μg/day). Assessment of neuropeptide expression and HPA output under basal conditions revealed no effects of V1A receptor antagonism in stress naive animals. Between the first and last day of restraint exposure, controls showed marked declines in ACTH and corticosterone responses, and maintained plasma concentrations of testosterone. In contrast, V1A receptor antagonized animals displayed significantly smaller declines in ACTH and corticosterone responses, and a decrease in plasma testosterone. Despite their reduced expression of HPA axis habituation, antagonized animals continued to show stress-induced increases in AVP mRNA in the hypothalamic paraventricular nucleus and bed nucleus of the stria terminalis, and even higher levels of AVP expression in the medial amygdala relative to controls. The data leave open the nature and extent to which these and other AVP-containing pathways are recruited during repeated restraint, but nevertheless reveal a critical role for central V1A receptors in stress adaptation. As the effects of V1A receptor antagonism were restricted to the repeated restraint condition, we conclude that normal adaptation to stress involves a shift toward enhanced AVP utilization and/or V1A receptor signaling.     

Renal vascular effects of angiotensin II, arginine-vasopressin and bradykinin in rats: interactions with prostaglandins

1. The renal vascular responses to the peptide hormones angiotensin II (ANG II), arginine-vasopressin (AVP) and bradykinin (BK) were studied in anaesthetized rats with flow-meter techniques. The contribution of prostaglandins (PG) to their renal vascular effects was assessed with the aid of the PG-synthesis inhibitor indomethacin. 2. ANG II and AVP induced a dose-dependent increase in renal vascular resistance (RVR). The renal vasoconstrictor effects of both peptides were significantly augmented in rats pretreated with indomethacin. Indomethacin alone induced an increase in RVR, but not in mesenteric vascular resistance (MVR). 3. BK in low doses (1 micrograms/kg . min) tended to decrease RVR but increased RVR in high doses (20 micrograms/kg . min). MVR was reduced after all doses. The renal vasoconstrictor effect of BK was not affected by the ANG II-antagonist saralasin but almost completely blocked by indomethacin. 4. These results suggest that in the rat, as in other animal species and in man, renal PG's attenuate the renal effects of vasoconstrictor hormones such as ANG II and AVP. Although it has no such effect in other species. BK in high doses induces renal vasoconstriction in the rat, which appears also to be mediated by PG's. This response might be peculiar to the rat, since PG's act as renal vasodilators in other species.     

Alterations in central neuropeptide expression, release, and receptor binding in rats bred for high anxiety: critical role of vasopressin.

To model aspects of trait anxiety/depression, Wistar rats were bred for extremes in either hyper (HAB)- or hypo(LAB)-anxiety as measured on the elevated plus-maze and in a variety of additional behavioral tests. Similar to psychiatric patients, HAB rats prefer passive stress-coping strategies, indicative of depression-like behavior, show hyper-reactivity of the hypothalamo-pituitary-adrenal axis, and a pathological response to the dexamethasone/corticotropin-releasing hormone (CRH) challenge test. Here we tested central mRNA expression, release patterns, and receptor binding of neuropeptides critically involved in the regulation of both anxiety-related behavior and the HPA axis. Thus, CRH, arginine-8-vasopressin (AVP), and oxytocin (OXT) were studied in brains of HAB and LAB males both under basal conditions and after exposure to a mild emotional stressor. In HAB rats, CRH mRNA was decreased in the bed nucleus of the stria terminalis only. While no significant difference in CRH1-receptor binding was found in any brain area, CRH2-receptor binding was elevated in the hypothalamic paraventricular nucleus (PVN), the ventromedial hypothalamus, and the central amygdala of HABs compared to LABs. AVP, but not OXT, mRNA expression as well as release of the neuropeptide, were higher in the PVN of HABs, whereas AVP V1a-receptor binding failed to show significant differences in any brain region studied. Remarkably, intra-PVN treatment of HABs with the AVP V1-receptor antagonist d (CH(2))(5) Tyr (Me) AVP resulted in a decrease in anxiety/depression-related behavior. The elevated expression and release of AVP within the PVN of HAB rats together with the behavioral effects of the AVP V1-receptor antagonist suggest a critical involvement of this neuropeptide in neuroendocrine and behavioral phenomena associated with trait anxiety/depression.     

Rho kinase contributes to androgen amplification of renal vasoconstrictor responses in the spontaneously hypertensive rat

Androgens modulate vascular tone and hypertension development. Rho kinase contributes to norepinephrine- (NE) and vasopressin- (AVP) induced vasoconstriction. This study tested the hypothesis that Rho kinase contributes to androgen amplification of renal vasoconstrictor responses to NE or AVP in isolated perfused kidney of spontaneously hypertensive rats (SHRs).SHRs (5 weeks) underwent sham operation, castration, or castration with testosterone replacement. At 16-17 weeks, mean arterial pressure and heart rate were measured in conscious SHRs. Renal vascular reactivity to NE (10 to 10 mol) and to AVP (10 to 10 mol) was assessed in an isolated perfused kidney preparation before and after Rho kinase inhibitor treatment (fasudil; 15 microM). Castration reduced mean arterial pressure, whereas testosterone treatment of castrated SHRs increased mean arterial pressure significantly. The dose-response curves to NE and AVP obtained in isolated perfused kidneys from castrated SHRs were displaced to the right of those obtained in sham-operated and castrated + testosterone-treated SHRs. Fasudil treatment produced a rightward shift in the dose-response curves for each agonist in all of the groups and greatly attenuated the differences in renal vascular reactivity to NE and AVP among the 3 groups of SHRs.Collectively, these findings indicate that androgen modulation of hypertension development in the SHR involves a fasudil-sensitive pathway and suggest that further study is warranted in this area.