Evidence for the implication of endogenous vasopressin in cardiovascular response to central alpha-adrenoceptor stimulation

To determine the role of endogenous vasopressin (AVP) in cardiovascular response to central alpha-adrenoceptor stimulation, alpha 1-agonist methoxamine or alpha 2-agonist clonidine was administered intracerebroventricularly (ICV) to conscious Long-Evans (LE) rats as well as Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI). In LE rats, ICV methoxamine increased blood pressure (BP) and decreased heart rate (HR), while ICV clonidine caused initial hypertension associated with bradycardia followed by prolonged hypotension with tachycardia. In DI rats, however, ICV methoxamine had no detectable effect on BP and HR, whereas ICV clonidine produced greater hypotension than in LE rats together with less initial bradycardia. Plasma levels of AVP increased 5-15 fold by methoxamine but did not change by clonidine. The intravenous (IV) but not ICV pretreatment with AVP vascular receptor antagonist d (CH2)5 Tyr (Me) AVP significantly attenuated the cardiovascular effects of methoxamine in LE rat, while neither IV nor ICV pretreatment with AVP antagonist modulated the cardiovascular effects of clonidine. These results provide the evidence for the implication of endogenous AVP in the cardiovascular response to central stimulation of alpha-adrenoceptors.     

Role of vasopressin in the cardiovascular response to stimulation of the locus coeruleus

Hypothalamic vasopressin synthesizing nuclei (paraventricular and supraoptic) send vasopressin-containing projections to a number of neural target areas thought to be involved in cardiovascular regulation. One area known to receive vasopressinergic projections from the paraventricular nucleus is the pontine nucleus locus coeruleus. To examine the possible functional participation of vasopressin in central cardiovascular regulation, we examined mean arterial pressure (millimeters of Hg) and heart rate (beats per min) responses to electrical stimulation of the locus coeruleus in conscious, unrestrained vasopressin-deficient Brattleboro rats homozygous for diabetes insipidus (DI rats) and long Evans (LE) rats. Rats received chronic arterial and venous catheters and bipolar stimulating electrodes 3-5 days before experiment. Stimulation of the locus coeruleus (100 microA, 10-40 Hz) produced frequency-dependent increases in mean arterial pressure and heart rate in LE and DI, but the responses were significantly less in the latter group. The deficiency in mean arterial pressure and heart rate responses to locus coeruleus stimulation in DI rats was found to be centrally mediated in that responses to peripherally administered phenylephrine were the same as those for LE rats. Ganglionic blockade significantly attenuated responses to locus coeruleus stimulation in LE rats but had little effect in DI rats. Pretreatment of DI rats with chronic intracerebroventricular infusion of vasopressin (osmotic minipump) at a dose that had no effect peripherally increased the mean arterial pressure and heart rate responses to locus coeruleus stimulation. Our results suggest that vasopressin acts in the region of the locus coeruleus to exert a central action on sympathetic outflow.     

Cardiovascular response to vasopressin vasopressor antagonist administration during water deprivation in the rat

The cardiovascular effects of intracerebroventricular (i.c.v.) and intravenous (i.v.) injection of a selective vasopressin vasopressor antagonist, [1-beta-mercapto-beta, beta-cyclopentamethylenepropionic acid-2-(0-methyl)tyrosine]arginine vasopressin (TMe-AVP) were examined in conscious rats under basal conditions and following 48 h of water deprivation. Pressor responses to i.v. vasopressin (50 ng/kg) were not blunted by i.c.v. treatment with either vehicle or 0.5 microgram/kg TMe-AVP. A dose of 5.0 microgram/kg TMe-AVP (i.c.v.) did reduce the pressor response to vasopressin, indicating peripheral leakage of the antagonist. Water deprivation for 48 h increased plasma vasopressin concentrations from 0.7 +/- 0.1 to 2.8 +/- 0.1 microU/ml and increased blood pressure from 112 +/- 2 to 123 +/- 1 mm Hg. No effect of the vasopressin antagonist on blood pressure could be detected following either i.c.v. (0.5 microgram/kg) or i.v. (5.0 micrograms/kg) treatment in water-deprived animals. However, a significant increase in heart rate was observed in water-deprived rats following i.v. injection of 5.0 micrograms/kg of TMe-AVP. Central vasopressin vasopressor receptor blockade appears to exert little effect on blood pressure either under basal conditions or during water deprivation. The data further delineate the relationship of plasma vasopressin concentrations to cardiovascular homeostasis.     

Reduction of the pressor effect of fluoxetine after V1A-vasopressin receptor blockade in the conscious rats]

Pharmacovigilance data have reported some cases of arterial hypertension in patients treated with serotonin reuptake inhibitors. This side effect is now called serotonin syndrome. Moreover, some authors have shown that these drugs could reduce, at least in part, the fall in blood pressure (BP) observed in experimental models or in human forms of orthostatic hypotension, suggesting a modulation of the autonomic nervous system by these drugs. These data led us to study in freely moving Wistar rats the mechanisms involved and the putative involvement of autonomic nervous system. Intracerebroventricular (i.c.v.) administration of fluoxetine (5-50 micrograms) induced an increase in BP similar to which was obtained following central administration of serotonin (5-HT) (0.5-5 micrograms). After 5-HT, the pressor effect was immediate (1 min following injection) and involved the baroreflex pathway (bradycardia). The fluoxetine-induced pressor response reached its maximal 1 hour after injection without any significant change in heart rate (HR). At the dose of 10 micrograms i.c.v., fluoxetine significantly increased mean BP by 16 +/- 4 mmHg. This pressor response was partially but significantly reduced by a pretreatment by the alpha 1-adrenoreceptor antagonist, prazosin (500 micrograms.kg-1 i.v.) (+7 +/- 4 mmHg, p < 0.05) or by a V1A-vasopressin receptor antagonist (20 micrograms.kg-1 i.v.) (+5 +/- 3 mmHg, p < 0.05). However, pretreatment by the beta-adrenoreceptor antagonist, propranolol (1 mg.kg-1 i.v.) and the antagonist 5-HT2, ketanserine (5 mg.kg-1 i.v.) did not modify the fluoxetine-induced pressor response. In freely moving rats receiving fluoxetine (10 micrograms i.c.v.), vasopressin plasma levels were significantly higher (+39 +/- 5 pg.mL-1) than in rats receiving saline (100 microL i.c.v.) (+14 +/- 4 pg.mL-1), thus confirming the involvement of vasopressinergic mechanisms in the fluoxetine-induced pressor response. These data suggest that in freely moving Wistar rats, central acute administration of fluoxetine induces a pressor response mediated by both an increase in sympathetic tone and a vasopressin release. This observation could suggest the putative use of alpha 1-adrenoreceptors antagonists and/or V1A-vasopressin receptor antagonists in the treatment of the serotonin syndrome.     

Centrally bradykinin B2-receptor-induced hypertensive and positive chronotropic effects are mediated via activation of the sympathetic nervous system.

OBJECTIVE: The presence of bradykinin B2 receptors in the cardiovascular regulatory centres of the brain indicates that increase in mean arterial pressure (MAP) and heart rate after intracerebroventricular (i.c.v.) injections of bradykinin is mediated via stimulation of sympathetic nervous system. METHODS: Adult Wistar- Kyoto (WKY) rats were instrumented chronically with an i.c.v. cannula, and the catheters were placed into the femoral artery and vein. Increasing doses of bradykinin (1 -300 pmol) were given i.c.v. and (i) MAP and heart rate, (ii) plasma dopamine, noradrenaline and adrenaline, and (iii) plasma arginine vasopressin (AVP) levels were determined. In addition, following blockade of peripheral alpha1 -adrenoceptors with prazosin (50 and 250 microg/kg i.v.) beta1-adrenoceptors with atenolol (10 mg/kg i.v.) or V1 -receptors with TMe-AVP (Manning compound) (10 microg/kg i.c.v. and 100 microg/kg i.v.) the effects of bradykinin (100 pmol i.c.v.) on MAP and heart rate were determined. RESULTS: Bradykinin increased MAP and heart rate dose-dependently. The pressor effects of 100 pmol bradykinin i.c.v. were completely blocked by pretreatment with the specific B2 receptor antagonist Hoe 140 (3 pmol, i.c.v.). There was no change in plasma dopamine, noradrenaline, adrenaline or AVP levels after increasing doses of bradykinin. However, peripheral blockade of alpha1- and beta1-adrenoceptors reduced the bradykinin-induced increase in MAP and heart rate, whereas central and peripheral V1 receptor blockade did not alter the cardiovascular responses to i.c.v. bradykinin. CONCLUSION: Our data suggest that the hypertensive and positive chronotropic effects induced by i.c.v. bradykinin are due to stimulation of sympathoneuronal rather than sympathoadrenal pathway in vivo.     

Role of endogenous nociceptin in the regulation of arginine vasopressin release in conscious rats

The effects of central administration of the opioid-like peptide nociceptin (also known as orphanin FQ) were investigated on the secretion of arginine vasopressin (AVP) in response to dehydration and hyperosmolar or hypovolemic stimulation in conscious rats. Intracerebroventricular (i.c.v.) administration of nociceptin suppressed plasma AVP concentration in a dose-dependent manner (0.1-10 microg/rat) in dehydrated rats, and the maximum effect was obtained 10 min after the administration (dehydration with 10 microg/rat nociceptin, 3.11 +/- 0.27 pg/ml vs. control, 10.32 +/- 0.96 pg/ml). The plasma AVP increase in response to either hyperosmolality [i.p. injection of hypertonic saline (HS) (600 mosml/kg)] or hypovolemia [i.p. injection of polyethylene glycol (PEG)] was also significantly blunted when nociceptin was injected i.c.v. (HS with 10 microg/rat nociceptin, 1.16 +/- 0.09 pg/ml vs. control, 1.82 +/- 0.30 pg/ml; PEG with 10 microg/rat nociceptin, 0.91 +/- 0.16 pg/ml vs. control, 2.41 +/- 0.26 pg/ml). Pretreatment with a selective opioid kappa-receptor antagonist, nor-binaltorphimine (1 microg/ rat, i.c.v.) or naloxone (2.5 mg/rat, s.c. injection) did not reverse the inhibitory effects of nociceptin on AVP release. Moreover, when plasma AVP was suppressed by acute water loading, immunoneutralization of endogenous nociceptin by antinociceptin-antiserum i.c.v. significantly reversed the suppression (0.57 +/- 0.12 pg/ml vs. control, 0.25 +/- 0.04 pg/ml). These results suggest that central nociceptin is physiologically involved in the control of AVP release through an inhibitory action.     

Non-specific inhibition of pressor agents in vivo by the renin inhibitor pepstatin A

The specificity of pepstatin A as an inhibitor of the cardiovascular actions of renin injected into anaesthetized rats has been investigated. Pepstatin A 70 micrograms/kg/min partially inhibited the pressor response to injected renin without affecting the pressor responses to injected angiotensin II, phenylephrine or vasopressin. Pepstatin A 150 micrograms/kg/min also produced partial inhibition of injected renin, but in addition caused significant inhibition of the other pressor agents. This was in contrast to the effects of the angiotensin converting enzyme inhibitor captopril, 100 micrograms/kg i.v., which caused greater inhibition of the renin pressor response than pepstatin A without affecting the pressor response to injected angiotensin II, phenylephrine or vasopressin. Finally the direct acting vasodilator hydralazine was found to have a similar non-specific inhibitory effect to pepstatin A on the pressor responses to injected pressor agents. It is concluded that pepstatin A reduces the pressor responsiveness to injected pressor agents and that this non-specific cardiovascular activity limits the usefulness of pepstatin A as a pharmacological tool to inhibit renal renin in vivo.     

The importance of vasopressin in the development and maintenance of DOC-salt hypertension in the rat

Experiments were performed to determine the role of vasopressin in deoxycorticosterone (DOC)-salt hypertension. In order to determine if vasopressin is necessary for the development of DOC-salt hypertension, rats with hereditary diabetes insipidus (DI) and normal Long-Evans rats (LE) were unilaterally nephrectomized, treated with DOC Pivalate (30 mg/kg . week) and given saline to drink for 8 weeks. A second group of DI rats were unilaterally nephrectomized, but received no treatment. Systolic blood pressure (SBP) increased 40 mm Hg in the LE group (p less than 0.01) but failed to increase significantly in either DI group. Urinary excretion of vasopressin (UADHV) and SBP were measured in unilaterally nephrectomized LE rats treated with DOC and salt (DOC-LE), salt alone (NaCl-LE) and untreated rats (H2O-LE). The UADHV was elevated in DOC-LE (p less than 0.01) and NaCl-LE (p less than 0.05), but only the DOC-LE rats became hypertensive. Finally, the I.V. injection of analogs of vasopressin, which block its pressor but not antidiuretic activity, lowered mean arterial blood pressure 27 +/- 5 mm Hg in 11 conscious DOC-salt hypertensive rats. It is concluded that vasopressin plays a major role as a pressor agent in both the onset and maintenance of DOC-salt hypertension.     

Kappa-opioid modulation of vasopressin secretion in conscious rats.

A series of studies has been performed in the conscious rat to investigate the effect of the intracerebroventricular (i.c.v.) administration of the selective kappa-opioid receptor agonist, U50 488H, on arginine vasopressin (AVP) secretion stimulated by i.c.v. administration of hypertonic NaCl. Similarly, the effect of the i.c.v. administration of morphine and the i.v. administration of naloxone on AVP secretion was investigated. The response of AVP to an i.c.v. injection of hypertonic NaCl was potentiated by naloxone at a dose of 0.4 mg/kg, but a higher dose (1.2 mg/kg) was required to increase the basal plasma concentration of AVP. Prior treatment with U50 488H or morphine attenuated the increase in plasma concentrations of AVP stimulated by i.c.v. injection of hypertonic NaCl from 13.92 +/- 4.44 to 1.22 +/- 0.34 and 1.78 +/- 0.74 pmol/l respectively (n = 7; P less than 0.05). Prior administration of U50 488H also attenuated the potentiating effect of naloxone on AVP secretion stimulated by i.c.v. injection of hypertonic NaCl. These results indicate that basal AVP secretion is under tonic inhibitory control by dynorphin, and that mu- and kappa-opioid receptors mediate an inhibitory influence of endogenous opioids on osmoreceptor-mediated AVP secretion.     

Pretreatment with vasodilator or V1-antagonist abolishes vasopressin withdrawal hypotension in spontaneously hypertensive rats

In spontaneously hypertensive rats (SHR), the cessation of a 3-h intravenous infusion of arginine vasopressin (AVP, 8 mU/kg per min) resulted in a large and prolonged fall in arterial pressure (46 +/- 7.5 mmHg below basal levels). Pretreatment of SHR with the specific V1-receptor antagonist, [1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid), 2-(O-methyl)-tyrosine] AVP (d(CH2)5Tyr (Me)AVP, 8 micrograms/kg followed by 0.05 micrograms/kg per min) abolished the pressor response to AVP, and markedly reduced the subsequent hypotensive response following the cessation of the AVP infusion. The hypotensive response to AVP withdrawal was abolished also when phenylephrine hydrochloride (PE, 20 nmol/kg per min) elicited a blood pressure rise during the course of AVP infusion in rats with V1-receptor blockade. Finally, the concurrent administration of sodium nitroprusside (30 micrograms/kg per min) not only counteracted the pressure rise during AVP infusion, but also prevented the hypotensive response that normally accompanied the withdrawal of AVP. These findings demonstrate that neither V1-receptor activation nor blood pressure elevation alone was sufficient to generate a hypotensive response to the withdrawal of AVP; rather, both V1-receptor activation and a blood pressure elevation associated with the activation of these receptors were essential to the hypotensive response that followed the withdrawal of AVP in SHR.     

Clonidine decreases plasma and cerebrospinal fluid arginine vasopressin but not oxytocin in humans

To evaluate the alpha 2-noradrenergic regulation of arginine vasopressin (AVP) and oxytocin (OT) in normal humans, we measured the effect of the alpha 2-agonist clonidine on concentrations of these neuropeptides in both plasma and cerebrospinal fluid (CSF). Subjects underwent two lumbar puncture studies, one of which was performed 100 min after oral administration of 5 micrograms/kg clonidine. Plasma AVP and OT were measured at a single time point 10 min before lumbar puncture. Both plasma and CSF AVP were significantly lower in the clonidine condition than in the control (no drug) condition. Neither plasma nor CSF OT differed significantly between conditions. Our data confirm previous reports of alpha 2-noradrenergic inhibition of neurohypophyseal release of AVP into blood, and extend these findings to healthy human subjects. Our data also suggest that AVP appearance in CSF, presumably from extraneurohypophyseal vasopressinergic neurons, is regulated by an inhibitory alpha 2-noradrenergic mechanism.     

Atrial natriuretic peptide in plasma, atria, ventricles, and hypothalamus of Long-Evans and vasopressin-deficient Brattleboro rats

To evaluate the role of vasopressin in the regulation of atrial natriuretic peptide (ANP) secretion, the plasma, atrial, ventricular, and hypothalamic levels of ANP were measured in Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. Total atrial immunoreactive ANP (IR-ANP) as well as right auricular IR-ANP concentration were higher in the DI than in the LE rats, whereas no significant difference was noted in left auricular IR-ANP concentration. In the left ventricle of DI rats, the IR-ANP concentration was 82% greater than that in the LE rats, while no substantial difference was found in the right ventricular IR-ANP concentration between the strains. Normal LE rats had low levels of left ventricular ANP mRNA and barely detectable ANP mRNA in the right ventricle, DI rats showed a 3-fold greater ANP mRNA concentration in the left ventricle than age-matched LE controls, and ANP mRNA levels were also increased in the left auricle of DI rats. The hypothalamic IR-ANP content, but not the concentration, was significantly increased in the DI compared to the LE rats. Despite increased cardiac IR-ANP and ANP mRNA levels, plasma IR-ANP concentrations were similar in the conscious DI rats (97 +/- 9 pg/ml; n = 13) and the LE rats (95 +/- 8 pg/ml; n = 15). Volume expansion (1.1 ml/100 g BW of 0.9% saline, iv) increased right atrial pressure and caused a significant rise in plasma IR-ANP in both strains (P less than 0.01). Elevations of plasma IR-ANP concentrations caused by volume loading were comparable in LE and DI rats in either the absence or presence of exogenous vasopressin (5 ng/kg.min, iv), which, when infused alone, did not significantly influence the plasma IR-ANP concentration. However, the relation between the change in IR-ANP concentration and the change in right atrial pressure shifted to the left, and thus, for a given increase in right atrial pressure, a greater amount of IR-ANP was released in the vasopressin-treated rats than in the control animals. These results demonstrate that although acute volume expansion does not necessarily require endogenous vasopressin for the ANP secretory response, vasopressin increased the ability of volume expansion to induce ANP release, thus modulating the direct mechanical stimulus-induced ANP secretion. The increased left ventricular levels of immunoreactive ANP and augmentation of ANP mRNA levels in Brattleboro rats despite normal left ventricular weight to body weight ratio show that increased ANP gene expression may occur in the ventricles independently of hypertrophy.     

Effect of a selective V1 vasopressin receptor antagonist on the sequelae of endotoxemia in the conscious rat

The following studies were designed to evaluate the efficacy of a potent and selective AVP V1 receptor antagonist ([1-beta-mercapto-beta, beta-cy?lopentamethyleneproprionic acid, 2-(O-methyl)tyrosine-8-arginine vasopressin]; AVPRA) in limiting the sequelae of endotoxemia. At 0.5 and 1.0 hr after intravenous injection of 30 mg/kg S. enteritis endotoxin (LPS) to male Sprague-Dawley rats, AVP plasma concentrations were increased to 171 +/- 20 and 100 +/- 24 pg/ml, respectively, and were significantly greater than the vehicle control values of 1 pg/ml. Injection of LPS was accompanied by the following: a decreased survival rate (20%) with a mean survival time of 21.6 +/- 6 hr (n = 10), an increased heart rate (+ 84 +/- 22 bpm), a reduced circulating platelet count (23% of initial), and an acute hemoconcentration that was maximal at 30 min after injection of LPS. In a separate group of conscious rats, it was determined that AVPRA (1-100 mg/kg/hr) produced a dose-dependent, parallel and rightward shift in the AVP vasopressor dose-response curve: the highest dose of AVPRA (i.e., 100 micrograms/kg/hr) produced approximately a 1,000-fold shift in the AVP dose-response curve. Administration of AVPRA (1-100 micrograms/kg/hr) beginning 15 min prior to the injection of LPS and continuing for 6 hr did not significantly limit any of the sequelae produced by endotoxemia. These results suggest that, in this model, acute administration of a potent V1 AVP antagonist (AVPRA) is not sufficient to prevent the cardiovascular sequelae and mortality associated with endotoxemia.     

The role of alpha 1- and alpha 2-adrenoceptors in canine systemic capacitance vessels--a study with measurement of mean circulatory pressure

We investigated the presence of alpha-adrenoceptor subtypes in systemic capacitance vessels by examining the effects of alpha 1- and alpha 2-agonists or antagonists on the mean circulatory pressure (MCP). Dogs were anesthetized with pentobarbital, and after total spinal anesthesia, epinephrine was given intravenously to maintain mean blood pressure at about 80 mmHg. 1. With intravenous injection of phenylephrine (alpha 1-agonist, 10 micrograms/kg, n = 7), and of BHT 920 (alpha 2-agonist, 5 micrograms/kg, n = 7), MCP increased significantly from 9.8 +/- 0.4 (mean +/- SE) to 10.9 +/- 0.3 mmHg (+11.2%, p less than 0.01), and from 9.3 +/- 0.4 to 10.3 +/- 0.4 mmHg (+10.8%, p less than 0.05), respectively. 2. Intravenous injection of prazosin (alpha 1-antagonist, 150 micrograms/kg, n = 7) and of yohimbine (alpha 2-antagonist, 30 micrograms/kg, n = 7) decreased MCP significantly from 9.9 +/- 0.4 to 8.2 +/- 0.5 mmHg (-17.2%, p less than 0.01), and from 9.8 +/- 0.2 to 7.6 +/- 0.3 mmHg (-22.4%, p less than 0.01), respectively. 3. Intravenous injection of phenylephrine (10 micrograms/kg, n = 7) after pretreatment with prazosin (150 micrograms/kg) decreased MCP significantly from 9.5 +/- 0.3 to 7.8 +/- 0.3 mmHg (-17.9%, p less than 0.01). MCP decreased significantly from 9.9 +/- 0.3 to 8.2 +/- 0.3 mmHg (-17.2%, p less than 0.01) after intravenous injection of BHT 920 (5 micrograms/kg, n = 7) following pretreatment with yohimbine (30 micrograms/kg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Origin and role of circulating catecholamines in the normotensive sympathectomized rat

Early chronic treatment with guanethidine destroys peripheral sympathetic nerves while sparing the adrenal medulla, and does not lower blood pressure (BP) in conscious normotensive rats (Julien et al. Am J Physiol 1990; 259: H1337). Therefore, the origin and role of circulating catecholamines (CAs) in BP maintenance were examined in conscious normotensive control, sympathectomized (SNX)--daily s.c. injections of guanethidine from 1 to 13 weeks of age--and sympathectomized-adrenalectomized (SNX-A) rats by measuring i) their plasma CAs (norepinephrine, NE and epinephrine, E) and 3,4-dihydroxyphenylglycol (DHPG) by HPLC-FD, and ii) their mean BP (MBP) responses to phenylephrine and phentolamine (5 mg/kg i.v.). The doses of phenylephrine that produced similar MBP rises were 3 micrograms/kg in controls (44 +/- 4 mmHg) and 1.5 micrograms/kg in SNX (47 +/- 3 mmHg) and SNX-A (48 +/- 2 mmHg) rats. Results are as follows: [table: see text] In conclusion, in conscious normotensive SNX rats: (1) most of the circulating NE is of adrenomedullary origin and plasma DHPG derives from neuronal NE; (2) due to supersensitivity of the cardiovascular system, stimulation of alpha-adrenoreceptors by circulating CAs play a significant role in BP maintenance.     

Central modulation of the baroreflex response to phenylephrine in rats. Lack of interaction between calcium channel modulators and the renin-angiotensin system

We have previously shown that a calcium channel activator (BAY K 8644) can decrease the baroreflex control of heart rate in SHR when intracerebroventricularly (i.c.v.) administered. In pentobarbital anesthetized SHR, the inhibitory effect of BAY (3 micrograms/kg i.c.v.) on baroreflex sensitivity (BRS; ramp method: phenylephrine 2 micrograms i.v.; BAY: 0.14 +/- 0.05 vs control: 0.39 +/- 0.08 msec/mmHg; p less than 0.01) was fully suppressed after pretreatment with the muscarinic antagonist atropine methylnitrate (80 micrograms/kg i.c.v.) suggesting the involvement of cholinergic pathways in the inhibitory effect. Since A II was reported to centrally increase arterial pressure through an enhanced release of acetylcholine and to depress BRS, we tested whether the effect of BAY on BRS could involve central A II systems. The A II antagonist [Sar 1Ile8] A II (30 micrograms/kg/min i.c.v.) suppressed the inhibitory effect of A II on BRS (control: 0.32 +/- 0.09; A II: 0.10 +/- 0.02; Sar1 Ile8 + A II: 0.39 +/- 0.08 msec/mmHg) but not the inhibitory effect of BAY (3 mu g/kg i.c.v.) on BRS. These results suggest that the central inhibition of BRS by BAY unlikely involves central A II systems.     

Humoral regulation of blood flow to choroid plexus: role of arginine vasopressin

The goal of this study was to examine humoral mechanisms that regulate blood flow to the choroid plexus. We determined the effects of arginine vasopressin on blood flow (microspheres) to the choroid plexus in anesthetized and awake rabbits. In anesthetized rabbits, blood flow to the choroid plexus was 342 +/- 31 (mean +/- SEM) ml/min/100 g under control conditions. Intravenous infusion of vasopressin at 4 and 40 mU/kg increased plasma vasopressin levels from 11 +/- 1 to 55 +/- 15 and 441 +/- 120 pg/ml, respectively, and blood flow to the choroid plexus decreased by 48 +/- 6% and 70 +/- 4%. Cerebral blood flow was not affected by infusion of vasopressin. Similar responses to infusion of vasopressin were observed in awake rabbits. The V1 antagonist [d(CH2)5Tyr(Me)AVP] (10 micrograms/kg i.v.) had no effect on resting blood flow, but abolished the effect of vasopressin on blood flow to the choroid plexus. Vasoconstrictor responses of the choroid plexus to intravenous infusion of phenylephrine were not attenuated by the V1 antagonist. Thus, circulating vasopressin, at plasma levels that are observed under physiological and pathophysiological conditions, has marked effects on blood flow to the choroid plexus. These effects appear to be mediated through a V1 receptor. We speculate that vasopressin may play an important role in regulation of blood flow to the choroid plexus and perhaps in the regulation of cerebrospinal fluid production.     

Increased number of angiotensin II binding sites determined by autoradiography in anterior pituitary of water-deprived and Brattleboro rats

Pituitary angiotensin II (ANG) binding sites were characterized by autoradiography in individual male Long Evans (LE) rats, heterozygous Brattleboro (HZ) rats, and homozygous Brattleboro (DI) rats which were water satiated or water deprived. An additional group of DI rats was treated with arginine vasopressin for 1 week. The technique utilized 8-micron pituitary sections which were incubated with 125I-[Sar1]-ANG in concentrations ranging from 25 pM to 10 nM. Angiotensin binding in the anterior pituitary of water-satiated LE rats was characterized by a single class of high-affinity, saturable sites with a Bmax of 1.309 +/- 119 fmol/mg of protein and a Ka of 0.51 +/- 0.03 X 10(9) M-1. Compared to LE rats the density of ANG-binding sites in anterior pituitary was higher in DI rats (+84.2%), with HZ having an intermediate concentration (+41.6). Dehydration increased the ANG-binding site density in all groups. Five days of water deprivation increased the number of ANG-binding sites by 86.5% and by 36.9% in LE and HZ rats, respectively, when compared to their water-satiated controls. After 1 day of water deprivation, the ANG-binding site density increased by 19.4% in DI rats. No changes in ANG-binding sites occurred after hormonal replacement with arginine vasopressin in water-satiated DI rats. The binding affinity constant of the agonist for the ANG-binding sites compared with LE rats was decreased in both HZ and DI rats (-27.5 and -19.4%) and was also decreased after 5 days of dehydration in LE rats (-34%) when compared to the water-satiated state.(ABSTRACT TRUNCATED AT 250 WORDS)     

Postsynaptic alpha 1- and alpha 2-adrenergic receptors in adrenergic control of capacitance vessel tone in vivo

The involvement of postsynaptic alpha 2-adrenergic receptors in the adrenergic constriction of the capacitance vessels was studied in anesthetized, spontaneously breathing dogs under ganglionic blockade (hexamethonium, 10 mg/kg + 10 mg/kg/hr; methylatropine, 0.5 mg/kg). Effective vascular compliance was measured as an indicator of venous tone (blood volume was varied by +/- 4 ml/kg in an 11-minute cycle of infusion, withdrawal, withdrawal, and reinfusion) and was calculated from the correlation between the observed changes in central venous pressure and the changes in blood volume. Sympathetic activity and central venous pressure were lower and effective vascular compliance was higher than values in untreated conscious dogs. The alpha 2-agonist UK 14,304 (5-bromo-6-[imidazolin-2-ylamino]-quinoxaline; 0.04 and 0.12 micrograms/kg/min; n = 6) dose-dependently lowered compliance and increased central venous pressure to levels found in conscious dogs, as did the alpha 1-agonist methoxamine (10 and 30 micrograms/kg; n = 6). Rauwolscine (alpha 2-antagonist), 0.3 mg/kg, significantly attenuated the effects of UK 14,304, but not those of methoxamine, while prazosin (alpha 1-antagonist), 0.12 mg/kg, attenuated the effects of methoxamine, but not those of UK 14,304 (n = 6 each). Under beta-blockade (nadolol, 2 mg/kg; n = 12) venous tone was increased to about physiological levels by norepinephrine, 0.15 micrograms/kg/min i.v., or by neuronal norepinephrine release induced by tyramine, 10 micrograms/kg/min i.v. These increases were significantly attenuated by prazosin as well as by rauwolscine and were abolished by a combination of both. These results indicate that postsynaptic alpha 2-adrenergic receptors (in addition to alpha 1-adrenergic receptors) are functional in the venous system in vivo and contribute substantially to adrenergic sympathetic and humoral regulation of venous tone.     

Role of the serotonergic nervous system in hemodynamic and vasopressin responses to centrally administrated angiotensin-II in spontaneously hypertensive rats

The purpose of the study is to investigate the role of the serotonergic nervous system in centrally administrated angiotensin II (A-II) mediated hemodynamic as well as vasopressin (AVP) responses. Eight-week-old male SHR and age-matched Wistar Kyoto rats (WKY) were used and the experiment was performed in the conscious state. In protocol 1, after resting observation of 30 minutes 10ng of A-II was given intracerebroventricularly (i.c.v.). This was followed by i.c.v. injection of 1 microgram of 5-HT2 receptor antagonist, xylamidine, 50 minutes later; then 10ng of i.c.v. A-II was repeated after 10 minutes (SHR: n = 7, WKY: n = 10). In protocol 2, plasma vasopressin (AVP) was measured in the following groups. In one group, 1.3ml of blood was sampled from the carotid cannula after resting observation, and the same amount of blood from an age-matched donor rat of the same strain was transfused immediately. Two hours later, 10ng of A-II was given i.c.v., and blood was sampled again after 1 minute (SHR: n = 7, WKY: n = 12). In another group, 1 microgram of xylamidine was given i.c.v. and was followed by 10ng of A-II 10 minutes later; then blood was collected after 1 minute (SHR: n = 8, WKY: n = 13). In protocol 1, resting MAP were 144 +/- 6mmHg in SHR and 99 +/- 2mmHg in WKY. I.c.v. A-II elicited a consistent pressor response in both SHR and WKY, but the response was significantly larger in SHR than that in WKY, +45 +/- 3 and +37 +/- 1mmHg, respectively. Xylamidine had no effect on MAP, and repeated A-II produced significant pressor responses. However, the responses were significantly smaller in both SHR (+36 +/- 3mmHg) and WKY (+25 +/- 1mmHg) as compared with those to initial A-II injection. In protocol 2, resting AVP were similar in SHR (1.5 +/- 0.2pg/ml) and in WKY (1.6 +/- 0.1pg/ml). However, after i.c.v. A-II injection, AVP became higher in SHR (131 +/- 14pg/ml) than in WKY (64 +/- 6pg/ml). AVP after A-II injection with xylamidine pretreatment were similar in SHR (48 +/- 6pg/ml) and in WKY (45 +/- 4pg/ml). Since the responses of both MAP and AVP to i.c.v. A-II were larger in SHR, and the responses were effectively suppressed by S2 receptor antagonists, the central serotonergic nervous system may play an important role in the hemodynamic as well as AVP responses to i.c.v. A-II administration.