Elevated dietary salt suppresses renin secretion but not thirst evoked by arterial hypotension in rats

Increased dietary salt intake was used as a nonpharmacological tool to blunt hypotension-induced increases in plasma renin activity (PRA) in order to evaluate the contribution of the renin-angiotensin system (RAS) to hypotension-induced thirst. Rats were maintained on 8% NaCl (high) or 1% NaCl (standard) diet for at least 2 wk, and then arterial hypotension was produced by administration of the arteriolar vasodilator diazoxide. Despite marked reductions in PRA, rats maintained on the high-salt diet drank similar amounts of water, displayed similar latencies to drink, and had similar degrees of hypotension compared with rats maintained on the standard diet. Furthermore, blockade of ANG II production by an intravenous infusion of the angiotensin-converting enzyme inhibitor captopril attenuated the hypotension-induced water intake similarly in rats fed standard and high-salt diet. Additional experiments showed that increases in dietary salt did not alter thirst stimulated by the acetylcholine agonist carbachol administered into the lateral ventricle; however, increases in dietary salt did enhance thirst evoked by central ANG II. Collectively, the present findings suggest that hypotension-evoked thirst in rats fed a high-salt diet is dependent on the peripheral RAS despite marked reductions in PRA.     

Oxytocin-induced renin secretion in conscious rats

Arterial hypotension and hypovolemia are known to stimulate neurohypophysial secretion of oxytocin (OT) in rats, although the physiological function of OT under these circumstances is uncertain. We now report that OT infused intravenously into conscious rats at 125 ng x kg(-1) x h(-1), a dose selected to mimic plasma OT levels during hypotension or hypovolemia, increased plasma renin concentration and plasma renin activity by twofold. This effect was prevented by systemic pretreatment with an OT receptor antagonist [[1-(3-mercaptopropionic acid)-2-O-ethyl-D-Tyr-Thr(4)-Orn(8)]-OT]. The OT antagonist did not block renin secretion induced by systemic injection of the beta-adrenergic receptor agonist isoproterenol, indicating that the OT antagonist does not interfere nonselectively with renin release. Pretreatment of rats with the beta-adrenergic receptor antagonist nadolol also prevented OT-induced renin secretion. Similarly, nadolol injected during infusion of OT markedly reduced the elevated plasma renin levels. These observations raise the possibility that pituitary OT secretion during hypotension or hypovolemia in rats may serve to support blood pressure by enhancing activation of the renin-angiotensin system via a beta-adrenergic receptor-dependent mechanism.     

Role of renin-angiotensin system in hypotension-evoked thirst: studies with hydralazine

Injection of rats either with diazoxide (25 mg/kg iv), isoproterenol (0.33 mg/kg sc), or hydralazine (HDZ) (10 mg/kg ip) decreased arterial blood pressure from approximately 120 to 70-80 mmHg and stimulated renin secretion. However, diazoxide and isoproterenol treatments each stimulated water ingestion, whereas HDZ treatment did not. HDZ treatment did not reduce water intake evoked by systemic injection of hypertonic saline or 20% polyethylene glycol solution or by 24-h water deprivation, suggesting that HDZ treatment did not interfere with drinking behavior. In contrast, HDZ treatment markedly reduced water intake evoked by injection of diazoxide or isoproterenol or by intravenous infusion of renin. Furthermore, a highly significant correlation was observed when plasma ANG II levels were plotted as a function of plasma renin activity after intravenous infusion of renin and after diazoxide and isoproterenol treatments. However, values obtained after HDZ treatment alone or in combination with intravenous infusion of renin did not fall near the 99% confidence interval of the regression line, suggesting that HDZ treatment blocks ANG II production and/or promotes its clearance. Thus rats apparently do not increase water intake after HDZ treatment, because this drug interferes with the renin-angiotensin system. These results provide further evidence that arterial hypotension evokes thirst in rats predominantly by activation of the renin-angiotensin system.     

Regulation of plasma vasopressin and renin activity in conscious hindlimb-unloaded rats

Cardiovascular deconditioning occurs in astronauts after spaceflight or in individuals subjected to bed rest. It is characterized by an increased incidence of orthostatic intolerance. The mechanisms responsible for orthostatic intolerance are likely multifactorial and may include hypovolemia, autonomic dysfunction, and vascular and cardiac alterations. The arterial baroreflex is an important compensatory mechanism in the response to an orthostatic stress. In a previous study, we demonstrated that arterial baroreflex mediated sympathoexcitation was blunted in hindlimb-unloaded (HU) rats, a model of cardiovascular deconditioning. The arterial baroreflex also contributes to the regulation of vasoactive hormones including vasopressin and angiotensin II. In the present study, we tested the hypothesis that the neurohumoral response to hypotension is also attenuated in rats after 14 days of hindlimb unloading. To test this hypothesis, the vasodilator diazoxide (15 or 25 mg/kg) or saline (0.9%) was administered to produce hypotension or control conditions, respectively, in conscious HU and control rats. Plasma samples were collected and assayed for vasopressin and plasma renin activity (PRA). Diazoxide (25 mg/kg) produced significant increases in vasopressin and PRA compared with saline controls. HU rats exhibited significantly higher levels of vasopressin at rest and the increase in vasopressin levels during hypotension was enhanced by hindlimb unloading. Neither resting nor hypotension-induced PRA was altered by hindlimb unloading. These data suggest that although baroreflex-mediated sympathoexcitation is blunted by hindlimb unloading, hypotension-induced vasopressin release is enhanced and hypotension-induced PRA is unaffected. Increased circulating vasopressin may serve to compensate for blunted baroreflex regulation of sympathetic nervous activity produced by hindlimb unloading or may actually contribute to it.     

Stimulation of brain mast cells by compound 48/80, a histamine liberator, evokes renin and vasopressin release in dogs

Because degranulation of brain mast cells activates adrenocortical secretion (41, 42), we examined whether activation of such cells increases renin and vasopressin (antidiuretic hormone: ADH) secretion. For this, we administered compound 48/80 (C48/80), which liberates histamine from mast cells, to pentobarbital-anesthetized dogs. An infusion of 37.5 microg/kg C48/80 into the cerebral third ventricle evoked increases in plasma renin activity (PRA), and in plasma epinephrine (Epi) and ADH concentrations. Ketotifen (mast cell-stabilizing drug; given orally for 1 wk before the experiment) significantly reduced the C48/80-induced increases in PRA, Epi, and ADH. Resection of the bilateral splanchnic nerves (SPX) below the diaphragm completely prevented the C48/80-induced increases in PRA and Epi, but potentiated the C48/80-induced increase in ADH and elevated the plasma Epi level before and after C48/80 challenge. No significant changes in mean arterial blood pressure, heart rate, concentrations of plasma electrolytes (Na+, K+, and Cl-), or plasma osmolality were observed after C48/80 challenge in dogs with or without SPX. Pyrilamine maleate (H1 histaminergic-receptor antagonist) significantly reduced the C48/80-induced increase in PRA when given intracerebroventricularly, but not when given intravenously. In contrast, metiamide (H2 histaminergic-receptor antagonist) given intracerebroventricularly significantly potentiated the C48/80-induced PRA increase. A small dose of histamine (5 microg/kg) administered intracerebroventricularly increased PRA twofold and ADH fourfold (vs. their basal level). These results suggest that in dogs, endogenous histamine liberated from brain mast cells may increase renin and Epi secretion (via the sympathetic outflow) and ADH secretion (via the central nervous system).     

Intravenous 6-hydroxydopamine attenuates vasopressin and oxytocin secretion stimulated by hemorrhage and hypotension but not hyperosmolality in rats

The present study sought to determine whether chemical destruction of peripheral catecholaminergic fibers with 6-hydroxydopamine (6OHDA) attenuates vasopressin (VP) and oxytocin (OT) secretion stimulated by hemorrhage, hypotension, and hyperosmolality. Rats received 6OHDA (100 mg/kg iv) or vehicle (1 ml/kg iv) on days 1 and 7, and experiments were performed on day 8. Serial hemorrhage (4 samples of 2 ml per 300 g body wt at 10-min intervals) increased plasma VP and OT levels in both groups; however, the increase in plasma VP and OT levels was significantly attenuated in 6OHDA-treated vs. control rats despite a significantly lower mean arterial blood pressure. Similarly, the increase in plasma VP and OT levels in response to hypotension produced by the selective arteriolar vasodilator diazoxide was significantly attenuated in 6OHDA-treated rats. In marked contrast to hemorrhage and hypotension, hyperosmolality produced by an infusion of 1 M NaCl (2 ml/h iv) stimulated increases in plasma VP and OT levels that were not different between 6OHDA-treated and control rats. In a parallel set of experiments, intravenous 6OHDA treatment reduced dopamine--hydroxylase immunoreactivity in the posterior pituitary but had no substantial effect in the hypothalamic paraventricular and supraoptic nuclei. In each experiment, the pressor response to tyramine (250 microg/kg iv) was significantly attenuated in 6OHDA-treated rats, thereby confirming that 6OHDA treatment destroyed sympathetic catecholaminergic fibers. Collectively, these findings suggest that catecholaminergic fibers located outside the blood-brain barrier contribute to VP and OT secretion during hemorrhage and arterial hypotension.     

Peripheral mechanisms involved in the pressor and bradycardic effects of centrally administered arachidonic acid

In the current study, we aimed to determine the cardiovascular effects of arachidonic acid and peripheral mechanisms mediated these effects in normotensive conscious rats. Studies were performed in male Sprague Dawley rats. Arachidonic acid was injected intracerebroventricularly (i.c.v.) at the doses of 75, 150 or 300 microg and it caused dose- and time-dependent increase in mean arterial pressure and decrease in heart rate in normal conditions. Maximal effects were observed 10 min after 150 and 300 microg dose of arachidonic acid and lasted within 30 min. In order to evaluate the role of main peripheral hormonal mechanisms in those cardiovascular effects, plasma adrenaline, noradrenaline, vasopressin levels and renin activity were measured after arachidonic acid (150 microg; i.c.v.) injection. Centrally injected arachidonic acid increased plasma levels of all these hormones and renin activity. Intravenous pretreatments with prazosin (0.5 mg/kg), an alpha1 adrenoceptor antagonist, [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1, O-Me-Tyr2-Arg8]-vasopressin (10 microg/kg), a vasopressin V1 receptor antagonist, or saralasin (250 microg/kg), an angiotensin II receptor antagonist, partially blocked the pressor response to arachidonic acid (150 microg; i.c.v.) while combined administration of these three antagonists completely abolished the effect. Moreover, both individual and combined antagonist pretreatments fully blocked the bradycardic effect of arachidonic acid. In conclusion, our findings show that centrally administered arachidonic acid increases mean arterial pressure and decreases heart rate in normotensive conscious rats and the increases in plasma adrenaline, noradrenaline, vasopressin levels and renin activity appear to mediate the cardiovascular effects of the drug.     

Histamine-induced enhancement of vasopressin and oxytocin secretion in rat neurohypophyseal tissue cultures

The effects of histamine (HA) on vasopressin (VP) and oxytocin (OT) secretion were studied in 13-14-day cultures of isolated rat neurohypophyseal (NH) tissue. The VP and OT contents of the supernatant were determined by radioimmunoassay (RIA) after a 1 or 2-h incubation. Significantly increased levels of VP and OT production were detected in the tissue culture media following HA administration, depending on the HA dose. The elevation of NH hormone secretion could be partially blocked by previous administration of the HA antagonist mepyramine (MEP, an H1 receptor antagonist) or cimetidine (CIM, an H2 receptor antagonist). Thioperamide (TPE, an H3-H4 receptor antagonist) did not influence the VP or OT secretion increase induced by HA. The application of MEP, CIM or TPE after HA administration proved ineffective. The H1 and H2 receptors are mainly involved in the HA-induced increase of both VP and OT secretion in isolated NH tissue cultures. The results indicate that NH hormone release is influenced directly by the histaminergic system, and the histaminergic control of VP and OT secretion from the NH tissue in rats can occur at the level of the posterior pituitary.     

Prazosin unmasks a renin response to intravenous para-chloroamphetamine

When injected intraperitoneally, p-chloroamphetamine (PCA) causes the acute release of catecholamines and serotonin, increases mean arterial pressure (MAP) and increases plasma renin activity (PRA) in rats. Experiments were designed to determine the dose-response and time-course for the effect of PCA administered intravenously on PRA in conscious, unrestrained rats. It was found initially that intravenous doses of PCA ranging from 0.3 - 6.0 mg/kg caused rapid and marked hypertension, but produced variable effects on PRA for up to 30 minutes after injection. In a second study PCA (0.3 - 6.0 mg/kg) did not alter PRA at 30 or 60 minutes after intravenous injection, but did increase PRA 60 minutes after 10 mg/kg, intraperitoneally. When the hypertension elicited by intravenous PCA was abolished by pretreatment with the alpha 1-adrenoceptor antagonist prazosin (100 micrograms/kg, iv), PCA produced marked elevations in PRA from 15 - 60 minutes. Thus it appeared that the renin response to intravenous PCA was masked by an elevation in MAP; when the vascular response to PCA was blocked, a large increase in PRA was observed.     

Influence of adrenergic nervous and prostaglandin systems on hydralazine-induced renin release

The role of the beta-adrenergic nervous and prostaglandin systems in vasodilator-induced activation of the renin-angiotensin system was studied in conscious rats. The plasma renin activity (PRA) response to intravenous hydralazine (0.25, 0.5 and 1 mg/kg body wt.) was compared to the PRA response following administration of similar doses of hydralazine to rats pretreated with either indomethacin (3 mg/kg body wt. i.v.) or indomethacin and propranolol (1 mg/kg body wt. i.v.). PRA increased significantly above control levels after each of the hydralazine doses. In rats pretreated with indomethacin, PRA did not increase with the 0.25 mg/kg dose of hydralazine; increased significantly with the 0.5 mg/kg dose but remained significantly lower than the PRA response in the absence of indomethacin; and increased with the 1 mg/kg dose to a level not significantly different from PRA in rats receiving only hydralazine. When rats were pretreated with indomethacin and propranolol, PRA did not increase significantly in response to either the 0.25 or 0.5 mg/kg doses of hydralazine. Although a statistically significant increase in PRA was noted with the 1 mg/kg dose of hydralazine, the level of PRA achieved was very low and only 15% of that observed with the other two treatment regimens (i.e., hydralazine alone or indomethacin and hydralazine). These results demonstrate that vasodilator-induced renin release is only partially mediated via the prostaglandin system, that the degree of this control is related to the intensity of vasodilator stimulus and that renin release following administration of hydralazine can be attributed almost entirely to activation of the beta-adrenergic nervous and prostaglandin systems.     

Influence of sedentary versus physically active conditions on regulation of plasma renin activity and vasopressin

Physical inactivity is an independent risk factor for cardiovascular disease. Sedentary animals compared to physically active controls exhibit enhanced sympathoexcitatory responses, including arterial baroreflex-mediated sympathoexcitation. Hypotension-induced sympathoexcitation is also associated with the release of vasoactive hormones. We hypothesized that sedentary conditions may enhance release of the vasoactive hormones AVP and ANG II. To test this hypothesis, the humoral response to hypotension was examined in conscious rats after 9-12 wk of sedentary conditions or "normally active" conditions. Normally active conditions were produced by allowing rats access to running wheels in their home cages. Running distance peaked after 4 wk (4.5 +/- 0.7 km/day), and the total distance run after 9 wk was 174 +/- 23 km (n = 25). Similar levels of hypotension were induced in conscious sedentary or physically active animals with the arterial vasodilator, diazoxide (25 mg/kg iv). Control experiments used a saline injection of equivalent volume. Plasma samples were collected and assayed for plasma AVP concentration and plasma renin activity (PRA). Sedentary conditions significantly enhanced resting and hypotension-induced PRA relative to normal physical activity. In contrast, resting and hypotension-induced AVP levels were not statistically different between groups. These data suggest that baroreflex-mediated activation of the renin-angiotensin system, but not AVP secretion, is enhanced by sedentary conditions. We speculate that augmented activation of the renin-angiotensin system may be related to enhanced sympathetic outflow observed in sedentary animals and may contribute to increased risk of cardiovascular disease in the sedentary population.     

Arterial baroreceptors control plasma vasopressin responses to graded hypotension in conscious dogs

We studied the role of cardiac and arterial baroreceptors in the reflex control of arginine vasopressin (AVP) and renin secretion during graded hypotension in conscious dogs. The dogs were prepared with Silastic cuffs on the thoracic inferior vena cava and catheters in the pericardial space. Each experiment consisted of a control period followed by four periods of inferior vena caval constriction, during which mean arterial pressure (MAP) was reduced in increments of approximately 10 mmHg. The hormonal responses were measured in five dogs under four treatment conditions: 1) intact, 2) acute cardiac denervation (CD) by intrapericardial infusion of procaine, 3) after sinoaortic denervation (SAD), and 4) during combined SAD+CD. The individual slopes relating MAP to plasma AVP and plasma renin activity (PRA) were used to compare the treatment effects using a 2 x 2 factorial analysis. There was a significant (P < 0.01) effect of SAD on the slope relating plasma AVP to MAP but no effect of CD and no SAD x CD interaction. In contrast, the slope relating PRA and MAP was increased (P < 0.05) by SAD but was not affected by CD. These results support the hypothesis that stimulation of AVP secretion in response to graded hypotension is primarily driven by unloading arterial baroreceptors in the dog.     

Acute hypertension inhibits thirst stimulated by ANG II, hyperosmolality, or hypovolemia in rats

The present study sought to determine whether increases in arterial blood pressure inhibited drinking behavior evoked by ANG II, hyperosmolality, or hypovolemia in rats. Cumulative water intakes in 60- or 90-min tests and latency to the first lick were recorded as indexes of thirst. During intravenous infusions of 100 ng. kg(-1). min(-1) ANG II, attenuation of the induced increases in arterial pressure with the arteriolar vasodilator diazoxide resulted in greater water intakes and shorter latencies to drink. Drinking behavior stimulated by intravenous infusion of hypertonic saline was significantly inhibited by increases in arterial pressure caused by intravenous infusion of phenylephrine or endothelin-1, and this inhibition of drinking was proportional to the induced increase in pressure. Upon termination of the phenylephrine infusion, mean arterial pressure returned to basal values, and drinking was restored. Phenylephrine-induced increases in arterial pressure also inhibited drinking behavior in response to hypovolemia that could not be explained by differences in plasma renin activity, plasma protein concentration, or plasma osmolality. Thus increases in arterial pressure inhibit water drinking behavior in response to each of these three thirst stimuli in rats.     

Tachykinin neurokinin 3 receptor signaling in cholecystokinin-elicited release of oxytocin and vasopressin

Neurokinin 3 receptor (NK3R) signaling has an integral role in the stimulated oxytocin (OT) and vasopressin (VP) release in response to hyperosmolarity and hypotension. Peripheral injections of cholecystokinin (CCK) receptor agonists for the CCK-A (sulfated CCK-8) and CCK-B (nonsulfated CCK-8) receptors elicit an OT release in rat. It is unknown whether NK3R contributes to this endocrine response. Freely behaving male rats were administered an intraventricular pretreatment of 250 or 500 pmol of SB-222200, a specific NK3R antagonist, or 0.15 M NaCl before an intraperitoneal or intravenous injection of CCK-8 (nonsulfated or sulfated) or 0.15 M NaCl. Blood samples were taken before intraventricular treatment and 15 min after intraperitoneal or intravenous injection, and plasma samples were assayed for OT and VP concentration. Intraperitoneal injection of both nonsulfated and sulfated CCK-8 significantly increased plasma OT levels and had no effect on plasma VP levels. Intravenous injection of sulfated CCK-8 stimulated an increase in plasma OT levels and did not alter plasma VP levels. However, intravenous injection of nonsulfated CCK-8 stimulated a significant increase in plasma levels of both OT and VP. No other studies have demonstrated CCK-8-stimulated release of VP in rat. NK3R antagonist did not alter baseline levels of either hormone. However, pretreatment of NK3R antagonist significantly blocked the CCK-stimulated release of OT in all CCK treatment groups and blocked VP release in response to intravenous injection of nonsulfated CCK-8. Therefore, central NK3R signaling is required for OT and VP release in response to CCK administration.     

Effect of celecoxib on the antihypertensive effect of losartan in a rat model of renovascular hypertension

Certain nonsteroidal anti-inflammatory drugs have been reported to elevate blood pressure in some hypertensive patients, who are either untreated or treated with antihypertensive agents. This study was undertaken to determine the effect of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, on the antihypertensive effects of the angiotensin II type 1 receptor (AT1) antagonist, losartan potassium. We studied the effect of oral treatment with losartan (30?mg/kg), celecoxib (3?mg/kg), and their combination on the mean arterial blood pressure (MAP), plasma renin activity (PRA), and plasma prostaglandin E2 (PGE2) in male Sprague-Dawley rats with renovascular hypertension (RVH) induced by partial subdiaphragmatic aortic constriction. Treatment was continued for 7 days after aortic coarctation. Aortic coarctation led to significant increases in the MAP, PRA, and plasma PGE2. In RVH rats, losartan treatment caused a significant decrease of MAP with a significant increase in both plasma PGE2 and PRA. Celecoxib caused a nonsignificant change in MAP with a significant decrease in the raised levels of plasma PGE2 and PRA. Concomitant administration of celecoxib and losartan did not significantly affect the lowering effect of losartan on MAP with a subsequent significant decrease in the plasma PGE2 and PRA in RVH rats. Therefore, celecoxib could be used in renin-dependent hypertensive patients who receive losartan, without fear of a rise in their blood pressure.     

Attenuation of homeostatic responses to hypotension and glucoprivation after destruction of catecholaminergic rostral ventrolateral medulla neurons

This study determined the effect of destruction of rostral ventrolateral medulla (RVLM)-C1 cells on integrated sympathetic and hormonal responses to hypotension or glucoprivation. Injection of anti-dopamine beta-hydroxylase-saporin into the RVLM resulted in 29-99% depletion of RVLM-C1 neurons and approximately 60% reduction in the number of A5 neurons. As in our previous study in unanesthetized rats, resting mean arterial pressure (MAP) was reduced by approximately 10 mmHg in rats with >80% depletion of RVLM-C1 cells compared with control rats, although resting heart rate (HR) did not differ significantly. In the present study, resting plasma levels of norepinephrine (NE) did not differ significantly between control rats and rats with >80% depletion of RVLM-C1 cells, although there was a tendency for RVLM-C1 lesioned rats to have lower levels. Also consistent with our previous study, hydralazine (HDZ)-evoked hypotension resulted in smaller increases in HR and plasma levels of NE in rats with >80% depletion of RVLM-C1 cells compared with control rats. Furthermore, the elevated plasma levels of posterior pituitary hormones vasopressin and oxytocin evoked by HDZ were blunted in RVLM-C1 lesioned rats compared with control rats, even though MAP fell to lower levels in the lesioned rats. Plasma renin activity, plasma osmolality, and plasma protein concentrations did not differ between control rats and rats with >80% depletion of RVLM-C1 neurons. In response to systemic administration of 2-deoxyglucose, the circulating level of epinephrine and the resulting hyperglycemia were attenuated in rats with >80% depletion of RVLM-C1 cells compared with control rats. These results demonstrate that RVLM-C1 cells, in addition to playing a role in acute cardiovascular reflexes, play an important role in integrated sympathetic and hormonal responses to homeostatic challenges such as hypotension and glucoprivation.     

Systemic and renal hemodynamic responses to vascular blockade of vasopressin in conscious dogs with ascites

A role for arginine vasopressin has been implicated in the compensatory control of arterial blood pressure in several animal models with reported increases in plasma levels of arginine vasopressin. A threefold elevation in plasma vasopressin has been reported in conscious dogs following constriction of the inferior vena cava. In the present study, infusion of the arginine vasopressin antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine] Arg8-vasopressin into conscious dogs with chronic caval constriction did not decrease mean arterial blood pressure. However, the dose of infused antagonist completely blocked the pressor response to 2 micrograms of exogenous vasopressin. Also the antagonist produced no effect on heart rate, plasma renin activity, or urinary volume and electrolyte excretions. A slight, transient increase (P less than or equal to 0.05) was observed in creatinine clearance and in PAH clearance following antagonist infusion, suggesting a possible decrease in renal vascular resistance. These data suggest that the direct vasoconstrictor actions of vasopressin contribute minimally, if at all, to blood pressure maintenance following chronic caval constriction. Alternatively, blockade of endogenous vasopressin receptors at the level of peripheral arterioles may have resulted in no depressor response due to a masking of this response by other compensatory hormonal and neural pressor systems.     

Blockade of NK3R signaling in the PVN decreases vasopressin and oxytocin release and c-Fos expression in the magnocellular neurons in response to hypotension

Tachykinin neurokinin 3 receptor (NK3R) signaling has a broad role in vasopressin (VP) and oxytocin (OT) release. Hydralazine (HDZ)-induced hypotension activates NK3R expressed by magnocellular neurons, increases plasma VP and OT levels, and induces c-Fos expression in VP and OT neurons. Intraventricular pretreatment with the specific NK3R antagonist, SB-222200, eliminates the HDZ-stimulated VP and OT release. NK3R are distributed in the central pathways conveying hypotension information to the magnocellular neurons, and the NK3R antagonist could act anywhere in the pathways. Alternatively, the antagonist could act at the NK3R expressed by the magnocellular neurons. To determine whether blockade of NK3R on magnocellular neurons impairs VP and OT release to HDZ, rats were pretreated with a unilateral PVN injection of 0.15 M NaCl or SB-222200 prior to an intravenous injection of 0.15 M NaCl or HDZ. Blood samples were taken, and brains were processed for VP/c-Fos and OT/c-Fos immunohistochemistry. Intravenous injection of 0.15 M NaCl did not alter plasma hormone levels, and little c-Fos immunoreactivity was present in the PVN. Conversely, intravenous injection of HDZ increased plasma VP and OT levels and c-Fos expression in VP and OT magnocellular neurons. Intra-PVN injection of SB-222200 prior to an intravenous injection of HDZ significantly decreased c-Fos expression in both VP and OT neurons by approximately 70% and attenuated plasma VP and OT levels by 33% and 35%, respectively. Therefore, NK3R signaling in magnocellular neurons has a critical role for the release of VP and OT in response to hypotension.     

Cardiovascular and renin responses to vanadate in the conscious dog: attenuation after calcium channel blockade

The effects of vanadate on cardiovascular function and on the secretion of renin and vasopressin were investigated by infusing sodium orthovanadate (0.32 mu mole/kg X min) intravenously into five conscious dogs. Vanadate caused significant increases in mean arterial pressure, total peripheral resistance, pulmonary arterial pressure, and cardiac output. These data illustrate that the hemodynamic effects of vanadate in the conscious dog are similar to those of the anesthetized dog but that minor differences do exist. Vanadate significantly suppressed plasma renin activity, but plasma vasopressin was unchanged. The effects of vanadate also were investigated in the same dogs on another day after administration of the calcium channel blocker, verapamil (0.3 mg/kg bolus + 0.01 mg/kg X min). After calcium channel blockade, the increases in arterial pressure and pulmonary arterial pressure induced by vanadate were attenuated, and cardiac output did not increase. Calcium channel blockade also prevented the vanadate-induced decrease in plasma renin activity. These data suggest that the cardiovascular and humoral alterations produced by vanadate in the conscious dog are at least partially mediated by changes in intracellular calcium.     

Pharmacological evidence for involvement of the sympathetic nervous system in the increase in renin secretion produced by a low sodium diet in rats

To determine the degree to which increased sympathetic activity contributes to the increase in renin secretion produced by a low sodium diet, the beta-adrenergic blocking drug propranolol or saline vehicle was injected through indwelling jugular cannulas in rats fed a normal diet and rats fed a low sodium diet for 9 days. Plasma renin activity (PRA) and plasma renin concentration (PRC) were elevated by the low sodium diet, and these values were reduced 42-45% by propranolol, although they were still higher than in the normal diet controls. Plasma corticosterone was moderately elevated in cannulated rats on regular diet, compared to decapitated controls, but corticosterone did not differ between cannulated and decapitated rats on low salt diet; propranolol reduced plasma corticosterone. However, PRA and PRC were comparable in cannulated rats and decapitated controls on both the normal and the low sodium diets, and propranolol did not produce a significant reduction in PRA and PRC in rats fed the normal diet. This indicates that the effects of propranolol on PRA and PRC in the low sodium rats were not simply due to reduction of a stress-induced increase in renin secretion. The results indicate that increased sympathetic activity makes a substantial contribution to the increase in renin secretion produced by 9 days of dietary sodium restriction.