Effects of 17beta-estradiol on the baroreflex control of sympathetic activity in conscious ovariectomized rats.

The effects of chronic treatment with 17beta-estradiol on baroreflex control of sympathetic activity were examined in conscious unrestrained ovariectomized rats. Baroreflex function was evaluated by logistic sigmoidal analysis of the relationships between changes in mean arterial pressure (MABP) and changes in heart rate (HR) and splanchnic nerve activity (SNA) when MABP was rapidly increased to 150 mmHg by intravenous phenylephrine after its reduction to 50 mmHg by intravenous nitroprusside. These baroreflex function curves were similar in vehicle- and estradiol-treated rats. However, after a 30-min infusion of vasopressin in vehicle-treated rats, the curve for HR was shifted downward, and the upper plateau and maximum gain for the SNA curve were reduced. These effects were abolished by estradiol. A 30-min phenylephrine infusion had no effect on the baroreflex curves. Thus estrogen can modulate the action of vasopressin on baroreflex control of sympathetic outflow and thereby participate in cardiovascular regulation.

Effects of 17beta-estradiol on sympathetic activity and pressor response to phenylephrine in ovariectomized rats.

The effects of 17beta-estradiol (E2) on sympathetic activity were examined in conscious unrestrained ovariectomized rats, instrumented under methohexital anesthesia to record mean arterial pressure (MABP), heart rate (HR), renal nerve activity (RNA), and splanchnic nerve activity (SNA) 1 day before the experiment. Injection of E2 (150 micrograms/kg iv) caused reductions (P < 0.01) in RNA (29 +/- 6%), SNA (25 +/- 2%), and HR (26 +/- 5 beats/min) within 20 min, but MABP remained unchanged. Ninety minutes after intravenous injection of E2 or vehicle, intravenous infusion of phenylephrine (PE; 6.2 micrograms . min-1 . kg-1) induced similar increases in MABP and decreases in HR, RNA, and SNA in both groups. By contrast, in rats chronically treated with E2, the pressor response to PE was smaller (P < 0.01; 22 +/- 5 mmHg) than in vehicle-treated rats (40 +/- 4 mmHg). The changes in HR, RNA, and SNA were similar in both groups, but the ratios of changes in HR and SNA to MABP, an index of baroreflex sensitivity, were greater in the E2-treated rats. These findings suggest that E2 can act centrally to modulate sympathetic function and thereby participate in cardiovascular regulation.

Sexual dimorphism in regional blood flow responses to vasopressin in conscious rats.

The greater pressor response to vasopressin in male than in nonestrous female rats results from a greater increase in total peripheral resistance in males. The present study was performed to identify the vascular beds that contribute to this difference. Mean arterial blood pressure (MABP) and changes in blood flow in the mesenteric and renal arteries and terminal aorta were measured in conscious male and nonestrous female rats 3 h after surgery. Graded intravenous infusions of vasopressin induced greater increases in MABP and mesenteric vascular resistance and a greater decrease in mesenteric blood flow in males. Vasopressin also increased renal vascular resistance to a greater extent in males. Because renal blood flow remained unchanged, this difference may be due to autoregulation. The vasopressin-induced reduction in blood flow and increased resistance in the hindquarters were moderate and did not differ between sexes. Thus the greater vasoconstrictor response to vasopressin in the mesenteric vascular bed of male than nonestrous females contributed importantly to the sexually dimorphic pressor response to vasopressin in these experiments.

Sex differences in the cardiovascular and renal actions of vasopressin in conscious rats.

The present study was carried out to investigate whether prostaglandins (PG) are involved in the mechanism that contributes to the sex difference in the antidiuretic and pressor actions of vasopressin. The experiments were performed in conscious male and nonestrous female rats. In hydrated rats, the graded infusion of vasopressin (10-1,000 pg.min 1.kg body wt-1) resulted in a dose-dependent antidiuresis: decreases in urine flow and free water clearance and an increase in urine osmolality. These responses were significantly greater in male than in nonestrous female rats. Pretreatment with a cyclooxygenase inhibitor, indomethacin (10 mg/kg body wt iv), significantly enhanced the antidiuretic response to vasopressin in both sexes. However, the magnitude of this enhancement was greater in female than in male rats. Thus indomethacin abolished the sex difference in the antidiuretic response to vasopressin. In a separate experiment in rats without water hydration and urine collection, infusion of pressor doses of vasopressin (1,000-6,000 pg.min-1.kg body wt-1) resulted in a greater increase in blood pressure in male than in nonestrous female rats. Treatment with indomethacin enhanced this response equivalently in both sexes and thus did not affect the sex difference in the pressor action of vasopressin. These data indicate that renal PG may mediate, at least in part, the sex difference in the antidiuretic action of vasopressin, whereas vascular PG seem not to play an important role in the sex difference in the pressor action of vasopressin.

Gonadal hormones modulate deoxycorticosterone-salt hypertension in male and female rats.

We have shown previously that, in rats with deoxycorticosterone (DOC)-salt hypertension, arterial blood pressure rises more rapidly and reaches a higher level in male than in female rats and that the course of the hypertension was ameliorated by gonadectomy in male rats and exacerbated by gonadectomy in female rats. The present investigation was undertaken to examine the role of the gonadal steroid hormones in modulating the course of DOC-salt hypertension in the rat. Our previous findings with respect to the effects of gender and gonadectomy on DOC-salt hypertension were confirmed in this study. Chronic treatment with gonadal steroids was begun 1 week before the start of the DOC-salt protocol. 17 beta-Estradiol attenuated the course of the hypertension in intact male rats and in gonadectomized females. Testosterone exacerbated the development of the hypertension in gonadectomized male rats but was without effect in intact females. Progesterone alone had no effect on the hypertension in ovariectomized rats but when given to ovariectomized rats in combination with estradiol transiently prevented the ameliorating effect of the estradiol. These effects of the gonadal steroid hormones could not be attributed to effects of saline intake. Thus, these findings demonstrate that the gonadal steroid hormones play an important role in modulating the pathogenesis of DOC-salt hypertension in the rat. It is suggested that the effects of the gonadal hormones on the course of the hypertension may be due to modulation of the cardiovascular and renal actions of vasopressin, since vasopressin is required for this model of hypertension.

Central vasopressin blockade enhances its peripheral release in response to peripheral osmotic stimulation in conscious rats.

Increased plasma osmolality results in increased central as well as peripheral release of vasopressin. Experiments were carried out to determine whether, in this circumstance, vasopressin can act centrally to modulate its peripheral release. Prior to the start of a thirty-min i.v. infusion of 2.5 M or 0.15 M NaCl, the rats were given an intracerebroventricular (i.c.v.) injection of a peptide V1/V2 vasopressin antagonist (2 micrograms), OPC-31260 (60 micrograms), a non-peptide V2 antagonist, or 1-desamino-8-D-arginine vasopressin (dDAVP, 5 ng), a V2 agonist. Experiments with the peptide antagonist were carried out in male and non-estrous female rats. Since there were no differences between males and females in the measured responses, experiments with the other two drugs were carried out only in males. Pretreatment with either the V1/V2 antagonist or the V2 antagonist enhanced the increase in plasma vasopressin levels in response to the hypertonic saline infusion by about 50% at the end of 30 min. dDAVP, on the other hand, had no effect. None of the i.c.v. drugs had an affect on either the pressor or bradycardic responses to hypertonic saline infusion. These observations suggest that vasopressin can act centrally in a negative feedback fashion to attenuate its own release into the peripheral circulation in response to increased plasma osmolality.

Sex difference in urinary concentrating ability of rats with water deprivation.

Our previous demonstration of sexual dimorphism in the antidiuretic response to exogenous vasopressin prompted us to investigate the response to moderately high levels of endogenous vasopressin stimulated by water deprivation in conscious rats. After 24 h water deprivation, urine flow was significantly higher and urine osmolality lower in females than in males. Plasma concentrations of vasopressin were higher in females than in males after water deprivation, but plasma osmolality did not differ. Gonadectomy, which had no effect in dehydrated males, decreased urine flow and increased urine osmolality in females to levels observed in intact and gonadectomized males. Spontaneous water intake was also measured and found to be lower in males and estrous females than in females in the other phases of the estrous cycle. These observations support the concept that there is a gender difference in the antidiuretic responsiveness to endogenous vasopressin, that this difference is dependent upon the ovarian hormones, and that it may lead to differences in consumptive behavior.

V2-receptor blockade enhances pressor response to vasopressin: gender difference.

The present study was performed to determine if the attenuated pressor response to vasopressin in conscious non-estrous female rats is due in part to an enhanced V2-like receptor vasodilator action. In male rats, infusion of vasopressin at a rate of 1 ng.min(-1).kg body weight-1 (wt) resulted in an increase in mean arterial blood pressure (MABP) of about 20 mm Hg. Thirty minutes after beginning the infusion of vasopressin, the iv bolus injection of a non-peptide V2-receptor antagonist, OPC-31260 (2 mg.kg body wt-1), resulted in a further gradual increase in MABP of approximately 8 mm Hg in the next 60 min (p < 0.05). Thus, the pressor response to vasopressin was greater in OPC-31260-treated than in vehicle-treated male rats (p < 0.01). The pressor response to vasopressin 30 min after the start of its infusion was lower (about 8 mm Hg) in non-estrous female rats than in males. During the next 60 min of vasopressin infusion, there was a small further increase (p < 0.05) in MABP in the females given either OPC-31260 or its saline vehicle. In contrast to the male rats, however, there was no difference in MABP between the OPC-31260 and vehicle treated females. Thus, the present study has provided additional evidence for a V2-like receptor related vasodilator effect in male rats. However, since female rats do not appear to express a V2-receptor mediated vasodilator response, the sexually dimorphic pressor response to vasopressin cannot be due to a gender difference in V2-receptor vasodilator activity.

Effects of gender on the central actions of neuropeptide Y and norepinephrine on vasopressin and blood pressure in the rat.

Neuropeptide Y (NPY) and norepinephrine are co-localized in the noradrenergic projection from the A1 nucleus of the medulla to the vasopressinergic magnocellular neurons of the supraoptic and paraventricular nuclei. Because this pathway is involved in the control of vasopressin release, we have examined the possibility that NPY and norepinephrine interact in this control. Because the stimulation of vasopressin release by the intracerebroventricular (i.c.v.) administration of norepinephrine is greater in male than in female rats, the experiments were carried out in conscious male rats and in female rats in the proestrous and non-proestrous phases of the estrous cycle. NPY (940 pmol i.c.v.) caused small sustained increases in plasma vasopressin concentrations that were greater in proestrous than in non-proestrous females and males. Norepinephrine i.c.v. increased plasma vasopressin levels transiently and to a greater extent in females than males. When NPY and norepinephrine were given together, the pattern of the vasopressin response was similar to that of norepinephrine alone. The magnitude of this response in males and proestrous females did not differ from that to norepinephrine alone; in non-proestrous females the response was twice that to norepinephrine alone. In non-proestrous rats, NPY also enhanced the pressor response to norepinephrine. Thus, NPY interacts centrally with norepinephrine in vasopressin release and cardiovascular function and this effect is dependent upon gender and phase of the estrous cycle.

Estradiol attenuates the antidiuretic action of vasopressin in ovariectomized rats.

To determine which ovarian hormone is involved in the sexually dimorphic antidiuretic action of vasopressin, the antidiuretic response to vasopressin was examined in sham-operated nonestrous female rats chronically treated with vehicle and in ovariectomized rats treated with vehicle, progesterone, estradiol, or the combination of estradiol and progesterone, respectively. Three-week-old female rats were sham operated or ovariectomized, and a slow-release hormone pellet was implanted at the 6th wk. The experiment was performed at the 10th to 12th wk in conscious, chronically instrumented rats hydrated with tap water (2% body wt). Infusion of vasopressin at rates of 10-1,000 pg.min-1.kg body wt-1 resulted in a dose-dependent antidiuretic response that was significantly enhanced in ovariectomized rats compared with the intact nonestrous females. Progesterone had no effect, whereas estradiol attenuated and restored the antidiuretic response to vasopressin to a level similar to that in intact nonestrous female rats. These results suggest that it is estrogen, but not progesterone, that reduces the antidiuretic response to vasopressin in the female rat.

Characteristics of vasopressin release during controlled reduction in arterial pressure.

Because of the interruption of the descending sympathetic nervous pathways, individuals with cervical spinal cord injury experience orthostatic hypotension when in an upright posture. The changes in hemodynamic parameters that occur during upright posture can be closely monitored and quantitated during progressive head-up tilting on a tilt table. We have utilized this method to assess the response of vasopressin and other vasoactive hormones to gradual, progressive reductions in arterial pressure and to identify possible threshold responses to baroreceptor stimulation in human subjects. Studies were performed in 12 quadriplegic subjects, 3 paraplegic subjects, and 3 normal control subjects. Data from the studies in paraplegic and normal subjects did not differ and were pooled as control data. In quadriplegic subjects, mean arterial pressure (MAP) decreased from 93 +/- 4 mm Hg to 60 +/- 3 mm Hg in a closely correlated (r = 0.948, p < 0.002) linear relationship with increasing degrees of tilt, whereas in control subjects, MAP increased from 81 +/- 4 to 88 +/- 3 mm Hg. Plasma vasopressin concentrations (Pavp) increased minimally in quadriplegic subjects until MAP was reduced to levels that were 25% to 30% lower than MAP with subjects in the supine posture. Beyond this level of hypotension, Pavp increased markedly. Log-linear regression analysis of these data showed a highly significant correlation (r = 0.85, p < 0.0002) between in Pavp and MAP, which defines Pavp as an exponential function of decreasing MAP. Changes in Pavp in control subjects were minimal during incremental head-up tilting. In contrast, plasma renin activity (PRA) increased in both quadriplegic and control subjects. Log-linear regression analysis of these data showed highly significant correlates between in PRA and degree of tilt in both quadriplegic (r = 0.958, p < 0.0002) and control (r = 0.873, p < 0.0002) subjects. Plasma atrial natriuretic peptide concentrations decreased linearly with increasing degrees of tilt. The rate of decline in Panp was greater in quadriplegic than in control subjects. These studies provide additional evidence that Pavp increases exponentially as a function of decreasing MAP and suggest that a critical threshold level of hypotension exists at which vasopressin release accelerates rapidly in response to baroreceptor stimulation. At this level of reduced MAP, Pavp reaches levels that are potentially capable of exerting a pressor effect.

Increased plasma osmolality stimulates peripheral and central vasopressin release in male and female rats.

It has been demonstrated that the neurohypophysial hormones can be released intrahypothalamically by the paraventricular (PVN) and supraoptic nuclei. The present experiments were undertaken to determine whether a physiological stimulus for vasopressin release, increased plasma osmolality, will stimulate the release of vasopressin by the PVN into the surrounding interstitial fluid, and whether the responses are affected by gender. Intravenous infusion of 2.5 M NaCl for 60 min (0.1 ml.kg-1.min-1) in conscious rats resulted in an increased vasopressin concentration in the dialysate from a microdialysis probe adjacent to the PVN. This response was greater in nonestrous females than in males. On the other hand, the rise in the plasma vasopressin concentration was greater in males than in nonestrous females. Mean arterial blood pressure increased and heart rate decreased, but these responses were not affected by gender. The role of centrally released vasopressin in the control of the peripheral release of vasopressin is conjectural, but both responses may be modulated by the gonadal steroid hormones.

Hemorrhage-induced vasopressin release in the paraventricular nucleus measured by in vivo microdialysis.

Experiments were carried out, using the technique of in vivo microdialysis in conscious rats, to determine whether hemorrhage, a potent stimulus for the release of vasopressin from the posterior pituitary into the circulation, would also result in a local release of vasopressin from the paraventricular nucleus (PVN), and whether this release is affected by gender. Male and non-estrous female rats were prepared with a microdialysis probe adjacent to the PVN and femoral arterial and venous catheters the day before the experiment. On the day of the experiment, rats was bled either 20% or 30% of blood volume. The concentration of vasopressin in the dialysate increased significantly in the males following both hemorrhages and in the females following the 30% hemorrhage. There were no statistically significant differences in the post-hemorrhage dialysate vasopressin concentration with respect to either gender or magnitude of the hemorrhage. The plasma vasopressin concentration increased markedly in response to the hemorrhage and this response was greater in females following the 30% hemorrhage. There were no gender differences in the reduction in arterial pressure following either hemorrhage. It is concluded that physiological stimuli for the release of vasopressin into the circulation also result in intrahypothalamic release of this hormone.

Effects of gonadectomy on sexually dimorphic antidiuretic action of vasopressin in conscious rats.

The present study examined whether the antidiuretic response to vasopressin is affected by the estrous cycle and by gonadectomy in conscious, chronically instrumented hydrated rats. Infusion of vasopressin (10-100 pg.min-1.kg body wt-1) resulted in a dose-dependent antidiuresis. Urine volume and free water clearance decreased and urinary osmolality increased with no significant changes in mean arterial blood pressure, heart rate, osmolar clearance, and urinary sodium and potassium excretion. The antidiuretic response to vasopressin was significantly greater in intact male and estrous female rats than in intact female rats in the other phases of the estrous cycle. Thus the calculated doses of vasopressin to reduce urine flow and free water clearance, as well as to increase urinary osmolality 50% from their control values, were significantly higher in nonestrous females than in males and estrous females. Gonadectomy was without effect on the antidiuretic potency of vasopressin in males, but in gonadectomized females the antidiuretic response to vasopressin was enhanced to a level similar to that observed in intact males. These data indicate that the antidiuretic activity of vasopressin is affected not only by gender but also by phase of the estrous cycle and that the ovarian hormone(s) may modulate the antidiuretic action of vasopressin.

Sex difference in the antidiuretic activity of vasopressin in the rat.

A possible gender difference in the antidiuretic activity of vasopressin was studied in male and female Sprague-Dawley rats. Infusion of vasopressin (3-100 pg.kg-1.min) into conscious, chronically instrumented water-loaded rats resulted in a dose-dependent antidiuresis in both male and female rats. Male rats, however, were more than three times more sensitive to vasopressin than female rats. Thus the effective doses of vasopressin (pg.kg-1.min-1) to decrease urine flow to 30 microliters.min-1.100 g-1 (18 +/- 5 in males; 58 +/- 12 in females), to increase urine osmolality to 600 mosmol/kgH2O (35 +/- 5 in males; 119 +/- 15 in females), and to decrease free water clearance to 30 microliters.min-1.100 g-1 (8 +/- 3 in males; 28 +/- 7 in females) were significantly (P < 0.05) lower in males. Furthermore, in vitro studies in papillary collecting duct cells demonstrated a significantly higher density of vasopressin V2 receptors and a greater ability of vasopressin to stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in males than in females. Vasopressin V2-receptor density (maximum binding) was 359 +/- 47 and 238 +/- 22 fmol/mg in male and female rats, respectively (P < 0.05). There was no difference in apparent dissociation constants (Kd). Vasopressin resulted in a dose-dependent increase in cAMP accumulation in papillary collecting duct cells, and at the highest concentration of vasopressin used (10(-8) M) cAMP increased from 44 +/- 10 to 182 +/- 51 fmol/micrograms protein in males and from 30 +/- 4 to 91 +/- 18 fmol/micrograms protein in females (P < 0.05). (ABSTRACT TRUNCATED AT 250 WORDS)

Role of vasopressin, the renin-angiotensin system and sex in Dahl salt-sensitive hypertension.

OBJECTIVE: To determine the roles of vasopressin, the renin-angiotensin system and sex in the pathogenesis of salt-sensitive hypertension in the Dahl rat. DESIGN: The effects of 12 days' treatment with a non-peptide, orally effective V1 antagonist (OPC-21,268) and captopril, individually or together, were compared in male and female Dahl salt-sensitive rats after 10 days on a high-salt diet. METHODS: OPC-21,268 was given in the food, and captopril was administered with osmotic pumps implanted subcutaneously. RESULTS: Systolic blood pressure (SBP) reached a higher level in untreated males than in untreated females. V1 blockade in males prevented any further increase in SBP during the first week of treatment, but SBP rose thereafter towards the levels found in the untreated males. In females OPC-21,268 had no effect. In males captopril prevented any further increase in SBP. There was no effect of captopril in females during the first week of treatment, but SBP fell to pretreatment levels during the second week. Combined treatment with OPC-21,268 and captopril in males had a smaller antihypertensive effect than either drug alone. In females combined treatment prevented any further increase in SBP. CONCLUSIONS: These findings suggest that both vasopressin and the renin-angiotensin system contribute to the pathogenesis of Dahl salt-sensitive hypertension, but that other factors, possibly including the sympathetic nervous system, are also involved. Sex also affects the severity of this form of hypertension and influences the relative roles of vasopressin and the renin-angiotensin system. It is likely that the gonadal steroid hormones modulate the activity of the pathogenetic factors in this form of hypertension at a central or peripheral level.

Vasopressin-independent alterations in renal water excretion in quadriplegia.

Postural effects on water excretion are known to be increased in patients with cervical spinal cord injury and may result in marked impairment of the ability to excrete a water load, especially in erect posture. Both vasopressin-dependent and vasopressin-independent mechanisms have been implicated. To assess the roles of these mechanisms and further identify the factors involved in the renal response to erect posture, sustained water loading studies were performed on 11 quadriplegic subjects and 9 healthy control subjects, supine and erect (sitting). Renal blood flow was assessed by p-aminohippurate clearance (CPAH) measurements in 7 quadriplegic and 5 control subjects. During maximal water diuresis, plasma vasopressin concentrations were reduced to unquantifiable levels in all subjects. Osmolar clearance, free water clearance (CH2O), and distal delivery of filtrate (DDF) were all lower in quadriplegic than in control subjects, supine and erect. The relationship between CH2O and DDF was the same in quadriplegic as in control subjects and was not altered by change in posture in either group. Creatinine clearance and CPAH were lower in erect than in supine posture in quadriplegic subjects but not in control subjects. We conclude that impairment of water excretion in stable normonatremic quadriplegic subjects can be attributed primarily to vasopressin-independent mechanisms involving reduced filtrate delivery to diluting segments of the renal tubules rather than to resistance to normal suppression of vasopressin release.

Evidence that nitric oxide can act centrally to stimulate vasopressin release.

Nitric oxide (NO) is the endothelium-derived relaxing factor, which causes relaxation of vascular smooth muscle. NO synthetase, the enzyme for the synthesis of NO from its precursor L-arginine, is also widely distributed in neurons in the brain, and it has been suggested that NO may serve as an important neuromodulator. Because NO synthetase is present in the hypothalamus in relatively high concentration, we have determined whether NO can affect the release of vasopressin in conscious, chronically prepared rats. The intracerebroventricular (i.c.v.) injection of S-nitroso-N-acetylpenicillamine (12.5 and 25 micrograms; SNAP), that spontaneously breaks down to form NO, caused transient dose-related increases in the plasma vasopressin concentration of 1 and 2 microU/ml (p < 0.01), respectively. In control experiments in which N-acetylpenicillamine (25 micrograms), the precursor for the preparation of SNAP, was injected i.c.v. there was a small, 0.4 microU/ml, increase (p < 0.01) in the plasma vasopressin level. The i.c.v. injection of L-arginine (0.5 and 1 mg), also the precursor for the biosynthesis of NO, resulted in dose-dependent increases in the plasma vasopressin concentration similar in magnitude to those caused by SNAP. When D-arginine (1 mg), which cannot serve as a substrate for NO synthetase, was injected i.c.v., there was only a slight delayed increase in the plasma vasopressin concentration. Thus, NO can act centrally to stimulate vasopressin release and may serve as a neuromodulator in the control of vasopressin release.

Sex differences in central cholinergic and angiotensinergic control of vasopressin release.

In conscious, unrestrained rats, the intracerebroventricular injection of the cholinergic agonist, carbachol, or angiotensin II resulted in the transient stimulation of vasopressin secretion, elevation of mean arterial blood pressure, and reduction of heart rate. After the injection of carbachol (25 ng) into a lateral cerebral ventricle, the plasma vasopressin concentration in male rats was increased to twice that of female rats in each phase of the estrous cycle; mean arterial blood pressure was elevated more in males than females, whereas heart rate fell to the same extent in both sexes. In contrast, the increase in the plasma vasopressin concentration of males after the injection of angiotensin II (20 ng) was one-half that of females, and the hypertensive and bradycardic responses were similar in both sexes. Phase of the female estrous cycle had no effect on the responses to either agent. These findings indicate that central cholinergic and angiotensinergic mechanisms controlling vasopressin release are influenced differently by gender. The role of the gonadal steroid hormones in these mechanisms remains to be determined.