L. Share

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

SUMMARY 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 < 0.01) but failed to increase significantly in either DI group. Urinary excretion of vasopressin (U ADH V) and SBP were measured in unilaterally nephrectomized LE rats treated with DOC and salt (DOC-LE), salt alone (NaCI-LE) and untreated rats (H.O-LE). The UADHV was elevated in DOC-LE (j> < 0.01) and NaCI-LE (p < 0.05) rats, but only the DOC-LE rats became hypertensive. Finally, the I.V. injection of analogs of vasopressin, which block its pressor but not antidluretic 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.

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.

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 difference in the development of deoxycorticosterone-salt hypertension in the rat.

To investigate a possible sex difference in the development of deoxycorticosterone (DOC)-salt hypertension in rats, systolic blood pressure was measured over 6 weeks in unilaterally nephrectomized male and female rats with or without DOC-salt treatment. Throughout the treatment, systolic blood pressure was significantly lower in female than in male DOC-salt rats (at the end of the sixth week: 190 +/- 8 vs 163 +/- 7 mm Hg, p less than 0.05). The difference in blood pressure was also confirmed by the direct measurement of mean arterial pressure at the end of the experiment. The 24-hour urinary excretion of vasopressin was significantly higher in male control rats than in female control rats; however, no difference was observed between male and female DOC-salt rats, in which the urinary excretion of vasopressin was four to five times higher than in control rats. The plasma vasopressin concentration was higher in DOC-salt rats, but there were no differences between sexes. There were no differences in the metabolic clearance rate of vasopressin among the four groups of rats. This indicates that the elevated plasma vasopressin concentration in DOC-salt hypertensive rats is due to increased release of the hormone, rather than to impaired metabolism. Thus, although vasopressin plays a pivotal role in the pathogenesis of DOC-salt hypertension, the sexual dimorphism in this form of hypertension cannot be attributed to differences in the secretion, metabolism, or plasma concentration of vasopressin.

Pressor responsiveness to vasopressin in the rat with DOC-salt hypertension.

SUMMARY To further characterize the role of rasopressin in DOC-salt hypertension, four groups of unilaterally nephrectomized rats were studied: control rats giren no further treatment, rats treated with DOC and giren 1% saline to drink, or rats treated with only DOC, or 1% saline. Only rats treated with DOC or DOC- salt became hypertensive. Control rats and rats treated with only DOC or 1% saline had similar pressor responses to exogenous rasopressin and angiotensin II. Within the DOC-salt group, two populations of rats were identified: one with normal pressor responsiveness to rasopressin, and one with markedly enhanced pressor responsireness to rasopressin. Incidence of enhanced responsiveness increased with duration of treatment. Urinary excretion of rasopressin was elerated in the 1% saline and DOC-salt groups after 1 week of treatment, and in the DOC group after 4 weeks. Howerer, the plasma rasopressin concentration was elerated only in the rats treated with both DOC and saline. It is suggested that rasopressin is essential for the expansion of blood rolume in the early stages of DOC-salt hypertension, and functions as a direct pressor agent only in the later stages.

Vasopressin: Sexual Dimorphism in Secretion, Cardiovascular Actions and Hypertension

We have investigated the issue of sexual dimorphism in the secretion of vasopressin, its pressor action, and the development of deoxycorticosterone (DOC)-salt hypertension. In normal human subjects on controlled salt intake, the basal secretion of vasopressin, indicated by plasma vasopressin levels and urinary excretion of vasopressin, was higher in men than in women and in blacks than in whites. Basal vasopressin secretion also was higher in male than in female rats. This effect was not associated with a difference in the metabolic clearance of the hormone. The sex-related difference in vasopressin release in rats was abolished by gonadectomy and restored by treatment of males with testosterone and females with ovarian hormones. The pressor responsiveness to vasopressin was higher in male than in randomly cycling female rats. Finally, DOC-salt hypertension, which is dependent on vasopressin, developed more rapidly in male than in female rats. Although there was no sex-related difference in the extent to which plasma vasopressin levels were elevated, pressor responsiveness to vasopressin was greater and baroreflex sensitivity was attenuated to a lesser extent in hypertensive males than in hypertensive females. Thus, it seems likely that gonadal hormones play a significant role in cardiovascular regulation.

Gonadectomy Abolishes the Sexual Dimorphism in Doc-Salt Hypertension in the Rat

Following our previous report that development of DOC-salt hypertension is attenuated in female rats, we have now determined the effects of gonadectomy on the pathogenesis of this model of hypertension. Male and female rats were gonadectomized at age three weeks, and the DOC-salt protocol was initiated two weeks later and continued for three weeks. In intact rats, hypertension developed more rapidly and to a higher level in males than in females. By contrast, in gonadectomized rats, there was no sex difference in blood pressure because the development of hypertension was attenuated in males and exacerbated in females. None of these differences could be attributed to differences in either saline consumption or vasopressin release since no differences were found among the groups for either variable. Although the underlying mechanisms are uncertain, our results clearly show that the gonadal hormones affect the development of DOC-salt hypertension in the rat.

Effect on Vasopressin Release of Microinjection of Angiotensin II into the Paraventricular Nucleus of Conscious Rats

We have studied in conscious unrestrained rats the role of angiotensin II receptors in the paraventricular nucleus (PVN) in the control of vasopressin secretion under basal conditions and after 24 h of water deprivation. In euhydrated rats, the microinjection rostral to the PVN of 1 and 5 ng of angiotensin II produced a transient, dose-dependent increase in the plasma vasopressin concentration. There was also a transient, but not dose-dependent, rise in mean arterial blood pressure (MABP), without a change in heart rate. However, the microinjection of angiotensin II into the PVN and sites caudal to it was without effect on the measured variables. In dehydrated rats, on the other hand, microinjection of 5 ng angiotensin II, both into the PVN and rostral to it, resulted in a prolonged increase in the plasma vasopressin concentration. The response from the rostral site was more rapid and was associated with an increased MABP. These findings suggest that angiotensin II receptors rostral to the PVN may participate in the control of vasopressin release in both euhydrated and dehydrated states, whereas angiotensin II receptors in the PVN are effective only following dehydration.

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 17β-estradiol on the baroreflex control of sympathetic activity in conscious ovariectomized rats

The effects of chronic treatment with 17β-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.