Dose-response studies of intracerebroventricular infusion of aldosterone in sensitized and non-sensitized rats

We have shown previously that the intracerebroventricular (icvt) infusion of 5 ng/h aldosterone (ALD) in the sensitized rat (one kidney removed, 1% NaCl plus 0.15% KCl solution to drink) produced hypertension similar in amplitude and time of onset to a 100-fold dose administered subcutaneously (s.c.), while a 5-ng/h subcutaneous infusion had no effect on blood pressure (BP). Dose-response studies on the icvt infusion of ALD were carried out in sensitized and non-sensitized (intact, with tap water to drink) male Sprague-Dawley rats (SDR). In both studies, a control group received the diluent, artificial cerebrospinal fluid (CSF), icvt. In sensitized rats, the pressures became significantly (P less than 0.05) elevated at day 7 in those receiving 15 ng/h icvt, day 11 in those receiving 5 ng/h icvt and 500 ng/h s.c. and day 18 in those receiving 1.5 ng/h icvt. The indirect systolic BPs at day 20 of infusion were 119 +/- 0.8 (s.e.) mmHg for controls, 182 +/- 5 for 15 ng/h icvt, 140 +/- 2 mmHg for 5 ng/h icvt, 131 +/- 1 mmHg for 1.5 ng/h icvt, 125 +/- 1 mmHg for 0.5 ng/h, and 159 +/- 5 mmHg for 500 ng/h s.c. Recovery (removal of pumps and return to water to drink) for 18 days resulted in the return of normal pressures in all groups except the 15 ng/h, icvt group in which pressures remained slightly, but significantly elevated at 127 +/- 3 mmHg. In non-sensitized rats, the pressures became significantly elevated in animals receiving 45 ng/h icvt and 1 microgram/h s.c. by day 14.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopamine inhibits the aldosterone response to upright posture

Aldosterone secretion in man is stimulated by potassium, ACTH, and angiotensin II and is inhibited by dopamine (DA). In normal sodium-replete supine individuals, aldosterone secretion is under maximum tonic inhibition by DA. Dopaminergic control of aldosterone secretion is modified by dietary sodium depletion. To determine the physiological significance of dopaminergic inhibition of aldosterone secretion, we studied the effect of DA on the aldosterone response to upright posture. Twelve normal men were studied while eating an ad libitum sodium diet, and the effect of DA was determined in the supine and upright positions. Plasma aldosterone (PAC), plasma cortisol (F), plasma aldosterone-stimulating factor (ASF), PRA, and blood pressure were measured while the men were supine and after 4 h of upright posture during an infusion of 5% dextrose vehicle and during a DA infusion of 4.0 micrograms/kg X min. The men also were studied as a time control in the supine position while receiving vehicle or DA. PAC increased from a mean basal value of 20.4 +/- 3.2 ng/dl (+/- SE) by 25.9 +/- 5.1 ng/dl to a peak of 44.4 +/- 2.4 ng/dl in response to upright posture during vehicle infusion. The PAC response to upright posture was reduced to 7.4 +/- 1.8 ng/dl (P less than 0.05) when DA was infused. The increase in PRA with upright posture was 3.7 +/- 1.3 ng/ml X h during the vehicle infusion and 4.1 +/- 1.1 ng/ml X h (P = NS) during the DA infusion. ASF, F, and blood pressure were not altered by upright posture and DA. PAC did not change in the six men infused with DA while supine. Therefore, DA inhibits upright aldosterone responses without affecting PRA, ASF, or F.     

Effects of the somatostatin analog BIM 23014 on the secretion of growth hormone, thyrotropin, and digestive peptides in normal men

BIM 23014 (BIM) is a long-acting octapeptide somatostatin analog. We studied the effects of this analog on the secretion of GH, TSH, and gastroenteropancreatic hormones [secretin, motilin, and pancreatic polypeptide (PP)] in normal men. In the first protocol three BIM doses (125, 250, and 500 micrograms) and vehicle were administered sc in random order at 2000 h to eight normal young men. Plasma GH concentrations decreased during the first part of the night only after the highest dose (P less than 0.05). Plasma secretin levels did not change, while plasma motilin decreased after the 250- and 500-micrograms doses (P = 0.05 and P = 0.02, respectively), and plasma PP decreased after all three doses (P less than 0.05, P less than 0.01, and P less than 0.01, respectively) during the first part of the night. In the second protocol, eight men received BIM, administered by constant sc infusion during the night in a dose of 2 mg/12 h, or vehicle, either alone or in association with a 10 ng/kg.min iv GHRH or vehicle infusion. Nocturnal GH secretion was suppressed by the BIM infusion (P less than 0.001). GH secretion, stimulated by GHRH infusion (P less than 0.001), was reduced by concomitant BIM infusion (P less than 0.001) and was pulsatile during the combined infusions. BIM infusion suppressed the physiological nighttime rise in plasma TSH levels. Plasma motilin and PP levels were reduced by BIM, when administered either alone or in combination with GHRH. We conclude that: 1) BIM is capable of reducing GH secretion when administered sc in a dose of 500 micrograms and of abolishing nocturnal GH secretion when constantly infused at a dose of 2 mg/12 h; 2) BIM, constantly infused, reduces the nocturnal rise in TSH secretion; and 3) motilin and PP secretion are more sensitive than that of GH to BIM, as they are reduced by a lower dose.     

Differential central effects of mineralocorticoid and glucocorticoid agonists and antagonists on blood pressure

Systolic blood pressure was measured, using an indirect tail method, in conscious male rats at several time intervals after the intracerebroventricular injection of mineralo-and glucocorticoid agonists and antagonists. Intracerebroventricular administration of the antimineralocorticoid RU 28318 (10 ng) decreased blood pressure, while the antiglucocorticoid RU 38486 (10 ng) caused an increase, which was slower in onset and of longer duration. The effect of the antimineralocorticoid was maximal at 8 h and had disappeared after 24 h. The antiglucocorticoid had a significant effect 24 and 48 h after injection. Neither antagonist was effective when administered sc at the same dose (10 ng). Intracerebroventricular administration of aldosterone (10 ng) and the selective glucocorticoid agonist RU 28362 (10 ng) increased and decreased blood pressure, respectively. Corticosterone given intracerebroventricularly (10-100 ng) did not affect blood pressure unless the dose was increased to 1 microgram. Two weeks after adrenalectomy a decrease in blood pressure was observed when the rats were given 0.9% saline instead of water to drink. Replacement therapy with corticosterone (12.5-mg steroid pellet, sc) restored blood pressure to the level in the sham-operated controls. The chronically elevated level of circulating corticosterone produced by a 100-mg sc corticosterone pellet increased blood pressure. The 12.5-and 100-mg sc corticosterone pellets resulted in plasma corticosterone levels of approximately 3 and 20 micrograms/100 ml, respectively. Intracerebroventricular administration of the glucocorticoid and mineralocorticoid antagonists (10 ng) increased and decreased, respectively, the blood pressure of the adrenalectomized rats receiving corticosterone substitution. From these data we conclude that corticosteroids can affect the central regulation of blood pressure. The mineralo- and glucocorticoids have opposite effects, which differ in onset and duration. The mineralocorticoids increased blood pressure, whereas the glucocorticoid decreased it.     

Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure

Systemic leptin increases energy expenditure through sympathetic mechanisms, decreases appetite, and increases arterial pressure. We tested the hypothesis that the pressor action of leptin is mediated by the central nervous system. The interaction of dietary salt with leptin was also studied. Leptin was infused for 2 to 4 weeks into the third cerebral ventricle of Sprague-Dawley rats. Arterial pressure was measured by radiotelemetry. To control for the effects of leptin on body weight, vehicle-treated rats were pair-fed to the leptin group. Intracerebroventricular infusion of leptin at 200 ng/h in salt-depleted rats caused a reduction in food intake, weight loss, tachycardia, and decreased arterial pressure. Leptin at 1000 ng/h caused further reduction in food intake, weight loss, and tachycardia and prevented the hypotensive effect of weight loss observed in pair-fed, vehicle-treated animals. Intracerebroventricular leptin at 1000 ng/h in high-salt-fed rats also caused a sustained pressor response (+3+/-1 mm Hg), but high-salt intake did not potentiate the pressor effect of leptin. Intracerebroventricular leptin potentiated the pressor effect of air-jet stress. Intravenous administration of the same dose of leptin (1000 ng/h) did not change weight or arterial pressure, suggesting a direct central nervous system action. In contrast, a high dose of intravenous leptin (18 000 ng/h) caused weight loss and prevented the depressor effect of weight loss. In conclusion, this study demonstrates that high-dose leptin increases arterial pressure and heart rate through central neural mechanisms but leptin does not enhance salt sensitivity of arterial pressure. Leptin appears to oppose the depressor effect of weight loss.     

Renal effects of the nitric oxide synthase inhibitor, L-NG-nitroarginine, in dogs.

L-NG-Nitroarginine (LNNA), an analog of L-arginine, was infused into the renal artery of anesthetized dogs to assess the contribution of nitric oxide production in the regulation of renal hemodynamics and urine formation. Following intrarenal arterial infusion of LNNA (15 micrograms/kg/min) for 25 min, renal blood flow (RBF) gradually decreased and there was no reversion even 60 min after cessation of infusion, with no change in mean arterial blood pressure (MBP) and heart rate. Urine flow (UF) decreased while the glomerular filtration rate (GFR) did not change. The highest dose of LNNA (75 micrograms/kg/min) remarkably decreased RBF and increased MBP. The renal vasocontriction and pressor responses induced by the highest dose of LNNA were significantly antagonized by an intravenous administration of L-arginine (100 mg/kg/min). LNNA is characterized as a potent and long-lasting renal vasoconstrictor and decreases GFR, UF, and sodium excretion. It is suggested that nitric oxide produced in the kidney may have a significant role in the regulation of basal renal circulation and exert diuresis and natriuresis.     

Aldosterone infusion into the rat and dose-dependent changes in blood pressure and arterial ionic transport

Induction of hypertension by implantation or injection of deoxycorticosterone acetate (DOCA) requires a dose well above the physiological range. The objective of this study was to produce hypertension in rats by chronic infusion of d-aldosterone, a more potent mineralocorticoid. Aldosterone infused at a dose of 1 microgram/hr for 4 weeks gave maximal rise in systolic blood pressure (132 +/- 3 vs 203 +/- 7 mm Hg). A significant rise in blood pressure was achieved at 0.1 microgram/hr (170 +/- 6 mm Hg) which was associated with a 2.3-fold rise in plasma aldosterone levels (7.6 +/- 0.4 vs 17.7 +/- 2.2 ng/dl). A series of isotope flux studies on the aorta and femoral artery from hypertensive animals demonstrated increases in 42K and 36Cl turnover. In both vessels the largest changes in ion turnover were observed in vessels from animals infused with aldosterone at 0.25 micrograms/hr. Increases in 42K and 36Cl turnover were detected as early as 1 week after the start of aldosterone infusion, well before a significant rise in blood pressure had occurred.     

Enhanced aldosterone response to angiotensin II in human hypertension.

Adrenal and vascular responsiveness to graded doses of angiotensin II (A II) were recorded for seven normal subjects and 12 patients with essential hypertension while in balance on an intake of 200 mEq sodium/100 mEq potassium. Patients with essential hypertension had been previously studied and known to have normal responses of plasma renin activity to sodium restriction and upright posture. A II was administered for 30 minutes at rates of 0.1, 0.3, 1, and 3 ng/kg per minute and plasma aldosterone responses were assessed 20 and 30 minutes later; blood pressure was monitored at intervals of 1 minute during infusion of A II at each rate. A significant increment in plasma aldosterone occurred at an infusion rate of 0.3 ng/kg per minute in patients with hypertension. This change was not seen until the infusion rate reached 1.0 ng/kg per minute in the normotensive control subjects. Even at an A II infusion rate of 1 ng/kg per minute, the increment in plasma aldosterone levels in normotensive subjects (4.2 +/- 0.6 ng/dl) was significantly less (P less than 0.001) than that in patients with essential hypertension (19 +/- 3 ng/dl). In both groups, a significant rise in mean arterial blood pressure occurred at an A II dose of 0.3 ng/kg per minute, but the pressor response of the hypertensive group was significantly greater at the highest infusion rate (3 ng/kg per minute) (P less than 0.05). Thus, enhanced adrenal and pressor responsiveness to infused A II was observed in the hypertensive subjects, suggesting a change in A II receptor affinity.     

Comparison of in vivo effects of insulin-like growth factors I and II and of growth hormone in hypophysectomized rats

Pure human IGF I (43 and 103 micrograms/day) and IGF II (131 micrograms/day) were infused into hypophysectomized rats during 6 days by means of sc implanted minipumps. Their effects on several growth indices were compared with those of various doses of sc infused human growth hormone. Growth hormone infusion produced a dose-dependent rise of endogenous rat IGF from 39 (without growth hormone) to 86 microU equivalents/ml (with 400 mU hGH/day) as determined by a competitive protein binding assay with a human IGF standard. In rats receiving the two doses of IGF I, total serum IGF levels rose to 83 and 99 microU equivalents/ml, respectively, in those receiving the IGF II dose the total serum IGF level rose to 146 microU equivalents/ml. These increases corresponded to steady state levels of 168 and 286 ng/ml of immunoreactive insulin-like growth factor (IR-IGF) I and 320 ng/ml of IR-IGF II. IGF I, but not IGF II led to an increase in body weight similar to that induced by the low doses of hGH (12.5 and 25 mU, respectively). The rise of endogenous rat IGF as well as the infused human IGF I and II caused a widening of the tibial epiphysis and an increase of the [3H]thymidine incorporation into costal cartilage. With respect to these two indices IGF II was clearly less potent that IGF I. When expressed in microU equivalents of the protein binding assay, endogenous rat IGF induced by hGH appeared to be relatively more effective than infused human IGF I or II.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolonged administration of human atrial natriuretic peptide in healthy men: evanescent effects on diuresis and natriuresis

Synthetic human atrial natriuretic peptide (hANP) was administered to six normal sodium- and fluid-replete men A) as an iv bolus dose of 25 micrograms followed by an infusion of 25 micrograms/h for 6 h; B) as an iv bolus dose of 175 micrograms; C) as an iv bolus dose of 175 micrograms followed by an infusion of 100 micrograms/h for 6 h; or D) as a continuous infusion of 100 micrograms/h for 6 h plus an iv bolus dose at 240 min. Although urinary flow rates and excretion rates of sodium and chloride increased during protocols B, C, and D, this effect either disappeared (protocol B) or waned (protocols C and D) at the end of the 6-h infusion period. A consistent decrease in blood pressure occurred only during protocols C and D. Serum concentrations of Na+, K+, and Cl- and plasma renin concentrations did not change, while plasma aldosterone concentrations declined after the administration of 175 micrograms hANP or more. These data confirm that hANP exerts a diuretic and natriuretic action in man. These effects are transient and are not maintained by prolonged continuous hANP administration.     

Acute and chronic dose-response relationships for angiotensin, aldosterone, and arterial pressure at varying levels of sodium intake.

We examined the acute and chronic dose-response relationships between intravenously infused angiotensin II (A II) and the resulting changes in arterial pressure and plasma aldosterone concentration at varying levels of sodium intake. Sequential analysis of plasma aldosterone at each A II infusion rate resulted in an acute dose-related increase in plasma aldosterone which was markedly attenuated after the first 24 hours of infusion, the final level being directly related to the dose of A II and inversely related to sodium intake. A II infused at 5,15, and 23 ng/kg per min was associated with an initial increase (2nd to 8th hour) in plasma aldosterone to 2,6, and 9 times control values, respectively, in dogs receiving 40 mEq Na+/day. But, after the 1st day, aldosterone averaged only 1, 1.7, and 3 times control values for the next 2 weeks at the same rates of A II infusion. Dogs receiving 120 mEq Na+/day during A II infusion exhibited only a transient increase in plasma aldosterone during the 1st day. Sustained hypertension developed over a period of a week at all doses of A II at normal and high sodium intake, but did not occur at any dose of A II in sodium-depleted dogs. Increasing sodium intake from 40 to 120 mEq/day resulted in higher levels of hypertension, 125% compared to 140% of ocntrol values for dogs infused with A II, 5.0 ng/kg per min. We conclude that primary angiotensin-induced hypertension need not be associated with increased levels of plasma aldosterone, which appears to remain elevated only with amounts of A II greater than those required to sustain a significant degree of hypertension.     

Therapeutic effects of tolvaptan, a potent, selective nonpeptide vasopressin V2 receptor antagonist, in rats with acute and chronic severe hyponatremia

The therapeutic efficacy of tolvaptan (OPC-41061), a potent, selective nonpeptide vasopressin V(2) receptor antagonist, on acute and chronic severe hyponatremia was assessed in rats. Experiments were designed to demonstrate the efficacy of tolvaptan reducing mortality in an acute model, and controlling the extent of serum sodium elevation without causing abnormal animal behavior suggesting neurological symptoms in a chronic model. In the acute model, rats developed rapidly progressive, severe hyponatremia by continuous sc infusion of [deamino-Cys(1), D-Arg(8)]-vasopressin (10 ng/h) and forced water-loading (additional 10% initial body weight per day). By d 6, untreated rats had a 47% mortality rate. However, rats treated with repeated oral administrations of tolvaptan (1, 3, and 10 mg/kg) produced dose-dependent aquaresis (i.e. urine volume increased and urine osmolality decreased) that resulted in a gradual increase in plasma sodium concentration. Consequently, tolvaptan treatment reduced mortality and, at higher doses, resulted in no observed deaths. In the gradual model, rats receiving a continuous sc infusion of [deamino-Cys(1), D-Arg(8)]-vasopressin (1 ng/h) combined with a liquid diet were induced to stable, severe hyponatremia (approximately 110 mEq/liter), which lead to increased organ weight and water content. Rats receiving dose titrations of tolvaptan (0.25, 0.5, 1, 2, 4, and 8 mg/kg) increased plasma sodium to healthy levels without causing abnormal animal behavior suggesting neurological symptoms or death, improved hyponatremia-driven increases in wet weight and water content in the organs. Thus, in animal models, analogous to the hyponatremia forms seen in humans, tolvaptan presents exciting therapeutic implications in the management of patients with severe hyponatremia.     

Endothelin-1 augments pressor response to angiotensin II infusion in rats.

To assess possible roles of endothelin in the regulation of blood pressure, we studied effects of a subpressor dose of endothelin-1 (3 micrograms/kg/day) on chronic blood pressure responses to infusion of angiotensin II and norepinephrine in rats. Rats were infused with angiotensin II at a subpressor dose (400 micrograms/kg/day i.p.) or with norepinephrine at a subpressor dose (360 micrograms/kg/day i.p.) for 6 days. Systolic blood pressure was significantly elevated during combined infusion of endothelin-1 and angiotensin II, whereas endothelin-1 alone or angiotensin II alone failed to induce any significant changes in systolic blood pressure compared with vehicle alone. This effect was sustained for the whole experimental period and was not associated with any significant changes in body weight, fluid intake, urine volume, or urinary electrolyte excretion. In contrast, combined infusion of endothelin-1 and norepinephrine failed to elevate systolic blood pressure, and no significant difference in systolic blood pressure was observed for the whole experimental period among the four groups of rats with endothelin-1 in combination with norepinephrine, endothelin-1 alone, norepinephrine alone, and vehicle alone. The present results indicate that angiotensin II and endothelin-1, but not norepinephrine and endothelin-1, work synergistically to raise the blood pressure and also suggest the possibility that endothelin-1 may modulate blood pressure control.     

Gonadotropins and testosterone escape from suppression during prolonged luteinizing hormone-releasing hormone antagonist administration in normal men

The ability of prolonged administration of a LHRH antagonist, [Ac-delta 3Pro1,4F-D-Phe2,D-Trp3,6]LHRH (4F-antagonist), to suppress serum gonadotropin and testosterone levels was studied in normal men. The 4F-antagonist was given either as a continuous 13.3 micrograms/kg X h sc infusion for 72 h or as intermittent sc injections of 100 micrograms/kg every 6 h for 7 days. Serum FSH, LH, and testosterone levels decreased in the period immediately following initiation of 4F-antagonist administration. However, an escape toward baseline levels for each of these hormones occurred during prolonged antagonist administration. When men receiving the continuous infusion were challenged with iv bolus doses of 50 micrograms LHRH, the response of LH after the first 12 h of 4F-antagonist administration was similar to that before its administration. This gonadotropin and testosterone escape suggests that, at the doses used, the inhibitory action of the antagonist on gonadotropin secretion is progressively lost. The initial decrease in androgen levels could serve to augment endogenous LHRH release, which, in turn, overcomes the pituitary effects of the antagonist, or to augment endogenous LH secretion directly. These results demonstrate that the pituitary can escape from the suppressive effects of prolonged LHRH antagonist administration and partially restore serum gonadotropin and testosterone levels to normal in man.     

Prolonged administration of human atrial natriuretic peptide in healthy men. Reduced aldosteronotropic effect of angiotensin II

The effect of angiotensin II (5, 10, 20 ng/kg/min) on blood pressure and on the plasma concentrations of aldosterone was studied in six healthy men with and without the concomitant administration of synthetic human atrial natriuretic peptide given 1) as an i.v. bolus of 25 micrograms followed by a 6-hour infusion of 25 micrograms/hr or 2) as an i.v. bolus of 175 micrograms followed by a 6-hour infusion of 100 micrograms/hr. The pressor effect of angiotensin II (i.e., the rise of mean blood pressure above individual basal levels) remained unchanged during the administration of both doses of human atrial natriuretic peptide. The angiotensin II-induced rise in plasma concentrations of aldosterone in terms of absolute values) was reduced by human atrial natriuretic peptide during both trials. The rise in plasma concentrations of aldosterone above individual basal concentrations was also reduced during the administration of human atrial natriuretic peptide, although this effect was only marginal during the low dose experiment. These effects of human atrial natriuretic peptide support the contention that its therapeutic impact in hypertensive patients might be mediated in part by a reduction of high aldosterone concentrations.     

Dopaminergic modulation of aldosterone responsiveness to angiotensin II with changes in sodium intake

The aldosterone response to infused angiotensin II (AII) is blunted by sodium (Na) loading. Since dopamine levels increase on a high Na diet and dopamine can inhibit aldosterone secretion, it is possible that dopamine mediates the blunted aldosterone secretion in this setting. To test this hypothesis, we assessed whether the dopamine antagonist, metoclopramide (MCP) would enhance the aldosterone response to infused AII. Six normal subjects received graded infusions of AII when they were in metabolic balance on diets containing both 10 and 200 meq Na/day (control infusions). The infusions were then repeated (on the same diets) during the administration of MCP (0.1 mg/kg iv bolus, then 0.05 mg/kg . h). During the control AII infusions, the aldosterone response to the highest dose of AII was significantly less on the 200 meq Na intake than on 10 meq (plasma aldosterone levels increased 17 +/- 5 vs. 30 +/- 8 ng/dl respectively; P less than 0.01). However, MCP administration eliminated this difference in aldosterone responsiveness by significantly enhancing (P less than 0.02) the response to infused AII during the 200 meq Na intake (plasma aldosterone increment of 25 +/- 9 ng/dl). This effect of MCP was limited to the adrenal response to AII: on a given Na intake, the mean blood pressure response to AII was similar both with and without concomitant MCP. These results suggest that dopamine may be an important regulator of the alterations in aldosterone responsiveness to AII that occur during changes in dietary sodium intake.     

Hormone ontogeny in the ovine fetus: XXI. The effect of insulin-like growth factor-I on plasma fetal growth hormone, insulin and glucose concentrations

We infused intravenously recombinant human Insulin-like Growth Factor-I (IGF-I; 1 microgram/kg/min for 120 minutes after an acute dose of 25 micrograms/kg) into chronically catheterized ovine fetuses (124-132 days gestation) to study its effect on the secretion of fetal ovine Growth Hormone (oGH). In all IGF-I infused fetuses, oGH concentrations fell during the infusion. The maximal change in the concentration of oGH (mean +/- SEM) was -54 +/- 10 ng/ml in contrast to +7 +/- 6 ng/ml in saline controls (p less than 0.005), a decrease of 33 +/- 4% (controls: +6 +/- 5%; p less than 0.005). By 60 minutes after the infusion of IGF-I was completed, the concentration of plasma oGH was comparable to control and pre-infusion values. In IGF-I infused fetuses, the mean concentration of insulin also decreased (p less than 0.02), whereas glucose levels remained unaltered. The results suggest that the lack of inhibitory feedback by the relatively low levels of circulating IGF-I is one factor in the hypersecretion of GH by the fetus.     

Attenuation of the development of spontaneous hypertension in rats by chronic central administration of captopril

Captopril infused into the lateral ventricle (ICV) of adult spontaneously hypertensive rats (SHR) decreases blood pressure. The current study was designed to explore the effects of brain converting-enzyme inhibition in young animals before the development of established hypertension and to characterize changes induced by captopril in a variety of pressor systems that might be responsible for the development of hypertension in this strain. Captopril (1.25 micrograms/0.5 microliter/hr) was infused into male SHR starting at 7 weeks of age. Four weeks later systolic blood pressure was only 157 +/- 3.3 compared to 181 +/- 3.9 mm Hg in vehicle-infused controls, and the pressor effect of ICV-injected angiotensin I was attenuated by 50%. When the same dose of captopril was infused intravenously, hypertension progressed as in vehicle-treated rats. Serum angiotensin-converting enzyme activity (SACE) and plasma arginine vasopressin (AVP) concentration were significantly higher (p less than 0.001 and 0.05, respectively), in the ICV captopril group than in the ICV vehicle group, while plasma aldosterone concentration and renin activity, fluid intake, urine volume, and urinary sodium excretion were similar in the two groups. Peripheral sympathetic nervous system activity assessed in the resting state was not altered by captopril treatment. In addition, AVP content of the telencephalon, diencephalon, mesencephalon, and pons medulla were not altered by ICV captopril. Renin activity was elevated in the telencephalon of ICV captopril-treated animals but unaltered in the other brain regions examined. These data demonstrate that ICV administration of captopril attenuates the development of hypertension in young SHR by mechanisms apparently independent of altered fluid and sodium balance and the sympathoadrenal system. The effect on blood pressure occurs in the absence of changes in renin activity or AVP content of plasma or those brain regions most often associated with blood pressure control.     

INHIBITION OF THE EFFECTS OF ANGIOTENSIN II ON ADRENAL STEROID PRODUCTION BY DIETARY SODIUM

The pressor octapeptide, angiotensin II, can stimulate the production of aldosterone by the adrenal cortex. The present results show that in the dog a high-sodium diet can eliminate the steroidogenic action of angiotensin II, which is thus dissociated from the pressor action which remains.Angiotensin II was infused intravenously for 48 hours into conscious, undisturbed hypophysectomized dogs that were receiving each day either 60 or 200 mEq of dietary sodium. Blood pressure and secretion of aldosterone, corticosterone, and cortisol were measured (1) throughout the infusion in some dogs, and (2) at the end of the infusion in all dogs. In those dogs receiving 60 mEq of sodium, angiotensin II elevated the blood pressure and produced sustained increases of secretion of aldosterone, corticosterone, and cortisol. In those dogs receiving 200 mEq of sodium, angiotensin II, while retaining its pressor activity, had no effect on the production of aldosterone, corticosterone, or cortisol after 24 hours. Thus, if angiotensin II can produce hypertension clinically, there need not be secondary aldosteronism as well.     

Effects of incremental infusions of atrial natriuretic factor on aldosterone, renin, and blood pressure in humans

To evaluate the physiological effects of human atrial natriuretic factor-(99-126) (ANF), we infused ANF, 0.1, 0.3, and 1.0 micrograms/min, or placebo for 125 minutes on different days into six sodium-deprived normal men. During the last 45 minutes of infusion, angiotensin II, 6 ng/kg/min, was infused. Blood pressure, heart rate, plasma concentrations of ANF, aldosterone, and cortisol, and plasma renin activity (PRA) were measured before and during infusion. Steady state mean plasma ANF levels during infusion were 26.2 (placebo), 68.8 (0.1 micrograms ANF/min), 221 (0.3 micrograms ANF/min), and 648 pg/ml (1.0 microgram ANF/min). Systolic blood pressure fell significantly (with 1.0 microgram ANF/min), and diastolic pressure tended to rise in a dose-dependent manner, while heart rate was unchanged. PRA and plasma aldosterone fell during ANF infusion in a dose-dependent manner (significant with 0.3 and 1.0 microgram ANF/min infused). The blood pressure-raising and aldosterone-stimulating effects of angiotensin II were blunted by ANF (significant only with 1.0 microgram ANF/min). It is concluded that effects of ANF on blood pressure and the renin-aldosterone system occur with plasma ANF levels close to the physiological range, as well as with slightly elevated ANF levels, as observed in congestive heart failure and renal insufficiency.