Effect of somatostatin on plasma renin activity and blood pressure in patients with essential hypertension

The effects of somatostatin on plasma renin activity (PRA) and blood pressure were evaluated in patients with essential hypertension (EH) and in normotensive subjects. All subjects examined were hospitalized and placed on a diet containing 7-8 g/day sodium chloride and received an intravenous infusion of somatostatin (500 microgram/20 ml of saline, for 60 min) in the basal condition. During somatostatin infusion, the mean blood pressure (MBP) remained unaffected in all patients with EH and the normotensive subjects, while the PRA decreased slightly in the EH group. When the patients with EH were classified according to their renin levels (low, normal and high), parallel significant decreases in MBP and PRA were found only in the high renin group during the somatostatin infusion. No significant change in MBP and PRA was observed in the other groups including the normotensive subjects. To assess the activity of synthetic somatostatin, the plasma levels of growth hormone (GH) and cyclic AMP were measured. These levels were lowered significantly during the infusion and the GH levels showed a rebound 15 min after cessation of the infusion. The cyclic AMP returned to the basal levels, but no rebound was observed. The above data indicate that the fall in blood pressure in the high renin group in the basal condition was probably due in part to reduced renin release by somatostatin, and the maintenance of high blood pressure especially in high renin EH.     

Effect of 1-desamino-8-D-arginine vasopressin (DDAVP) on vasopressin release and blood pressure during hemorrhage.

Whether or not 1-desamino-8-D-arginine-vasopressin (DDAVP) reduces blood pressure or affects the release of arginine vasopressin (AVP) and renin is controversial, although evidence suggests AVP and renin are important in maintaining blood pressure during hemorrhage. We therefore investigated the effect of DDAVP on endogenous release of AVP and renin and on blood pressure during hemorrhage in dogs. In the control group the hemorrhage was performed at a rate of 0.4 ml.kg-1.min-1 for 40 min from the femoral artery. The plasma AVP concentration and renin activity (PRA) increased progressively in response to the hemorrhage, from 7.5 +/- 0.5 to 40.3 +/- 7.3 pg.ml-1, and from 11.8 +/- 1.5 to 20.5 +/- 4.2 ng.ml-1.h-1, respectively, while blood pressure decreased slightly. In the DDAVP group, intravenous infusion of DDAVP (2.5 ng.kg-1.min-1 for 40 min) and hemorrhage were simultaneously performed. The plasma DDAVP concentration increased progressively to 218 +/- 21.0 pg.ml-1. There was no significant difference, however, between the control and DDAVP groups in the response of AVP, PRA and blood pressure. The results suggested that DDAVP may not affect the release of AVP and renin or blood pressure during hemorrhage.     

Effects of brain renin-angiotensin on cardiovascular function and saline intake in awake dogs

Initial studies were undertaken to investigate the effects of prolonged administration of angiotensin II (AII), 1 micrograms twice daily, via the lateral ventricles to mongrel dogs on arterial blood pressure and to determine if sodium intake was essential for the development of hypertension. Increasing AII levels in the cerebrospinal fluid for a prolonged period of time produced a sustained hypertensive state only in those dogs in which the daily intake of sodium was increased. The hypertension appeared to be due to an increase in total peripheral resistance. Central administration of AII increased both fluid intake and urine output. In order to assess the hemodynamic effects of increasing endogenous brain AII, renin was injected in doses of 0.025, 0.05, 0.1 and 0.3 units (from porcine kidney) into the lateral ventricles of chronically instrumented awake dogs. Hemodynamic variables were recorded prior to and one and 2 h after the central administration of renin. Renin produced a dose-dependent increase in mean arterial pressure with no significant change in heart rate or carotid, coronary and renal blood flow velocities. Chronic intraventricular administration of renin, 0.15 units twice daily to awake instrumented dogs receiving saline as the drinking fluid, markedly increased the daily intake of saline and increased diastolic and systolic blood pressure without increasing heart rate or carotid, coronary or renal blood flow velocities. There appears to be a direct significant relationship between the increase in mean blood pressure due to the intraventricular administration of renin and the volume of saline consumed.     

Participation of substance P in the control of renin release.

The effect of the hypothalamic undecapeptide substance P on renin secretion rate was studied in the denervated dog kidney. Intrarenal infusion of substance P at a rate of 0.2 ng/kg/min suppressed renin secretion rates from 258.5 ± 28.5 ng/min to 133.1 ± 23.2 ng/min (p<0.001). Substance P infused at this dose neither changed blood pressure nor did it affect renal cortical plasma flow, glomerular filtration rate or sodium excretion. Thus, the suppression of renin release by substance P cannot be explained by any of the known control mechanisms. It is proposed that substance P participates in the control of renin release by a direct effect on the juxtaglomerular cells.     

Renin release in anesthetized rats is enhanced by the calmodulin antagonist W-7

In foregoing work, we found that the release of renin from rat kidney cortical slices was stimulated by the calmodulin antagonist W-7. The present work was done to determine whether W-7 would stimulate renin release in vivo. W-7 and its control agent, W-5 were directly infused into the renal artery of anesthetized rats. W-7 and W-5, at 50 micrograms/kg/min, produced no significant effects on renin release. Infusion of W-7 at 100 micrograms/kg/min resulted in a marked stimulation of renin release, but there was no significant alteration in the release when the same dose of W-5 was infused. Both compounds elicited a slight decrease in renal blood flow. The alterations in renin release and renal blood flow seen with W-7 were not affected by pretreatment with phentolamine or propranolol. As W-7 stimulates renin release in vivo, the hypothesis that Ca2+-calmodulin plays an inhibitory role in renin release from the kidney is given added support.     

Beta-adrenoreceptor blockade in the conscious rabbit: effects on plasma renin activity and blood pressure.

The administration of a single dose of dl-propranolol, 1 mg/kg i.v., in the conscious unstimulated rabbit produced effective beta-adrenoreceptor blockade (inhibition of isoprenaline tachycardia) for 150 min. During this period there was a positive correlation between plasma concentrations of propranolol and the degree of beta-blockade observed. In a further group of animals treated with propranolol, plasma renin activity (PRA) fell to 50% of control (P < 0.001) within 60 min, the rate of change of PRA also correlating with plasma propranolol levels. Similarly, there were reductions in mean blood pressure (P < 0.025) and heart rate (P < 0.025). Statistical relationships between the fall in blood pressure and either pre-treatment PRA or the change in PRA were consistent with the hypothesis that the hypotensive effect of propranolol was dependent upon its suppression of renin release. However, an alternative possibility that the fall in blood pressure was due to an acute reduction in cardiac output could not be excluded.     

Effect of somatostatin on plasma renin activity.

Intravenous infusion of somatostatin in mongrel dogs caused a significant decrease in the peripheral plasma renin activity (PRA) enhanced by pentobarbital sodium anesthesia or furosemide treatment. However, the inhibitory activity vanished within 10 min after termination of somatostatin infusion. Intrarenal arterial infusion of somatostatin decreased furosemide-enhanced PRA in renal vein by 24.0%, 16.6% and 8.6% in dose of 0.1, 0.5 and 1.0 microgram, respectively. On the other hand, high doses of the peptide (50-200 microgram) failed to decrease. The changes in PRA occurred in the absence of any alteration in blood pressure during the intravenous infusion under furosemide treatment. In an in vitro study, the addition of somatostatin in doses of 0.01 and 0.05 microgram suppressed the renin release in dog renal cortical cell suspension by 74.3% and 53.6%, respectively. Therefore, in both intrarenal arterial infusion and the cell suspension system, somatostatin was increasingly effective in decreasing renin release towards the lower end of the dose range tested. These results suggest that the effect of somatostatin on hyperreninemia may involve an inhibition of renin release at the cell level in the kidney.     

Cyclosporine A inhibits prostaglandin E2 release, and has no effect on renin secretion, from rat renal cortical slices

These experiments were designed to test the hypothesis that cyclosporine A (CSA) inhibits renin secretion and stimulates renal prostaglandin E2 (PGE2) release in vitro. In rat renal cortical slices incubated at 37 degrees C in a buffered and oxygenated physiological saline solution containing 4 mM KCl, CSA concentrations ranging from 1 to 30 microM had no significant effect on renin secretion. Furthermore, partial depolarization of the cells, produced by increasing extracellular KCl concentration to 20 mM, failed to reveal any latent inhibitory or stimulatory effects of CSA on renin secretion. On the other hand, PGE2 release was significantly inhibited by CSA over the same range of concentrations. This inhibitory effect might be explained by the previous findings of others, that CSA inhibits phospholipase A2 activity, thereby decreasing arachidonic acid production, the rate-limiting step in PG synthesis. In conclusion, CSA inhibits PGE2 release but fails to affect renin secretion in vitro. These results suggest that the occasional effects of CSA on renin secretion in intact animals must be attributable to indirect and/or chronic effects.     

Sodium outflow rate through lymphocyte cell membranes, serum levels of sodium, potassium, aldosterone, total catecholamines, 6-keto- PGF2alpha and plasma renin activity in patients with primary arterial hypertension treated with captopril]

Sodium ions outflow rate through lymphocyte membranes, serum sodium, potassium, aldosterone, total catecholamines and 6-keto-PGE alpha levels, and plasma renin activity were studied in patients with mild hypertension associated with low and hugh plasma renin activity treated with captopril in a single dose of 12.3 mg and after the treatment with daily doses of 12.5 mg and 25 mg for 3 days. It was found, that captopril in hypertensive patients with high plasma renin activity decreases both systolic and diastolic blood pressure, decelerates heart rate, and decreases serum total catecholamines and plasma renin activity. Sodium ions outflow rate and serum sodium, potassium, aldosterone, and 6-keto-PGE alpha remain unchanged. Captopril in hypertensive patients with low plasma renin activity. The remaining parameters are unchanged. Moreover, it was noted that serum 6-keto-PGE alpha levels are lower in hypertensive patients with low plasma renin activity.     

Role of beta-1 and beta-2 adrenoceptors in isoproterenol-induced renin release in conscious dogs.

The present experiments were designed to classify the ß-adrenoceptors pertaining to the renin release induced by isoproterenol in conscious dog. Atenolol (ß-1 adrenoceptor antagonist), in oral dose of 6 mg/kg, produced a significant inhibition of renin release caused by isoproterenol. This dose of atenolol suppressed effectively the tachycardia of isoproterenol. On the other hand, the renin release produced by isoproterenol was not modified significantly by a ß-2 adrenoceptor antagonist, IPS-339, at a oral dose of 3 mg/kg which fully antagonized hypotensive response to isoproterenol. These results strongly suggest that the renin release induced by isoproterenol is largely due to stimulation of ß-1 type adrenoceptors.     

The effect of naloxone on blood pressure, heart rate, plasma catecholamines, renin activity and aldosterone following exercise in healthy males

There is evidence that endogenous opioids are involved in blood pressure regulation. In the present study the effect of naloxone on the cardiovascular, sympathoadrenomedullary and renin-aldosterone response to physical exercise was investigated in 8 healthy males. Each subject performed a submaximal work test twice, i.e. with and without naloxone. The test consisted of ergometer bicycling for 10 minutes on 50% of the maximal working capacity (MWC), immediately followed by 10 min on 80% of MWC. Ten minutes before exercise the subjects received in a single blind randomized order a bolus dose of naloxone (100 micrograms/kg) or a corresponding volume of the preservatives of the naloxone preparation (control) followed by a slow infusion of naloxone (50 micrograms/kg/h) or preservatives, respectively. Naloxone was without effect on the exercise-induced changes in systolic blood pressure, heart rate, plasma noradrenaline, renin activity and aldosterone, but the adrenaline response increased markedly. The present results indicate that opioid receptors are involved in the plasma adrenaline response to submaximal exercise, but not in the regulation of systolic blood pressure, heart rate, plasma noradrenaline, renin activity and plasma aldosterone.     

Contribution of atenolol,bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.     

Effect of a potassium-deficient diet on arterial blood pressure, plasma and tissue cations, and tissue norepinephrine in the hypertensive dog

Chronic potassium deficiency in one-kidney one-clip hypertensive dogs significantly reduces blood pressure and plasma potassium, with a simultaneous increase in plasma renin activity. Tissue potassium concentration was decreased and tissue sodium concentration was increased in striated muscle and adrenal glands, which may suggest that the sodium-potassium pump was inhibited. In myocardium the sodium concentration was higher but the potassium concentration was not significantly lower than in control hypertensive dogs on normal diets. Arterial cation concentrations in the potassium-deficient group were not significantly different from those in the control group. Tissue norepinephrine concentration was higher in arteries from potassium-deficient animals, significantly so in the mesenteric and femoral arteries. The conclusion is that potassium deficiency may decrease blood pressure in the one-kidney one-clip hypertensive dogs by impairing the release of norepinephrine.     

High salt intake attenuates the development of hypertension in two-kidney, one-clip Goldblatt rats.

Effects of high salt intake on the early onset of hypertension were examined in two-kidney, one-clip rats. They were divided into high salt and control groups which were supplied with 1.0% NaCl and tap water, respectively, as a drinking solution for 12 days after clipping the left renal artery. The high salt group showed a lower plasma renin concentration and a higher plasma atrial natriuretic peptide (ANP) along with an attenuation of the magnitude of early hypertension, as compared with the control group. A significant positive correlation between blood pressure and plasma renin concentration and an inverse correlation between plasma renin concentration and ANP were shown. Cortical renal renin content was comparable between the two groups. In another two groups of sham-clipped rats, the high salt group did not differ from the tap water-drinking group in any of the parameters examined, except that ANP was significantly higher. These results demonstrate that high salt intake attenuates the developmental phase of hypertension in two-kidney, one-clip rats by increasing the ANP and suppressing the release of renin.     

Hypertension, hypokalemia and hypoaldosteronism with suppressed renin: a clinical study of a patient with Liddle's syndrome

A 24-yr-old woman with hypertension, hypokalemic alkalosis, low plasma renin and hypoaldosteronism was studied. Plasma aldosterone, renin and potassium returned to normal and blood pressure fell after sodium restriction or the administration of triamterene. Thiazide therapy also normalized her blood pressure while dexamethasone, spironolactone and furosemide did not improve her symptoms. Plasma aldosterone levels were low and responded poorly to a short term ACTH injection, but responded well to the maximal adrenal stimulation by ACTH-Z. Plasma levels of cortisol, corticosterone and deoxycorticosterone were within the normal range. Adrenal scintigram with 131I-adosterol and abdominal computed axial tomography did not reveal the presence of a sizeable adrenal tumor. In addition, the urinary kallikrein excretion was low after sodium restriction and showed no response to saline infusion. These findings suggest that the excessive secretion of unusual mineralocorticoids may not exist in this case. From these observations and the results of the therapeutic responses to the diuretic agents, we conclude that the primary cause of the disorder of this patient seems to be a renal defect in the distal tubule in handling sodium and potassium which is similar to that in Liddle's syndrome.     

Renin-angiotensin system, blood pressure homeostasis and renal function in galactosamine-induced fulminant hepatic failure in the guinea pig

Arterial blood pressure, renal function and plasma concentrations of renin and renin substrate (angiotensinogen) were investigated in guinea pigs subjected to galactosamine-induced (1 g/kg i.v.) liver cell necrosis. Blood pressure declined continuously by 50% during a follow-up period of 72 h which was associated with a decrease in diuresis and natriuresis to 36 and 31%, respectively. Simultaneously, plasma renin concentration increased 30-fold indicating marked reduction of renal perfusion, while plasma renin substrate concentration fell to 6% of the baseline level. There was microscopic evidence of oligemic circulatory renal damage characterized by acute proximal tubular necrosis with concomitant tubular dilatation. Short-term infusion of homologous renin substrate-enriched plasma, derived from nephrectomized animals, was followed by marked increase in mean arterial blood pressure from 34 +/- 9 to 77 +/- 7 mm Hg accompanied by marked diuresis and natriuresis. Renin substrate depletion following galactosamine-induced fulminant liver failure may represent impaired hepatic biosynthesis as well as increased renin substrate consumption due to excessive renin secretion. Angiotensinogen repletion has a beneficial effect on both renal function and blood pressure probably due to marked generation of the potent vasoconstrictor angiotensin II which consequently inhibits renin secretion. These observations strongly support the suggestion that the renin-angiotensin system is of major importance to cardiovascular homeostasis in acute liver failure.     

The relationship between sodium excretion and renin secretion by the perfused kidney.

The effect of altered tubular sodium reabsorption on renin secretion (RSR) was examined under conditions in which other factors influencing renin release could be controlled or excluded. To do this, isolated canine kidneys were perfused at constant pressure with blood circulating from donor animals. Volume expansion or hemorrhage of the donor dogs produced large changes in the animal's blood pressure, renal function, sodium excretion (UNaV), and RSR, but were without effect on renal hemodynamics, UNaV, or RSR in the perfused kidney. Hemodilution without volume expansion, resulted in hypotension, decreased UNaV and increased RSR in the donor dogs, and increased UNaV and suppressed RSR in the perfused kidney. These effects of hemodilution in the perfused kidney were partially reversed when plasma protein concentration was restored to control levels with hyperoncotic albumin, and, overall, there was a significant inverse relationship between electrolyte excretion and RSR. These results provide new evidence for the hypothesis that the rate at which sodium is delivered to the macula densa is an important determinant of the rate of renin secretion.     

Beta-adrenoceptors and the regulation of blood pressure and plasma renin during exercise

The relative role of beta 1- and beta 2-adrenoceptors in the regulation of blood pressure and plasma renin at rest and during exercise was studied in 17 normal male volunteers. They performed, in a randomized order and according to a double-blind crossover study design, three graded and uninterrupted exercise tests until exhaustion after being pretreated during 3 consecutive days with a placebo, with a predominantly beta 1-blocker (atenolol, 50 mg once/day), or with a predominantly beta 2-blocker (ICI 118551, 20 mg 3 times/day). Both drugs caused a decrease of heart rate, but the reduction by ICI 118551 was less pronounced at rest and no additional decline occurred at exercise. ICI 118551 did not affect blood pressure at rest, but during exercise diastolic blood pressure was higher than after a placebo. Atenolol lowered systolic blood pressure at rest and suppressed the exercise-induced increase in systolic blood pressure. At rest and during exercise plasma renin activity was lowered by predominantly beta 1-blockade and unchanged during beta 2-antagonism. The exercise-induced increase in plasma renin was, however, not affected by the beta 1-blocker. After atenolol the urinary excretion of aldosterone was decreased but the plasma aldosterone concentration was not changed. ICI 118551 did not alter plasma or urinary aldosterone. Our results therefore provide further evidence that the adrenoceptors mediating the release of renin at rest and during exercise in humans are partially of the beta 1-subtype, whereas beta 2-adrenergic receptors probably play only a minor role in the control of renin secretion, especially at exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of volume and prostaglandin synthesis in the suppression of renin by saline in the rat

To evaluate the contribution of plasma volume expansion per se on acute inhibition of renin release by sodium chloride infusion, renin responses to comparable plasma volume expansion with intravenous infusions of sodium chloride, sodium bicarbonate, or albumin were studied in separate groups of sodium chloride-depleted rats. In addition, urinary prostaglandin E2 (PGE2) excretion rate was compared in the saline- and sodium bicarbonate-infused animals to evaluate the relationship between acute changes in renin release and intrarenal PGE2 synthesis. All three groups were plasma volume-expanded by approximately 55%. Plasma renin activity (PRA) decreased in response to saline (12.3 +/- 1.0 to 6.7 +/- 0.7 ng AI/ml/hr; P less than 0.01) whereas PRA did not change with sodium bicarbonate (11.3 +/- 1.4 to 10.2 +/- 1.5) or albumin (9.9 +/- 0.7 to 8.2 +/- 1.0). The rate of PGE2 excretion was not changed by either saline (72.2 +/- 13.1 to 72.3 +/- 18.7 pg/min) or sodium bicarbonate infusion (70.7 +/- 8.8 to 64.9 +/- 7.0). These results support the hypothesis that acute suppression of PRA by infusion of saline is not dependent upon volume expansion per se. In confirmation of earlier observations, inhibition of renin release by sodium chloride was related to chloride. Finally, the results suggest that the renal tubular mechanism for inhibition of renin release by sodium chloride is not related to overall changes in renal PGE2 synthesis in the rat.     

Effect of insulin pump therapy on blood pressure and the renin-angiotensin system of diabetic rats

Insulin therapy, administered by continuous subcutaneous infusion with osmotic pumps over a 28 day period at doses of 2.5 and 5.0 units/day, resulted in a statistically significant increase in body weight of diabetic rats. The concentration of blood glucose was reduced by 68% to 109 mg/dl blood sugar by the higher dose of insulin and only partial control of diabetes was achieved by the lower dose (185 mg/dl blood sugar, -39%). Blood pressure was normalized by both doses of insulin. Elevated serum angiotensin converting enzyme activity and plasma renin activity, expressed as generated angiotensin I, were unaffected by the lower dose of insulin, but were reduced by 26% and 40%, respectively at the higher dose. These data suggest that elevated serum ACE and plasma renin activity, commonly found in the streptozotocin-diabetic rat, may not be primarily responsible for hypertension in this model.