Mediating Renin Release Research Articles

Analysis of beta-adrenoceptors mediating renin release produced by isoproterenol in conscious dogs.

Types of beta-adrenoceptors mediating renin release induced by isoproterenol were investigated in conscious dogs. The nonselective beta-adrenoceptor blocking drugs propranolol, D-32, and pindolol significantly inhibited increases in heart rate and plasma renin activity and a fall of blood pressure produced by intravenous infusion of isoproterenol (10 microgram . kg-1 . 20 min-1). d-Propranolol and d-D-32 did not inhibit these three responses to isoproterenol. The selective beta 1-adrenoceptor blocking drug atenolol, at the oral dose of 6 mg/kg, which selectively suppressed isoproterenol-induced tachycardia, significantly inhibited the renin release caused by isoproterenol. By contrast, the renin release induced by isoproterenol was not modified by the selective beta 2-adrenoceptor blocking drug IPS-339 at an oral dose of 3 mg/kg, which fully and selectively antagonized the fall of blood pressure in response to isoproterenol. There was good correlation between suppression of isoproterenol-induced renin release and that of isoproterenol-induced tachycardia after various beta-adrenoceptor blocking drugs. These results lead to the conclusion that in conscious dogs the beta-adrenoceptors mediating release are mainly of the beta 1 type.

Role of renal prostaglandins in sympathetically mediated renin relase in the rat.

Renal prostaglandins (PG) appear to mediate renin release due to stimulation of the intrarenal baroreceptor, but not that due to activation of the macula densa. However, as the role of PG in sympathetically mediated renin release remains unclear, a possible interrelationship between these factors was examined in conscious rats. Hydralazine increased the serum renin levels from 3.1+/-0.8 to 16.7+/-3.0 ng/ml per h at a dose of 1 mg/kg. Indomethacin (5 mg/kg) suppressed urinary PGE(2) and PGF(2alpha) excretion by 89 and 74%, respectively, arachidonate hypotension by 82%, and inhibited the elevated renin levels from hydralazine by 100% without altering the hypotensive effect of the drug. Another PG synthetase inhibitor, meclofenamate, was also effective in attenuating hydralazine-induced renin release, urinary PGE(2) and PGF(2alpha) excretion, and arachidonate hypotension. Isoproterenol, a nonselective beta-adrenergic agonist, increased heart rate, lowered blood pressure, and also stimulated the release of renin when administered intraperitoneally. However, intrarenal infusion of the drug only resulted in increased renin release. Indomethacin inhibited isoproterenol-induced renin release by 66 and 67%, respectively, without altering the hemodynamic effects associated with the intraperitoneal administration of the drug. The selective beta(1) agonist, H133/22, increased the release of renin and heart rate in a dose-related manner without altering blood pressure. H133/22-induced renin release was inhibited by 80% by indomethacin pretreatment. Finally, intrarenal infusions of dibutyryl cyclic AMP (3 mg/kg per min) increased the serum activity from 4.1+/-0.2 to 20.4+/-3.9 ng/ml per h without altering mean arterial pressure. Indomethacin inhibited this renin response to dibutyryl cyclic AMP by 96%. Thus, renal PG appear to be important mediators of sympathetically stimulated renin release acting as a site distal to the beta-adrenergic receptor.

Blockade of isoprenaline-induced changes in plasma free fatty acids, immunoreactive insulin levels and plasma renin activity in healthy human subjects, by propranolol, pindolol, practolol, atenolol, metoprolol and acebutolol.

Abstract 1 The effects of intravenously administered propranolol 0.01 and 0.03, pindolol 0.001 and 0.003, practolol 0.12 and 0.36, atenolol 0.03 and 0.09, metoprolol 0.045 and 0.135 and acebutolol 0.12 and 0.36 mg/kg, on isoprenaline-induced changes in heart rate, blood pressure, plasma free fatty acids, immunoreactive insulin plasma levels and plasma renin activity were determined in six healthy human subjects. 2 Propranolol, atenolol and metoprolol had a stronger effect on resting heart rate than practolol, acebutolol and pindolol, probably reflecting differences in intrinsic β-sympathomimetic activity. Antagonist potencies against isoprenaline-induced changes in heart rate and blood pressure suggested cardioselectivity for practolol, atenolol, metoprolol and the lower dose of acebutolol and non-cardioselectivity for propranolol, pindolol and the higher dose of acebutolol. 3 All six β-adrenoceptor blocking agents were able, to a varying extent, to antagonize the isoprenaline-induced increases in plasma free fatty acids and plasma immunoreactive insulin levels. In general, the cardioselective agents were relatively less effective antagonists than the non-cardioselective agents. 4 Resting plasma renin activity was reduced by all six β-adrenoceptor blocking agents, suggestive of the presence of β1-adrenoceptors mediating renin release, but the non-cardioselective agents propranolol and pindolol seemed relatively more effective in antagonizing isoprenaline-induced increases in plasma renin activity than the cardioselective agents, which indicates that β2-adrenoceptors might also be involved. 5 The results are compatible with the hypothesis that both β1- and β2-adrenoceptors are involved in the regulation of lipolysis, insulin release and renin release.

Effects of salbutamol and metoprolol on plasma renin activity and plasma potassium of normal subjects and of hypertensive patients

The effect of β2-agonist salbutamol on plasma renin activity (PRA) and plasma potassium was investigated in seven normal subjects, in twenty-three patients with essential hypertension and in one patient with primary aldosteronism. The action of β1-antagonist metoprolol on PRA and plasma potassium changes induced by salbutamol was also studied in one normal subject and in seven patients with essential hypertension. Salbutamol significantly increased PRA in normal subjects and in patients with essential hypertension with normal (8 cases) or high (5 cases) PRA, while it did not modify PRA in patients with essential hypertension with low PRA (10 cases), and in the patient with primary aldosteronism. Plasma potassium was significantly decreased after salbutamol both in normal and hypertensive patients: no correlation was found between PRA and plasma potassium changes. Metoprolol inhibited both PRA increments and plasma potassium decrements induced by salbutamol. These data suggest the following conclusions. β-Adrenergic receptors mediating renin release in man cannot be clearly differentiated into β-subtypes. The PRA unresponsiveness observed in patients with essential hypertension with low PRA and in the patient with primary aldosteronism indicates a decreased renal response to adrenergic stimuli, probably due to a decreased renin storage. The hypokalemic action of salbutamol cannot be explained by changes of the renin angiotensin system. Moreover the β-receptors mediating the decrease of plasma potassium cannot be clearly differentiated into β-subtypes.

Renin Release, Saralasin and the Vasodilator-Beta-Blocker Drug Interaction in Man

Saralasin, an angiotensin antagonist, was used to study the role of renin-angiotensin in the vasodilator-beta-blocker drug interaction in hypertensive subjects. Plasma renin activity was elevated by withdrawal of propranolol in seven patients using minoxidil and propranolol. After propranolol withdrawal, saralasin caused hypotension (100/60 mm Hg or less) in five. Propranolol lowered blood pressure and plasma renin activity and diminished the hypotensive response to saralasin. Saralasin induced renin release in all patients, an effect blocked by propranolol. We conclude that angiotensin can be the major determinant of blood pressure in vasodilator-drug treated patients, that propranolol lowering of blood pressure in this vasodilator-beta-blocker drug interaction is related to suppression of renin release, and that the angiotensin feed-back-suppression mechanism for inhibiting renin release in functionally located proximal to beta-adrenergic receptors mediating renin release.

Abolition of the renin-releasing action of frusemide by acute renal denervation in dogs.

1. The effects of infusions of frusemide at low (0.05-0.1 mg.kg-1.min-1) and high (0.5-2.0 mg.kg-1.min-1) rates were studied on renin secretion and urinary outputs of sodium and potassium in anaesthetized dogs in which one kidney was removed and the remaining kidney was either innervated or denervated. 2. When the kidney was innervated, low rates of infusion of frusemide did not significantly affect renin secretion if urinary volume and sodium losses were replaced. Without replacement of urinary losses, renin secretion increased at sodium deficits of 0.7-0.9 mmol.kg-1 in the presence of elevated rates of sodium and potassium excretion. 3. High rates of infusion of frusemide caused an immediate increase in renin secretion from innervated kidneys which was not related to urinary losses. 4. Denervation of the kidney increased the urinary outputs of sodium and potassium while it decreased the rate of renin secretion to one-tenth of the resting value. 5. Denervation of the kidney abolished the renin-releasing action of frusemide at both low and high infusion rates even when the sodium deficit amounted to 4.3 mmol.kg-1. 6. Constriction of the aorta producing a fall of 10-30 mmHg in perfusion pressure raised the rate of renin secretion from denervated kidneys to control levels and partially restored the renin-releasing action of frusemide at high infusion rates. 7. The findings indicate that frusemide has a site of action apart from the macula densa in mediating renin release.

Renal blood flow and renin activity in renal venous blood in essential hypertension.

The intrarenal distribution of blood flow measured by the 133 xenon washout method and the renin activity of renal venous blood were determined in 16 patients with early essential hypertension. None of the patients had evidence of systemic disease except for the elevation in blood pressure (> 150/100 mm Hg). Fifteen of the subjects received a controlled sodium diet during 7 to 9 days before study, at the time of renal angiography. An inverse relationship was noted between the cortical component of the renal blood flow and renin activity of renal venous blood (r = 0.64, P < 0.02). Renin secretion rates were also calculated in 12 patients confirming the inverse relationship between cortical distribution of blood flow and renin secretion (r = 0.763, P < 0.01). The cortical renal blood flow in 10 patients on a low salt intake was 79.6% ± 2.6 (SE) of the total renal blood flow. The cortical blood flow in five patients on a high salt diet was 87.6% ± 1.9 (SE); the statistical difference between the two groups is significant ( P < 0.05). A direct relationship was noted between cortical blood flow and the logarithm of the 24-hour urinary sodium excretion from the day preceding the study (r = 0.54, P < 0.05). Renin secretion rate and renin in renal venous blood were directly correlated (r = 0.813, P < 0.01). Changes in corticomedullary distribution of flow were inversely related to the changes in cortical distribution. The degree of reduction of cortical renal blood flow correlated with the degree of increase in renin secretion and in renin activity in renal venous blood. Our data are compatible with reduced cortical renal blood flow mediating renin release or vice versa. Either mechanism would result in more efficient conservation of salt and water by the kidney.

Release of prostaglandin-like material from dog kidney during nerve stimulation

Canine kidneys were autoperfused in situ at constant flow in 28 experiments. Renal venous effluent was examined for (PLM) prostaglandin-like material following acidic lipid extraction and thin layer chromatography or by continuous bioassay utilizing the bloodbathed organ technique. There was a low basal efflux of PLM from the kidney which was markedly enhanced during the renal vascular constriction elicited by renal nerve stimulation at 2-10 cycles/second or by infusion of norepinephrine. The PLM was tentatively identified as an E-type prostaglandin based on chromatographic behavior and bioassay. The present study indicates that PLM is released from the dog kidney during an increase in renal vascular resistance. Release is not necessarily dependent upon changes in total renal blood flow although alterations in the distribution of intrarenal blood flow might be involved. (authors)