The role of adrenergic receptors in mediating renin secretion was studied in normal subjects with the use of upright posture and administration of diazoxide, ethacrynic acid and theophylline to provoke renin release. Each of these stimuli produced the expected rise in plasma renin activity (PRA), despite marked differences in their effect on urinary sodium excretion. In each case the increase in PRA was markedly suppressed on retesting with an infusion of either phentolamine, an alpha-adrenergic blocking agent, or propranolol, a beta-adrenergic blocking agent, whereas adrenergic blockade had little or no affect on sodium excretion. Since the stimuli chosen for provoking renin release have diverse mechanisms of action, it is noteworthy that PRA was suppressed by adrenergic blockade, regardless of the stimulus used. These findings suggest that many, if not all, of the stimuli for renin release are mediated by a common pathway which may involve alpha-and beta-adrenergic receptors. Moreover, renin release may occur independently of changes in sodium excretion. (J Clin Endocr 29: 1168
Renal vein renin activity was measured by bioassay of plasma obtained from anesthetized dogs during renal arterial infusion of sympathomimetic amines, cyclic AMP, and other nucleotides. Renin secretion was calculated as the product of renal blood flow and the arterial-renal venous renin difference. Infusion of cyclic AMP significantly increased renin secretion, while administration of ATP, ADP, 5'AMP, and adenosine in quantities equimolar to cyclic AMP had no effect. Phentolamine, an rt-receptor antagonist, and dlpropranolol, a /3-receptor blocker, abolished the cyclic AMP-induced rise in renin secretion. Paradoxically, the increase in renin production induced by infusion of norepinephrine, a predominantly a-receptor agonist, was suppressed by propranolol administration, and the renin-stimluating effect of isoproterenol, a /3-receptor stimulator, was blocked by phentolamine administration. In addition, the d-and /-isomers of propranolol were equipotent in suppressing the isoproterenol-induced rise in renin secretion. Administration of AY-21,011, a Breceptor antagonist which lacks local anesthetic properties, also prevented the isoproterenol-induced rise in renin secretion, but lidocaine had no suppressive effect. The effects on renin secretion of cyclic AMP and sympathomimetic amines alone and in combination with adrenergic receptor antagonists were independent of changes in glomerular filtration rate, sodium excretion, urine flow, systemic blood pressure, and heart rate. The data suggest that cyclic AMP acts within the kidney as an intracellular mediator of renin secretion, and that phentolamine and propranolol suppress renin secretion at a site distal to cyclic AMP production, rather than by blockade of plasma membrane adrenergic receptors or inhibition of adenyl cyclase. KEY WORDS phentolamine nucleotides propranolol norepinephrine adenyl cyclase isoproterenol lidocaine• We have previously reported that the renin release provoked by upright posture and administration of agents such as diazoxide, ethacrynic acid, and theophylline could be inhibited by adrenergic receptor-blocking agents (1). These data suggested that many, if not all, stimuli for renin release might be mediated by a final common pathway, possi- bly involving a-and /3-receptor sites. Since catccholamines increase renin secretion when infused into the renal artery of the dog (2, 3) and also enhance adenyl cyclase activity (4), it seemed possible that intracellular accumulation of adenosine 3', 5' cyclic monophosphoric acid (cyclic AMP) might play a role in mediating the increased renin secretion induced by catecholamines and other stimuli. Cyclic AMP mediates a vast array of physiological phenomena (5, 6) and has been postulated to act as a "second messenger" in the intracellular action of several hormones (7). Moreover, cyclic AMP stimulates renin release in vitro (8).
Renin release is mediated by such diverse stimuli as changes in vascular volume and sodium balance, upright posture, stimulation of renal nerves, and infusion of catecholamines. However, the exact mechanisms by which renin secretion is enhanced by these stimuli are not well understood. Winer et al.(1) found that renin release provoked by upright posture, and infusion of diazoxide, theophylline and ethacrynic acid could be blocked by infusion of phentolamine or propranolol. The authors suggested that renin release was possibly mediated by adrenergic receptors.To test this hypothesis further, we studied the effects of dopamine, a naturally occurring catecholamine and a precursor of norepinephrine, and isoproterenol, a potent betaadrenergic agonist, on renin secretion before and after beta-adrenergic blockade induced by propranolol.Materials and Methods. Eight adult mongrel dogs (weighing 20-25 kg) were anesthetized with intravenous sodium pentobarbital (30 mg/kg) and were mainltained on artificial respiration. Additional small maintenance doses of the anesthetic were administered when necessary. Aortic blood pressure was measured through a catheter connected to a Statham transducer (type P23 D B ) . The kidney was exposed through a subcostal incision, care was taken in handling the organ as little as possible. The renal nerves were left intact. A curved 23 gauge needle was placed in the renal artery for the infusion of drugs or 5% dextrose in water. A 19 gauge 1Requests for reprints: Dr. Yeh, Mount Sinai Hospital, 4300 Alton Road, Miami Beach, FL 33140. Medicine, Miami, Florida 33140needle was placed in the renal vein, secured in place by purse string sutures for obtaining blood samples for renin assay using the method of Gunnells et al.(2). The renal venous catheter was kept patent by a slow infusion of 5% dextrose in water except during the collection of specimens.Renal blood flow was measured by an electromagnetic flowmeter (Statham blood flowmeter, model SP220). The flowmeter was calibrated against known blood flow.Drug infusion was begun 2 hr or more after surgery. The rates of infusion of the drugs were as follows: dopamine, 3 pg/kg/ min ; isoproterenol, 0.15 pg/kg/min ; and propranolol, 0.5 pg/kg/min. After base line control values were obtained, dopamine or isoproterenol dissolved in 5% dextrose in water was infused in random order a t a constant rate (1 ml/min) by a Harvard infusion pump, over a 15 min period. Each period of drug infusion was preceded and followed by a 30 min control period. At the end of each infusion period, blood pressure, renal blood flow and renin activity were measured. Dopamine and isoproterenol infusion were repeated after a 15 min infusion of propranolol, again in random order. Results are expressed in arithmetic mean t standard deviation. Statistical significance was determined by Student's paired t test.
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