Renin Release Induced by Losartan (DuP 753), an Angiotensin II Receptor Antagonist

The AT2 angiotensin receptor antagonist, PD123177, did not elicit plasma renin activity (PRA) or blood pressure effects in conscious unrestrained normal rats at a dose of 30 mg/kg iv. In contrast, losartan (DuP 753), a nonpeptide AT1 angiotensin receptor antagonist, elicited dose-dependent increases in PRA. PRA increased between five- and fifty-fold after intravenous administration of 1-10 mg/kg in the absence of changes in blood pressure. At 3 mg/kg iv, losartan induced a twenty-fold increase of PRA which was of renal origin inasmuch as bilateral nephrectomy blocked the effect. Cyclooxygenase blockade with indomethacin or meclofenamate did not alter losartan-induced renin release at 3 mg/kg iv and suggested that the hyperreninemia was not mediated by renal prostaglandins. The nonselective beta-blocker propranolol and the beta 1 selective blocker atenolol attenuated losartan-induced renin release approximately 70 and 80% respectively without altering blood pressure. These results were consistent with a modulation of renin release by sympathetic nerve activity via beta-adrenergic receptors. The findings suggest that losartan interferes with the ability of angiotensin II to suppress that renin release which is mediated by sympathetic nerve activity.