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

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Abstract
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 bilteral 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 β-blocker propranolol and the β1 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 β-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.