Abstract

The objective of this study was to evaluate the mechanisms of the renin secretion response to the angiotensin II (AII) receptor type 1 (AT1) antagonist losartan (DuP 753) in anesthetized rabbits. All receptor blockade with losartan (4 mg/kg bolus and 2 mg/kg/hr i.v.) decreased blood pressure (BP) and increased plasma renin activity (PRA) and heart rate (HR) significantly, whereas the beta-1 adrenoceptor antagonist atenolol (0.02 mg/kg/min i.v.) caused significant reductions in these parameters. Atenolol blocked HR and PRA responses but not the effect of losartan on BP. Cyclooxygenase inhibition with indomethacin (5 mg/kg bolus and 40 micrograms/kg/min i.v.) did not result in significant effects, and the coadministration of indomethacin and losartan resulted in a greater PRA effect than with losartan alone. These results preclude the involvement of prostaglandins, such as PGE2 and PGI2, in the renin response to losartan. The PRA response to atenolol alone suggests that renin release in anesthetized rabbits is under tonic control by beta adrenergic receptors. Furthermore, the discrepancy in the PRA responses to equipotent hypotensive doses of hydralazine and losartan indicates that beta adrenoceptor activation in the kidney, probably the result of blockade of AII-mediated inhibition of renin secretion, contributes to the renin-releasing effect of the AT1 receptor antagonist losartan.