Inhibition by BMS 186295, a selective nonpeptide AT1 antagonist, of adrenal catecholamine release induced by angiotensin II in the dog in vivo.

Abstract

The aim of the present study was to investigate whether a novel nonpeptide AT1 selective antagonist, BMS 186295 (BMS), can antagonize adrenal catecholamine release induced by local administration of angiotensin II (AII) in anesthetized dogs. Plasma catecholamine concentrations in adrenal venous and aortic blood were determined by an HPLC-electrochemical method. AII was locally administered to the left adrenal gland in the absence and presence of BMS. In the first group (n = 7), local infusion (0.5 mL/min, 1 min) of AII (0.001-1.0 micrograms/mL) resulted in a significant dose-dependent increase in the basal secretion of adrenal catecholamines. Aortic catecholamine levels and mean aortic pressure remained unchanged at all doses tested. In the second group (control, n = 10), four repeated infusions (at intervals of 15 min) of AII at 0.1 micrograms/mL resulted in significant increases of adrenal catecholamine secretion compared with the baseline. In the third group receiving BMS given locally to the gland (n = 8), the basal adrenal catecholamine secretion was not significantly altered by BMS itself at any dose tested. However, the net catecholamine response to AII (0.1 micrograms/mL) was significantly and dose dependently attenuated by approximately 40, 60, and 80% in the presence of BMS at doses of 0.1, 1.0, and 10 micrograms/mL, respectively, compared with the control group. The study indicates that BMS dose dependently blocks AII-induced catecholamine secretion in the dog adrenal gland in vivo.