Cardiovascular activity of SK&F 64139 in the hypertensive rat

SK&F 64139 (7,8-dichloro-1,2,3,4-tetrahydroisoquinoline) produces a dose-related antihypertensive effect in rats treated with desoxycorticosterone acetate and administered saline in their drinking water (DOCA-salt rats), lowering both systolic and diastolic blood pressure by 40 mm Hg after an oral dose of 25 mg/kg in a conscious animal. This antihypertensive effect can also be observed after intravenous infusion in an anesthetized DOCA rat. The fall in blood pressure is accompanied by bradycardia, which can be blocked by the combination of propranolol plus vagotomy, and a decrease in peripheral vascular resistance. In contrast to the results in the DOCA rat, only minimal effects on blood pressure were produced in normotensive rats. Although SK&F 64139 is a potent inhibitor of phenylethanolamine N-methyltransferase (PNMT), the time course of blood pressure reduction is not consistent with PNMT inhibition as a mechanism for its antihypertensive action. SK&F 64139 decreases the turnover rate of cardiac norepinephrine in DOCA-salt rats, suggesting that its antihypertensive effect may results from a centrally mediated inhibition of sympathetic outflow to the periphery.