To assess the mechanism by which inhibitors of angiotensin converting enzyme (ACE) lower blood pressure, we evaluated the role of endogenous angiotensin II in the antihypertensive effect of MK 421, a long-lasting ACE inhibitor, in rats made hypertensive by chronic infusion of norepinephrine or vasopressin. The hypertensive effect of norepinephrine (1.8 mg/kg/day, ip) or vasopressin (7.2 U/kg/day, ip) was inhibited by the simultaneous administration of MK 421 (6 mg/kg/day, ip). Additional administration of angiotensin II at a subpressor dose (36 micrograms/kg/day, ip) did not revert the antihypertensive effect of MK 421 in rats made hypertensive by chronic infusion of norepinephrine or vasopressin. The present results suggest that the hypotensive effect of ACE inhibitors may depend on a reduced sensitivity of the vasculature to vasoconstrictor substances. In addition, it is also suggested that the suppressed angiotensin II may not be essential for the antihypertensive effect of ACE inhibitors in rats made hypertensive by chronic infusion of norepinephrine or vasopressin.