Inhibition of plasma angiotensin II generation does not fully explain the chronic hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors. Therefore, the pattern of tissue ACE inhibition in rats was studied after oral administration of perindopril, a new ACE inhibitor. Tissue ACE was measured by quantitative in vitro autoradiography using [125I]-351A as a radioligand and compared with plasma ACE and the pressor response to intravenous (i.v.) angiotensin I. Following oral perindopril (1 mg/kg), plasma ACE activity was acutely reduced, but recovered over 24 h. The peak concentration of plasma perindoprilic acid, the active diacid of perindopril, occurred at 1 h, and the drug was undetectable by 24 h. The pressor response to i.v. angiotensin I was inhibited by 95% at 4 h and had not fully recovered by 24 h. Four hours after oral administration of perindopril, ACE was markedly inhibited in the proximal tubules of the kidney (24% control), lung parenchyma (10%), and aortic wall (18%) (p less than 0.01). At 24 h, ACE in these tissues had only partially recovered (32-63%). ACE was also identified in vascular endothelium of organs, including the lung, kidney, and testis; in these sites, vascular ACE showed a pattern of inhibition similar to that of aortic ACE. In contrast, ACE in testicular seminiferous tubules was unaffected by perindopril. These results demonstrate a prolonged effect of ACE inhibitors on tissue ACE that may better explain the time course of these drugs than the changes in plasma ACE or plasma levels of the drug.