ACUTE AND CHRONIC IN-VIVO INHIBITION OF ANGIOTENSIN-CONVERTING ENZYMEBY PERINDOPRIL IN THE ENDOTHELIUM AND ADVENTITIA OF LARGE ARTERIES AND ORGANS OF THE RABBIT

Angiotensin-converting enzyme (ACE) inhibitors are widely used in trea ting hypertension and chronic heart failure, but their precise sites a nd mechanisms of the actions are not completely understood. In this st udy, we evaluated the acute and chronic in vivo inhibition of ACE by p erindopril in both the endothelium and adventitia of large blood vesse ls including the aorta, carotid, and femoral arteries, heart, lung, an d kidney by using in vitro autoradiography with [I-125]351A as a ligan d. After short-term (0.1, 0.3, and 1 mg/kg) or long-term oral administ ration (0.3 mg/kg), perindopril significantly inhibited plasma ACE (p < 0.001), the plasma angiotensin II (Ang II)/Ang I ratio (p < 0.01), a nd decreased mean arterial pressure (p < 0.001) in a dose-related mann er. In the aorta, carotid, and femoral arteries, free ACE was inhibite d to a similar extent in both the endothelium and adventitia by perind opril, in a dose-dependent manner, whereas total ACE in both layers of these vessels was unaltered. Similar short- and long-term ACE inhibit ion by perindopril was observed in the lung and heart, with somewhat g reater inhibition of kidney and plasma ACE. Vascular and tissue ACE in hibition correlated highly with both plasma ACE and the plasma Ang II/ Ang I ratio (r = 0.63-0.89; p < 0.001). Whereas the effects of perindo pril on blood pressure, plasma Ang II/Ang I ratio, plasma and vascular ACE were all highly dose dependent, there were no significant differe nces on the degree of ACE inhibition observed between the three large blood vessels or between their adventitial and endothelial layers. The se results demonstrate that perindopril readily penetrates the vascula r wall after short- or long-term oral administration, and in a dose-de pendent manner, potently inhibits both endothelial and advential vascu lar ACE to a comparable degree. Therefore ACE inhibitors may be benefi cial in inhibiting both circulating Ang II and its local formation in the vascular wall.