Acute and chronic in vivo inhibition of angiotensin-converting enzyme by perindopril in the endothelium and adventitia of large arteries and organs of the rabbit.
Angiotensin-converting enzyme (ACE) inhibitors are widely used in treating hypertension and chronic heart failure, but their precise sites and mechanisms of the actions are not completely understood. In this study, we evaluated the acute and chronic in vivo inhibition of ACE by perindopril in both the endothelium and adventitia of large blood vessels including the aorta, carotid, and femoral arteries, heart, lung, and kidney by using in vitro autoradiography with [(125)I]351A as a ligand. After short-term (0.1, 0.3, and 1 mg/kg) or long-term oral administration (0.3 mg/kg), perindopril significantly inhibited plasma ACE (p < 0.001), the plasma angiotensin II (Ang II)/Ang I ratio (p < 0.01), and decreased mean arterial pressure (p < 0.001) in a dose-related manner. In the aorta, carotid, and femoral arteries, free ACE was inhibited to a similar extent in both the endothelium and adventitia by perindopril, in a dose-dependent manner, whereas total ACE in both layers of these vessels was unaltered. Similar short- and long-term ACE inhibition by perindopril was observed in the lung and heart, with somewhat greater inhibition of kidney and plasma ACE. Vascular and tissue ACE inhibition 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 perindopril on blood pressure, plasma Ang II/Ang I ratio, plasma and vascular ACE were all highly dose dependent, there were no significant differences on the degree of ACE inhibition observed between the three large blood vessels or between their adventitial and endothelial layers. These results demonstrate that perindopril readily penetrates the vascular wall after short- or long-term oral administration, and in a dose-dependent manner, potently inhibits both endothelial and advential vascular ACE to a comparable degree. Therefore ACE inhibitors may be beneficial in inhibiting both circulating Ang II and its local formation in the vascular wall.
Zhuo
J
J
Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria, Australia.
Casley
D
D
Murone
C
C
Mendelsohn
F A
FA
D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D001158:Arteries / Q000187:drug effects / Q000201:enzymology*; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D005263:Femoral Artery / Q000187:drug effects / Q000201:enzymology; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D008168:Lung / Q000201:enzymology; D008297:Male; D009206:Myocardium / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism; D020913:Perindopril; D011817:Rabbits; D012083:Renin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D020913:Perindopril