BACKGROUND: ACE inhibitors are widely used in treating hypertension and heart failure, but the sites and mechanisms of ACE inhibition in human blood vessels are not understood. The present study was undertaken to assess the sites and extent of in vivo inhibition of ACE by long-term perindopril treatment in different layers of the internal mammary artery in patients with ischemic heart disease. METHODS AND RESULTS: Sixteen patients with ischemic heart disease were treated either with perindopril (4 mg/d PO) for up to 36 days before surgery (n = 9) or without the inhibitor as control subjects (n = 7). The segments of the internal mammary artery were collected for measurement of vascular free and total ACE by quantitative in vitro autoradiography with 125I-351A binding. The patients treated with perindopril had lower plasma ACE (P < .001) and plasma angiotensin (Ang) II-to-Ang I ratio (P < .05). In the internal mammary artery, free ACE was similarly inhibited by perindopril in the endothelium (P < .05) and adventitia (P < .05), and the free ACE-to-total ACE ratio, an index of ACE inhibition, was markedly decreased by perindopril in parallel in the endothelium (P < .001) and adventitia (P < .001). Moreover, plasma ACE correlated highly with vascular ACE in the endothelium (r = .85, P < .001) or adventitia (r = .78, P < .001), and mean arterial pressure correlated significantly with free ACE in the endothelium (r = .52, P < .05) or adventitia (r = .53, P < .05) and with the plasma Ang II-to-Ang I ratio (r = .53, P < .05). Light microscopic autoradiographs of 125I-351A binding revealed a marked inhibition of ACE by perindopril in both layers of the vascular wall. CONCLUSIONS: The present demonstrates that long-term administration of perindopril potently inhibits both endothelial and adventitial ACE to a comparable degree in the human internal mammary artery. These results indicate that perindopril effectively penetrates the vascular wall to inhibit ACE in the adventitia, thus providing evidence that perindopril may be beneficial in inhibiting both circulating Ang II and its local formation in the vascular wall.
BACKGROUND:ACE inhibitors are widely used in treating hypertension and heart failure, but the sites and mechanisms of ACE inhibition in human blood vessels are not understood. The present study was undertaken to assess the sites and extent of in vivo inhibition of ACE by long-term perindopril treatment in different layers of the internal mammary artery in patients with ischemic heart disease. METHODS AND RESULTS: Sixteen patients with ischemic heart disease were treated either with perindopril (4 mg/d PO) for up to 36 days before surgery (n = 9) or without the inhibitor as control subjects (n = 7). The segments of the internal mammary artery were collected for measurement of vascular free and total ACE by quantitative in vitro autoradiography with 125I-351A binding. The patients treated with perindopril had lower plasma ACE (P < .001) and plasma angiotensin (Ang) II-to-Ang I ratio (P < .05). In the internal mammary artery, free ACE was similarly inhibited by perindopril in the endothelium (P < .05) and adventitia (P < .05), and the free ACE-to-total ACE ratio, an index of ACE inhibition, was markedly decreased by perindopril in parallel in the endothelium (P < .001) and adventitia (P < .001). Moreover, plasma ACE correlated highly with vascular ACE in the endothelium (r = .85, P < .001) or adventitia (r = .78, P < .001), and mean arterial pressure correlated significantly with free ACE in the endothelium (r = .52, P < .05) or adventitia (r = .53, P < .05) and with the plasma Ang II-to-Ang I ratio (r = .53, P < .05). Light microscopic autoradiographs of 125I-351A binding revealed a marked inhibition of ACE by perindopril in both layers of the vascular wall. CONCLUSIONS: The present demonstrates that long-term administration of perindopril potently inhibits both endothelial and adventitial ACE to a comparable degree in the human internal mammary artery. These results indicate that perindopril effectively penetrates the vascular wall to inhibit ACE in the adventitia, thus providing evidence that perindopril may be beneficial in inhibiting both circulating Ang II and its local formation in the vascular wall.
Authors: Mitsuru Ohishi; Gregory J Dusting; Paul A Fennessy; Frederick Ao Mendelsohn; Xiao C Li; Jia L Zhuo Journal: Int J Physiol Pathophysiol Pharmacol Date: 2010-04-30