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(Hypertension. 2002;39:634.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Perindopril Alters Vascular Angiotensin-Converting Enzyme, AT₁ Receptor, and Nitric Oxide Synthase Expression in Patients With Coronary Heart Disease

Jia Long Zhuo; Frederick A.O. Mendelsohn; Mitsuru Ohishi

From the Howard Florey Institute, University of Melbourne (J.L.Z., F.A.O.M.), Victoria, Australia; Department of Geriatric Medicine, Osaka University Medical School (M.O.), Osaka, Japan; and Division of Hypertension and Vascular Research, Henry Ford Hospital (J.L.Z.), Detroit, Mich.

Correspondence to Jia L. Zhuo, MD, PhD, Division of Hypertension and Vascular Research, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202-2689. E-mail jzhuo1{at}hfhs.org

Angiotensin-converting enzyme inhibitors (ACEi) reduce cardiovascular morbidity and mortality by improving coronary perfusion, reducing ventricular hypertrophy and remodeling, and preventing progression of coronary atherosclerosis. However, the cellular mechanisms underlying the beneficial effects of ACEi are not fully understood. We studied the in vivo effects of ACE inhibition with perindopril on cellular expression of ACE, AT₁ receptors and 2 nitric oxide synthase (NOS) isoforms, endothelial (eNOS) and inducible NOS (iNOS), in human blood vessels using quantitative in vitro autoradiography and immunocytochemistry. Seven patients with ischemic heart disease were treated with perindopril (4 mg/d) for up to 5 weeks before elective coronary bypass surgery, whereas controls did not receive the ACEi (n=7). Perindopril decreased plasma ACE by 70% and the plasma angiotensin II to angiotensin I ratio by 57% and reduced vascular ACE to approximately 65% of control levels in both endothelium and adventitia. By contrast, AT₁ receptor binding in vascular smooth muscle cells was increased by 80% in patients treated with perindopril as confirmed by immunocytochemistry. eNOS was expressed primarily in endothelial cells, whereas little iNOS expression occurred in vascular smooth muscle cells of untreated patients. Both eNOS and iNOS expression seemed to increase during perindopril treatment. These results suggest that suppression of angiotensin II formation in the vascular wall and increased expression of eNOS and iNOS during ACE inhibition may be beneficial in reversing endothelial dysfunction in patients with cardiovascular disease. Because vascular AT₁ receptor expression is increased during chronic ACE inhibition, more clinical studies are required to determine whether it is necessary to combine ACE inhibitors and AT₁ receptor antagonists in clinical management of heart failure, coronary heart disease, and hypertension

Key Words: angiotensin-converting enzyme • angiotensin II • atherosclerosis • coronary artery disease • ACE inhibitor • nitric oxide synthase

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