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CARDIOVASCULAR
Department of Internal Medicine, Section of Cardiology, Southern Arizona Veterans Affairs Health Care System (H.T., S.G., M.G.) and the Sarver Heart Center (H.T., J.W., S.G., M.G.), University of Arizona, Tucson, Arizona
To determine whether angiotensin receptor blockade decreases vascular tone in heart failure by improving endothelial-dependent vasorelaxation and increasing nitric oxide (NO) bioavailability, we treated infarcted adult male Sprague-Dawley rats with candesartan for 7 days or 8 weeks (10 mg/kg/day in drinking water). Candesartan, at both time points, lowered left ventricular (LV) systolic pressure (P < 0.05) (122 ± 22 versus 74 ± 16 and 73 ± 10 mm Hg) and LV dP/dt (5914 ± 1294 versus 2857 ± 1672 versus 3175 ± 769 mm Hg/s), but lowered LV end-diastolic pressure only at 8 weeks (16.9 ± 9.7 versus 11.2 ± 5.7 versus 6.9 ± 5.3 mm Hg). The vasorelaxation response to acetylcholine (ACh) in thoracic aortic segments was decreased with infarction (P < 0.05), remained unchanged with 1 week of candesartan, but increased 84 and 86% at 10–4 and 10–5 M ACh (P < 0.05) at 8 weeks. The enhanced candesartan-induced vasorelaxation at 8 weeks was abolished with NG-nitro-L-arginine methyl ester (200 µM). In bovine pulmonary endothelial cells, 20 µM candesartan increased endothelial nitric-oxide synthase (eNOS) protein levels (P < 0.05) (28.9 ± 2.6 versus 16.1 ± 3.7 intensity units/µg of protein); the increased eNOS was abolished by a specific angiotensin subtype 2 (AT2) receptor antagonist, PD 123319. These data suggest that AT1 receptor blockade enhances vasorelaxation in heart failure by increasing NO bioavailability, in part via an AT2 receptor-mediated up-regulation of eNOS protein.
Address correspondence to: Dr. Hoang M. Thai, Assistant Professor of Medicine, Cardiology Section, 1-111C, Southern Arizona Veterans Affairs Health Care System Hospital, 3601 S. 6th Avenue, Tucson, AZ 85723. E-mail: hoang.thai{at}med.va.gov
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