title: Angiotensin subtype 1 rReceptor (AT1) blockade improves vasorelaxation in heart failure by up-regulation of endothelial nitric-oxide synthase via activation of the AT2 receptor.
abstract: 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 microM). In bovine pulmonary endothelial cells, 20 microM candesartan increased endothelial nitric-oxide synthase (eNOS) protein levels (P < 0.05) (28.9 +/- 2.6 versus 16.1 +/- 3.7 intensity units/microg 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.
authors.affiliation: Cardiology Section, 1-111C, Southern Arizona Veterans Affairs Health Care System Hospital, 3601 S. 6th Avenue, Tucson, AZ 85723, USA. hoang.thai@med.va.gov
authors.forename: Hoang
authors.initials: H
authors.lastname: Thai
authors.forename: Jason
authors.initials: J
authors.lastname: Wollmuth
authors.forename: Steven
authors.initials: S
authors.lastname: Goldman
authors.forename: Mohamed
authors.initials: M
authors.lastname: Gaballa
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001158:Arteries / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D015153:Blotting, Western; D002417:Cattle; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000201:enzymology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists*; D013777:Tetrazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C081643:candesartan; D019331:NG-Nitroarginine Methyl Ester