Angiotensin Subtype 1 Receptor (AT1) Blockade Improves Vasorelaxation in Heart Failure by Up-Regulation of Endothelial Nitric-Oxide Synthase via Activation of the AT2 Receptor

Hoang M. Thai, Jason Wollmuth, Steven Goldman, Mohamed Gaballa

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

To determine whether angiotensin receptor blockade decreases vascular tone in heart failure by improving endothelial-dependent vasorelaxation and increasing nitric oxide (NO) bio-availability, 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.

Original languageEnglish (US)
Pages (from-to)1171-1178
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume307
Issue number3
DOIs
StatePublished - Dec 1 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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