title: Improvement of endothelial dysfunction in experimental heart failure by chronic RAAS-blockade: ACE-inhibition or AT1-receptor blockade?
abstract: Chronic heart failure (CHF) is associated with endothelial dysfunction. Activation of the renin-angiotensin-aldosterone system (RAAS) is believed to be important in the deterioration of endothelial dysfunction in CHF through stimulation of oxidative stress. Whereas angiotensin-converting enzyme inhibitors (ACE-I) improve endothelial function in CHF, the effects of angiotensin II AT1-receptor blockers (ARB) are less well established. Therefore we compared the effects of the ACE-I lisinopril vs. the ARB candesartan on endothelial dysfunction in a rat model of CHF. CHF was induced by myocardial infarction (MI) after coronary ligation. Two weeks after MI, daily treatment with lisinopril (2 mg/kg) or candesartan cilexetil (1.5 mg/kg) was started. After 13 weeks, rats were sacrificed and endothelial function was determined by measuring acetylcholine (ACh)-induced vasodilation in aortic rings, with selective presence of the nitric oxide synthase (NOS)-inhibitor NG-monomethyl-L-arginine (L-NMMA) to determine the contribution of nitric oxide (NO). ACh-induced vasodilation was attenuated in untreated MI (-50%) compared with control rats. This was in part due to an impaired contribution of NO (-49%). Lisinopril and candesartan cilexetil fully normalised ACh-induced dilation, including the part mediated by NO. Chronic RAAS-blockade with lisinopril and candesartan cilexetil normalised endothelial function in CHF in a comparable way. The effect of both treatments included the increase of the NO-mediated dilation, further indicating the important role of oxidative stress in the relationship between the RAAS and endothelial dysfunction in CHF.
authors.affiliation: Department of Cardiology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, l.j.wagenaar@thorax.azg.nl, Department of Clinical Pharmacology, University of Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Lodewijk J
authors.initials: LJ
authors.lastname: Wagenaar
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Buikema
authors.affiliation: Department of Cardiology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Yigal M
authors.initials: YM
authors.lastname: Pinto
authors.affiliation: Department of Cardiology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Department of Clinical Pharmacology, University of Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Wiek H
authors.initials: WH
authors.lastname: van Gilst
keywords: ACE-inhibition; AT1-receptor blockade; endothelial function; heart failure; myocardial infarction; oxidative stress; rats