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Improvement of endothelial dysfunction in experimental heart failure by chronic RAAS-blockade: ACE-inhibition or AT1-receptor blockade?

Department of Cardiology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, l.j.wagenaar{at}thorax.azg.nl, Department of Clinical Pharmacology, University of Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands

Hendrik Buikema

Department of Clinical Pharmacology, University of Groningen, A Deusinglaan 1, 9713 AV Groningen, The Netherlands

Yigal M Pinto

Department of Cardiology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands

Wiek H van Gilst

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

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 N_G-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.

Key Words: rats • myocardial infarction • heart failure • endothelial function • ACE-inhibition • AT1-receptor blockade • oxidative stress

Journal of Renin-Angiotensin-Aldosterone System, Vol. 2, No. 1 suppl, S64-S69 (2001)
DOI: 10.1177/14703203010020011101


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