Role of nitric oxide during coronary endothelial dysfunction after myocardial infarction An Berges a,b , Luc Van Nassauw b , Jean-Pierre Timmermans b , Christiaan Vrints a, * a Laboratory of Cardiology, University of Antwerp, Wilrijkstraat 10, Edegem 2650, Belgium b Laboratory of Cell Biology and Histology, University of Antwerp, Belgium Received 18 March 2005; accepted 15 April 2005 Abstract This study aimed to investigate whether permanent ischaemia influences subacute vasodilatation responses of non-infarcted rat coronary vasculature, and to characterise these coronary changes. Ischaemia led to a significant impairment of the endothelium-dependent vasodilator response, while coronary vasodilatory capacity remained unaltered. In normal coronary circulation, nitric oxide (NO) and prostanoids contributed to vasodilatation, while basal involvement of endothelium-derived hyperpolarising factor was limited. Vasodilatory impairment following myocardial infarction did not originate from alterations in the prostanoid pathway, and only a slightly increased influence of K + channels was observed. However, NO-mediated vasodilatation was significantly increased after ischaemia, as also confirmed by higher mRNA and protein levels of iNOS and eNOS. Additionally, the amount of superoxide was enhanced following infarction. We conclude that subacute postinfarction remodeling is accompanied by endothelial dysfunction in non-infarcted coronary arteries. Although the NO-mediated response is increased after ischaemia, its final action is restricted due to the presence of superoxide. D 2005 Elsevier B.V. All rights reserved. Keywords: Coronary circulation; Endothelial function; Myocardial infarction; Remodeling; Vasodilatation; Nitric oxide; Superoxide 1. Introduction A large transmural myocardial infarction initiates a cascade of changes, including myocardial hypertrophy, to deal with reduced contractility and increased workload (Vannan and Taylor, 1992). In addition, clinical and experimental reports (Gibson et al., 1999; Karam et al., 1990; Uren et al., 1994) have described a reduced basal coronary flow and an impaired flow reserve in the infarcted and non-infarcted myocardium after myocardial infarction and heart failure. While research interest has focussed largely on coronary blood flow in the culprit artery after ischaemia, the flow in the non-infarcted arteries has received little attention and has been assumed to be normal. However, it has been reported that the reactivity of endothelium in remote vessels is impaired after an acute ischaemic insult (Gibson et al., 1999; Uren et al., 1994; Ve ´rroneau et al., 1997). The initial clinical event of myocardial infarction is a rupture of an atherosclerotic lesion in a coronary vessel. Atherosclerosis is an inflammatory disease of the vessel wall, strongly characterised by a diffuse endothelial dysfunction (Ross, 1999). This endothelial dysfunction is an early marker of atherosclerosis (Bonetti et al., 2003) and contributes to enhanced plaque vulnerability, triggers plaque rupture, and favours thrombus formation (Behrendt and Ganz, 2002). However, it is not clear whether the reduced endothelium-dependent vasodilatation response observed after myocardial infarction is a result of atherosclerosis and concomitant endothelial dysfunction in non-infarcted arteries, or a supplementary negative influence of ischaemia on coronary vessels. The aim of this study was to elucidate whether permanent ischaemia itself can influence endothelium- dependent vasodilatation responses in non-infarcted coro- nary vessels, and to characterise these coronary changes 0014-2999/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2005.04.028 * Corresponding author. Tel.: +32 3 821 35 29; fax: +32 3 830 23 05. E-mail address: christiaan.vrints@ua.ac.be (C. Vrints). European Journal of Pharmacology 516 (2005) 60 – 70 www.elsevier.com/locate/ejphar