Angiotensin II receptor blockade and myocardial fibrosis of the infarcted rat heart.J Lab Clin Med. 1997 Apr; 129(4):439-46.JL
Tissue angiotensin II (AngII) is increased in the infarcted rat heart, where it may have autocrine or paracrine properties that influence cellular protein synthesis and growth and therefore tissue repair. It was our hypothesis that treatment with an AT1 receptor antagonist would attenuate fibrous tissue formation after myocardial infarction (MI). To investigate a role for local AngII in the regulation of connective tissue formation during early and late wound healing that follows MI, this study was undertaken. Animals were randomized into two groups in which rats were or were not treated with the AT1 receptor antagonist losartan (10 mg x kg(-1) daily gavage). At 1 and 4 weeks after experimental MI was induced by coronary artery ligation, rat hearts were examined. Infarct size, infarct area, and collagen volume fraction at the site of infarction and in noninfarcted myocardium were determined by picrosirius red staining with videodensitometry. Quantitative in vitro autoradiography was used to detect AngII receptor binding density ((125)I-(Sar1,Ile8)AngII). Compared with an untreated MI control group, in losartan-treated rats we found (1) infarct size was comparable in both groups at weeks 1 and 4, (2) infarct area was comparable between groups at week 1 but was significantly reduced (p < 0.05) at week 4 in losartan-treated rats, (3) a detectable reduction in collagen volume fraction at the site of MI was not found at week 1 but was reduced (p < 0.05) at remote sites at week 4, (4) AngII receptor binding density was reduced (p < 0.05) by 50% at the site of MI at both weeks 1 and 4 in keeping with delivery of losartan to this site of injury. Thus AT1 receptor antagonism appears to influence late phase wound healing at and remote to the site of MI and suggests an association between AngII and the fibrogenic response that appears in the injured rat heart. Although still speculative, an attenuation in fibrosis after MI may account for less ventricular dysfunction and geometric remodeling of right and left ventricles and ventricular arrhythmias that have been observed in such rats treated with angiotensin converting enzyme inhibitor or AT1 receptor antagonist.