Left ventricular (LV) remodelling following myocardial infarction (MI) is associated with increased morbidity and mortality. Previous data suggest that angiotensin II (Ang II) plays a central role in the molecular events contributing to LV remodelling. We explored the effects of angiotensin-converting-enzyme (ACE) inhibition versus Ang II (AT1) receptor blockade on LV remodelling in mice post-MI. Mice underwent sham procedure or left coronary artery ligation, and received placebo, the AT1 receptor antagonist, losartan or the ACE inhibitor, enalapril. At 6 weeks, echocardiography and haemodynamic studies were performed. Infarct size and interstitial collagen content were determined. Expression of genes encoding atrial natriuretic peptide (ANP), collagen type I, AT1a and AT1b receptors were measured. The placebo MI group showed increased LV end-diastolic diameter, LV end-systolic diameter with depressed fractional shortening (P<0.01 versus shams), increased LV mass and volume (both P<0.01 versus shams). The placebo MI group also exhibited increased non-infarct zone collagen content (P<0.01), ANP (P<0.01) and collagen type 1 (P<0.01) gene expression, with a non-significant rise in AT1a receptor gene expression. Neither losartan or enalapril prevented LV dilation or improved fractional shortening. Both similarly lowered systolic blood pressure (P<0.01 for each versus placebo). Losartan and enalapril inhibited LV hypertrophy (P<0.01), and decreased ANP (P<0.01) and collagen type 1 gene expression (P<0.05). Levels of AT1a receptor gene expression were higher than shams (P<0.05 for both), but similar to placebo. AT1b receptor gene expression was much lower than that for AT1a receptor and similar in all groups. Thus, in this model, AT1 receptor antagonism and ACE inhibition have equivalent inhibitory effects on myocardial hypertrophy and fibrosis. These results serve as an important basis for planned investigations to evaluate the anti-remodelling effects of these agents on mice in which genetic manipulations are used to disrupt components of the Ang II signalling system.
Effects of angiotensin II receptor blockade versus angiotensin-converting-enzyme inhibition on ventricular remodelling following myocardial infarction in the mouse
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Richard D. PATTEN, Mark J. ARONOVITZ, Michael EINSTEIN, Matthew LAMBERT, Natesa G. PANDIAN, Michael E. MENDELSOHN, Marvin A. KONSTAM; Effects of angiotensin II receptor blockade versus angiotensin-converting-enzyme inhibition on ventricular remodelling following myocardial infarction in the mouse. Clin Sci (Lond) 1 February 2003; 104 (2): 109–118. doi: https://doi.org/10.1042/cs1040109
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