Angiotensin II Receptor Antagonist, E-4177, Inhibits Progression of Reactive Cardiac Hypertrophy Associated with Myocardial Infarction in Rats

Abstract

There is increasing evidence that the renin-angiotensin system (RAS) may play a important role in the development of left ventricular remodeling and hypertrophy after myocardial infarction (MI). Previous studies have demonstrated that chronic treatment with angiotensin converting enzyme (ACE) inhibitors has beneficial effects for survival survival after MI. To elucidate the role of the RAS in the reactive hypertrophy after MI, we evaluated the effect of an angiotensin II (Ang II) receptor antagonist, E-4177 (AT-1 antagonist), on rat myocardium with infarct (IF) and noninfarcted (NI) regions, and also determined the relationship between the role of RAS and the trans-sarcolernmal Ca2+ transport activity because of the disorder in Na+-Ca2+ exchange] described previously. Myocardial infarctions were induced by surgical occlusion of the left main coronary artery in rat, and oral drug therapy was initiated beginning on the next day. Rats were killed 4, 8, and 12 weeks later, and left ventricular (LV) weight, LV to body weight (BW) ratio, and inter-ventricular septal (IVS) weight to BW were measured. The left ventricule was separated into three sections with IF (scar) or NI myocardium (LV free wall and IVS). At 4 weeks after MI, the ratio of IVS to BW was significantly higher in the MI group and indicated that reactive hypertrophy was observed in NI myocardium. Collagen concentration and ACE activity were significantly increased in NI myocardium compared with the same region of the sham-operated rat, although the ACE activity in the IF region increased 10-fold. The denmsity of Ang II receptor was also increased in NI compared with sham-operated rats. The administration of E-4177 significantly reduced the ratio of IVS to BW, collagen concentration, and ACE activity in NI myocardium, and also reduced the collagen concentration in the IF region of the LV. Na+-Ca2+ exchange activity (Na+-dependent Ca2+ uptake) in sarco-lemmal membrane was significantly decreased in NI myocardium at 8 and 12 weeks after MI compared with that sham-operated rats. By E-4177 administration, Na+-Ca2+exchange activity was significantly increased in MI rats compared with untreated MI rats. When we determined the relationship between Na+-Ca2+ exchange and cardiac ACE activities in sham-operated, treated, and untreated hearts in NI myocardium, a significant negative correlation was obtained. These results suggest that the AT-1 antagonist, E-4177, inhibited the development of reactive hypertrophy and improved its Ca2+ transport activity. Therefore, E-4177 may be clinically useful for the treatment of the development of left ventricular remodeling and hypertrophy after MI.