Combined angiotensin converting enzyme inhibition and angiotensin AT(1) receptor blockade up-regulates myocardial AT(2) receptors in remodeled myocardium post-infarction

Objectives: In an ovine model of left ventricular (LV) remodeling after tra nsmural anteroapical myocardial infarction (MI), we have previously demonst rated that the combination of angiotensin converting enzyme (ACE) inhibitio n and AT(1) receptor blockade is more effective at limiting LV remodeling t han either therapy alone. We hypothesized that the beneficial effect of com bined therapy is due in part to upregulation of AT(2) receptor levels. Meth ods: Two days after transmural anteroapical MI by coronary ligation, 16 she ep were randomized to losartan (50 mg/day), ramipril (10 mg/day), ramiprillosartan (combined therapy), or no therapy. At 8 weeks after MI, radioligan d receptor assay were deployed with homogenates from regional LV tissues. R esults: We found that AT receptors in normal sheep myocardium are predomina ntly of the AT(2) receptor subtype. Binding studies of remodeled myocardium 8 weeks later showed that the apparent maximum binding (B-max) was increas ed from 23 to 48 fmol/mg protein only in animals with combined therapy. The AT(2)/AT(1) proportion was increased significantly in animals with combine d therapy compared to infarcted controls (18.0 vs. 5.17). Conclusions: Thes e results indicate that AT(2) receptor expression increased significantly d uring LV remodeling with combined therapy but not with either therapy alone . In combination with prior work demonstrating the effectiveness of combine d therapy in limiting LV remodeling, this study is consistent with the hypo thesis that AT(2) receptors play a cardioprotective role in LV remodeling a fter MI. (C) 2001 Elsevier Science B.V. All rights reserved.