© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Combined angiotensin converting enzyme inhibition and angiotensin AT1 receptor blockade up-regulates myocardial AT2 receptors in remodeled myocardium post-infarction
aDepartments of Medicine and Physiology and Biophysics, Georgetown University Medical Center, 394 Building D, 4000 Reservoir Road, NW, Washington, DC 20007, USA
bDepartments of Medicine and Radiology, University of Virginia Health System, Richmond, VA, USA
cDepartment of Medicine, Allegheny General Hospital, Allegheny, NY, USA
dKorea Research Institute of Chemical Technology, Taejon, South Korea
* Corresponding author. Tel.: +1-202-687-4179; fax: +1-202-687-7278 sandberg{at}gusun.georgetown.edu
Objectives: In an ovine model of left ventricular (LV) remodeling after transmural anteroapical myocardial infarction (MI), we have previously demonstrated that the combination of angiotensin converting enzyme (ACE) inhibition and AT1 receptor blockade is more effective at limiting LV remodeling than either therapy alone. We hypothesized that the beneficial effect of combined therapy is due in part to upregulation of AT2 receptor levels. Methods: Two days after transmural anteroapical MI by coronary ligation, 16 sheep were randomized to losartan (50 mg/day), ramipril (10 mg/day), ramipril+losartan (combined therapy), or no therapy. At 8 weeks after MI, radioligand receptor assay were deployed with homogenates from regional LV tissues. Results: We found that AT receptors in normal sheep myocardium are predominantly of the AT2 receptor subtype. Binding studies of remodeled myocardium 8 weeks later showed that the apparent maximum binding (Bmax) was increased from 23 to 48 fmol/mg protein only in animals with combined therapy. The AT2/AT1 proportion was increased significantly in animals with combined therapy compared to infarcted controls (18.0 vs. 5.17). Conclusions: These results indicate that AT2 receptor expression increased significantly during LV remodeling with combined therapy but not with either therapy alone. In combination with prior work demonstrating the effectiveness of combined therapy in limiting LV remodeling, this study is consistent with the hypothesis that AT2 receptors play a cardioprotective role in LV remodeling after MI.
KEYWORDS ACE inhibitors; Angiotensin; Antihypertensive/diuretic agents; Infarction; Remodeling; Receptors; Renin angiotensin system
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