Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat

• Published in: Circulation (New York, N.Y.) Vol. 89; no. 5; pp. 2273 - 2282
• Main Authors: SCHIEFFER, B, WIRGER, A, MEYBRUNN, M, SEITZ, S, HOLTZ, J, RIEDE, U. N, DREXLER, H
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-05-1994; American Heart Association, Inc
• Subjects: Angiotensin II - antagonists & inhibitors; Angiotensin Receptor Antagonists; Animals; Biological and medical sciences; Biphenyl Compounds - therapeutic use; Cardiovascular system; Coronary Circulation - drug effects; Enalapril - therapeutic use; Hypertrophy, Left Ventricular - prevention & control; Imidazoles - therapeutic use; Losartan; Male; Medical sciences; Myocardial Infarction - complications; Myocardial Infarction - pathology; Myocardium - pathology; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Tetrazoles - therapeutic use; Time Factors; Vascular wall; Heart; Vasodilator agent; Infarct; Rat; Cardiovascular disease; Myocardial disease; Peptidyl-dipeptidase A; Heart disease; Complication; Angiotensin II; Proteinases; Heart failure; Enzyme; Rodentia; Enzyme inhibitor; Receiver; Experimental study; Coronary heart disease; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; Myocardium; Hydrolases; Peptidyl-dipeptidases; Inhibitor; Hemodynamics; Comparative study; Hypertrophy
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.89.5.2273

After myocardial infarction, the noninfarcted left ventricle develops reactive hypertrophy associated with a depressed coronary flow reserve, myocardial interstitial fibrosis, and reduced capillary density. The present study investigated the comparative cardiac effects of chronic angiotensin-converting enzyme (ACE) inhibition and selective angiotensin II type 1 receptor (AT1) blockade in the rat model of myocardial infarction and failure.
Seven days after coronary ligation (MI), rats were randomized to enalapril (n = 8; 500 micrograms.kg-1.d-1), losartan (n = 9; 3 mg.kg-1.d-1), or placebo (n = 8) and treated for 6 weeks. Sham-operated rats (n = 10) served as controls. Coronary blood flow was measured with radiolabeled microspheres during baseline and maximal coronary dilation induced by dipyridamole (2 mg.kg-1.min-1 over 10 minutes). Right and left ventricular (LV) weight was increased in infarcted rats compared with sham-operated animals and enalapril- and losartan-treated MI rats. Minimal LV and right ventricular coronary vascular resistance was increased in MI rats but normalized with enalapril and losartan (LV:sham, 8.9; MI-placebo, 12.7; MI-enalapril, 9.2; MI-losartan, 8.8 mm Hg.mL-1.min-1.g-1, all P < .05 versus MI-placebo). Interstitial fibrosis determined from perfusion-fixed hearts was increased in infarcted rats but reduced by both enalapril and losartan. Myocardial capillary density improved with enalapril and losartan. In separate groups treated as above, plasma and tissue ACE activity was determined and demonstrated significantly higher ACE activity in noninfarcted LV tissue of MI-placebo rats compared with sham (0.64 vs 0.27 nmol.mg protein-1.min-1, P < .05). Enalapril and losartan reduced LV ACE activity (0.39 and 0.29 nmol.mg protein-1.min-1, P < .05 versus MI-placebo).
The present study demonstrates that both chronic ACE inhibition and AT1 receptor blockade (1) reduces cardiac hypertrophy, (2) restores minimal coronary vascular resistance in postinfarction reactive hypertrophy, and (3) attenuates the development of myocardial interstitial fibrosis in the noninfarcted LV. These results suggest that inhibition of generation of angiotensin II and AT1 receptor blockade are equally effective in preventing important features of ventricular remodeling after myocardial infarction.