(Circulation. 2000;102:1556.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade Prevent Cardiac Remodeling in Pigs After Myocardial Infarction
Role of Tissue Angiotensin II
From the Departments of Internal Medicine I (J.P.v.K., M.P.S., F.B., M.A.D.H.S.), Experimental Cardiology (J.P.v.K., D.J.D., D.B.H., R.N., R.S., P.D.V.), and Pharmacology (M.P.S., A.H.J.D.), Erasmus University Rotterdam, Rotterdam, the Netherlands.
Correspondence to A.H.J. Danser, PhD, Department of Pharmacology, Room EE1418b, Erasmus University Rotterdam, Dr. Molewaterplein 50, 3015 GE Rotterdam, Netherlands. E-mail danser{at}farma.fgg.eur.nl
Background—The mechanisms behind the beneficial effects of renin-angiotensin system blockade after myocardial infarction (MI) are not fully elucidated but may include interference with tissue angiotensin II (Ang II).
Methods and Results—Forty-nine pigs underwent coronary artery ligation or sham operation and were studied up to 6 weeks. To determine coronary angiotensin I (Ang I) to Ang II conversion and to distinguish plasma-derived Ang II from locally synthesized Ang II, 125I-labeled and endogenous Ang I and II were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during 125I-Ang I infusion. Ang II type 1 (AT1) receptor–mediated uptake of circulating 125I-Ang II was increased at 1 and 3 weeks in noninfarcted LV, and this uptake was the main cause of the transient elevation in Ang II levels in the noninfarcted LV at 1 week. Ang II levels and AT1 receptor–mediated uptake of circulating Ang II were reduced in the infarct area at all time points. Coronary Ang I to Ang II conversion was unaffected by MI. Captopril and the AT1 receptor antagonist eprosartan attenuated postinfarct remodeling, although both drugs increased cardiac Ang II production. Captopril blocked coronary conversion by >80% and normalized Ang II uptake in the noninfarcted LV. Eprosartan did not affect coronary conversion and blocked cardiac Ang II uptake by >90%.
Conclusions—Both circulating and locally generated Ang II contribute to remodeling after MI. The rise in tissue Ang II production during angiotensin-converting enzyme inhibition and AT1 receptor blockade suggests that the antihypertrophic effects of these drugs result not only from diminished AT1 receptor stimulation but also from increased stimulation of growth-inhibitory Ang II type 2 receptors.
Key Words: angiotensin • inhibitors • receptors • myocardial infarction • hypertrophy
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