Angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade prevent cardiac remodeling in pigs after myocardial infarction : Role of tissue angiotensin II

• Published in: Circulation (New York, N.Y.) N.Y.), 2000-09, Vol.102 (13), p.1556-1563
• Main Authors: VAN KATS, Jorge P, DUNCKER, Dirk J, HAITSMA, David B, SCHUIJT, Martin P, NIEBUUR, Remko, STUBENITSKY, René, BOOMSMA, Frans, SCHALEKAMP, Maarten A. D. H, VERDOUW, Pieter D, DANSER, A. H
• Format: Article
• Language: English
• Subjects: Angiotensin II - blood; Animals; Biological and medical sciences; Captopril - blood; Cardiology. Vascular system; Coronary heart disease; Heart; Medical sciences; Models, Cardiovascular; Myocardial Infarction - blood; Peptidyl-Dipeptidase A - blood; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin - blood; Swine
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.102.13.1556

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). 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, (125)I-labeled and endogenous Ang I and II were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during (125)I-Ang I infusion. Ang II type 1 (AT(1)) receptor-mediated uptake of circulating (125)I-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 AT(1) 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 AT(1) 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%. 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 AT(1) receptor blockade suggests that the antihypertrophic effects of these drugs result not only from diminished AT(1) receptor stimulation but also from increased stimulation of growth-inhibitory Ang II type 2 receptors.