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

Background-The mechanisms behind the beneficial effects of renin-angiotensi n system blockade after myocardial infarction (MI) are not fully elucidated but may include interference with tissue angiotensin II (Ang TI). Methods and Results-Forty-nine pigs underwent coronary artery: ligation or sham operation and were studied up to 6 weeks. To determine coronary angiot ensin I (Ang I) to Ang II conversion and to distinguish plasma-derived Ang II from locally synthesized Ang II,I-125-labeled and endogenous Ang I and I I were measured in plasma and in infarcted and noninfarcted left ventricle (LV) during I-125-Ang I infusion, Ang II type 1 (AT(1)) receptor-mediated u ptake of circulating I-125-Ang II was increased at 1 and 3 weeks in noninfa rcted 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) rec eptor-mediated uptake of circulating Ang II were: reduced in the infarct ar ea at all time points. Coronary Ang I to Ang II conversion was unaffected b y MI. Captopril and the AT(1) receptor antagonist eprosartan attenuated pos tinfarct remodeling, although both drugs increased cardiac Ang Il productio n. Captopril blocked coronary conversion by >80% and normalized Ang LI upta ke in the noninfarcted LV. Eprosartan did not affect coronary conversion an d blocked cardiac Ang LI uptake by >90%. Conclusions-Both circulating and locally generated Ang II contribute to rem odeling after MI. The rise in tissue Ang IJ production during angiotensin-c onverting enzyme inhibition and AT(1) receptor blockade suggests that the a ntihypertrophic effects of these drugs result not only from diminished AT(1 ) receptor stimulation but also from increased stimulation of growth-inhibi tory Ang II type 2 receptors.