Abstract

Cardiac expression of angiotensin II (Ang II) AT₁ and AT₂ receptor subtypes is species dependent, and changes in their relative proportion may influence myocardial hypertrophy and fibrosis. Regional differences in the distribution of Ang II receptors in the normal and failing human heart were assessed using¹²⁵I-(Sar¹,Ile⁸)Ang II binding and quantitative autoradiography. Receptor subtypes were distinguished by their affinity for selective nonpeptide antagonists (losartan and PD123319) and sensitivity to dithiothreitol. Ventricular and atrial tissues displayed a heterogeneous distribution of ligand binding sites. AT₂ receptors predominated, representing 70% to 77% of the sites in normal and noninfarcted myocardium. Endocardial, interstitial, perivascular and infarcted regions in the ventricles of patients with end-stage ischemic heart disease or dilated cardiomyopathy exhibited a significantly greater density (P < .001) of high affinity AT₂ binding sites (K_d = 0.57 nmol/liter) compared with adjacent noninfarcted myocardium. Regions displaying the relative increase in AT₂ binding sites corresponded to areas of fibroblast proliferation and collagen deposition, shown by picrosirius red staining. AT₁ binding sites were localized to nerves, occurred at relatively low density in coronary vessels and represented only 23% to 29% of myocardial¹²⁵I-(Sar¹,Ile⁸)Ang II binding sites. The border zone between infarcted and noninfarcted myocardium characteristically contained numerous microvessels, exhibiting perivascular AT₂ receptors and endothelial angiotensin converting enzyme activity, as demonstrated by binding of¹²⁵I-351A. Specific myocardial AT₂ receptor mRNA transcripts (≈3 kb) were identified and exhibited alternative splicing of untranslated 5′ exons. The differential distribution of cardiac Ang II receptor subtypes and selective increase in binding to AT₂ sites in the diseased heart suggest that cells bearing the AT₂ receptor represent a significant target for Ang II, possibly contributing to its growth-related actions.