REGULATION, CHAMBER LOCALIZATION, AND SUBTYPE DISTRIBUTION OF ANGIOTENSIN-II RECEPTORS IN HUMAN HEARTS

Background To assess the chamber localization, subtype distribution, a nd regulation of human myocardial angiotensin II receptors in heart fa ilure, we determined the binding of angiotensin II, Sar(1)Ile(8)-angio tensin II, and the subtype-specific antagonists Dup 753 (AT1-specific) and PD 123319 (AT2-specific) in atria from patients with normal (left ventricular ejection fraction >55%) or moderately impaired (left vent ricular ejection fraction 30% to 55%) cardiac function and in atria an d ventricles from explanted end-stage failing hearts. Sarcolemmal and combined fractions, the latter including internalized receptors, were studied. In addition, AT1 mRNA content was analyzed by polymerase chai n reaction after reverse transcription. Methods and Results The number of angiotensin II binding sites (B-max) in sarcolemmal fractions was significantly reduced in explanted end-stage failing hearts in compari son with control subjects and moderate heart failure (B-max 3.9+/-0.8 versus 11.2+/-1.7 and 9.61+/-0.8 fmol/mg protein, respectively). A com parable 65% reduction in receptor numbers was found in combined fracti ons from end-stage failing hearts, indicating that the loss of binding sites was not due to their internalization. The dissociation constant s were comparable in sarcolemmal and combined fractions and in nonfail ing and failing hearts, ranging from 0.5+/-0.2 to 1.2+/-0.5 nmol/L. In nonfailing hearts, 69+/-4% of binding sites were blocked by the subty pe-2-specific inhibitor PD 123319 and were therefore classified as AT2 ; 33+/-5% were blocked by the subtype-1-specific inhibitor DUP 753 and thus classified as subtype 1. In explanted hearts, comparable ratios of 66+/-5% AT2 sites and 34+/-5% AT1 sites were found. AT1 cDNA amplif ication signals by polymerase chain reaction were reduced to about one third of the level in control subjects in end-stage failing hearts. C onclusions Angiotensin II receptors in human myocardium are present in relatively low numbers, and AT2 is the predominant subtype. A signifi cant loss of angiotensin II receptors occurs in end stage but not in m oderate heart failure. The loss of receptors affects both subtypes to a comparable degree. The data suggest that the decrease in receptor de nsity is due to a decrease in steady-state mRNA abundance.