Angiotensin II receptors in normal and failing human hearts

Abstract

To demonstrate the existence and help clarify the function of angiotensin II (Ang II) receptors in the human heart, we characterized the cardiac Ang II receptor and examined the levels and distribution of ventricular Ang II receptors in normal (n = 6) and failing (n = 14) hearts. Ang II receptors were characterized using the Ang II receptor agonist [125I]Ang II. Cardiac [125I]Ang II-binding sites were of high affinity (Kd, approximately 1 nmol/L) and low capacity (Bmax, approximately 3 fmol/mg membrane protein) and were pharmacologically specific [IC50 values for Ang II, [Sar1,Ile8]Ang II, and Ang III were 1.2, 3.0, and 400 nmol/L, respectively; the inactive Ang II metabolite Ang-(1-5), at a concentration of 1 mumol/L, inhibited [125I]Ang II binding by less than 10%]. These characteristics of cardiac [125I]Ang II-binding sites are similar to those of previously characterized mammalian heart Ang II receptors. In normal adult donor hearts (n = 5), Ang II receptor density in the left ventricle [LV, 2.90 +/- 1.40 (+/- SE) fmol/mg] was similar to that in the right ventricle (RV, 3.82 +/- 1.10 fmol/mg). The ventricular Ang II receptor density in adult patients with idiopathic (LV, 1.77 +/- 0.35 fmol/mg; RV, 1.58 +/- 0.29 fmol/mg; n = 8) or dilated cardiomyopathy (LV, 2.00 +/- 0.58 fmol/mg; RV, 2.56 +/- 0.52 fmol/mg n = 5) was similar to that in the normal heart. Ventricular Ang II receptors, localized by autoradiography using the Ang II receptor antagonist [125I]-[Sar1,Ile8]Ang II, were consistently found in the myocardium, cardiac adrenergic nerves, and coronary vessels of normal and failing ventricles. In human ventricles Ang II receptor levels were not correlated with age. Because ventricular Ang II receptor density in a normal neonatal human heart and that in a heart from an adolescent patient with idiopathic cardiomyopathy were more than 10-fold and more than 5-fold higher, respectively, than in normal adult ventricles, we investigated whether postnatal changes occur in ventricular Ang II receptors in rats. In male and female rats ventricular Ang II receptor density was about 2-fold higher in 1-day-old rats compared to that in 10-day-old or peripubertal rats. These data suggest developmental regulation of ventricular Ang II receptors. Our findings suggest that direct and neural angiotensinergic inputs to the myocardium play a role in the regulation of cardiac function in man and that these inputs are preserved in the failing heart.