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Angiotensin II Receptors in Normal and Failing Human Hearts^*

Department of Heart Cleveland, Ohio 44195–5071
Department of Hypertension Research Cleveland, Ohio 44195–5071
Department of Thoracic Cleveland, Ohio 44195–5071
Department of Cardiovascular Surgery Cleveland, Ohio 44195–5071

Address all correspondence and requests for reprints to: Ahsan Husain, Ph.D., Department of Heart and Hypertension Research, Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195–5071.

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 (K_d, 1 nmol/L) and low capacity (B_max, 3 fmol/mg membrane protein) and were pharmacologically specific [IC⁵⁰ values for Ang II, [Sar¹Ile⁸]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 µmol/L, inhibited [¹²⁵I]Ang II binding by <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.

^* This work was supported in part by a grant from the Reinberger Foundation, NIH Grant HL-33713, and a postdoctoral fellowship (to H.U.) from the American Heart Association, Northeast Ohio Affiliate.

Received December 16, 1988.

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