Regulation of Myocardial and Vascular a-Adrenergic Receptor Affinity Effects of Guanine Nucleotides, Cations, Estrogen, and Catecholamine Depletion

The threshold sensitivity of cardiovascular tissues to a-adrenergic stimulation is determined largely by the affinity of a-adrenergic receptors for agonists. To determine whether changes in a-adrenergic receptor affinity could contribute to the regulation of cardiac and vascular responsiveness, we used the a-adrenergic-selective radioligands, [H]prazosin, [H]-WB-4101, and [H]rauwalscine, to study and contrast the determinants of a-adrenergic receptor affinity in myocardium and vascular smooth muscle from the rat. In both tissues, /-epinephrine binding to the a, -adrenergic receptor describes a shallow curve suggesting more than one affinity state. Computer analysis of binding to myocardial a^receptors indicates that 15% are of high affinity (Kd = 11 nM) and 85% are of low affinity (Kj = 400 nM). Expression of high affinity sites is magnesium dependent (maximum effect, 5-10 nun), and suppressed by the guanosine 5'triphosphate analogue Gpp(NH)p (maximum effect, 1 mni) and sodium (maximum effect, 100200 HIM). In vascular smooth muscle, agonist-binding curves are also shallow and exhibit a similar response to that of Gpp(NH)p. Basal receptor affinity in myocardium is significantly higher (5.4fold) than in vascular smooth muscle. Unlike vascular smooth muscle, in which ct\ -adrenergic receptor affinity is increased by estrogen or reserpine treatment of the animal, the receptor in myocardium is unaffected by these treatments. In vascular smooth muscle, following reserpineinduced increase in a-adrenergic receptor affinity, the Gpp(NH)p effect is still present. Thus, a,adrenergic receptors in both myocardium and vascular smooth muscle exist in two affinity states and are subject to regulation by several factors, including guanine nucleotides, monoand divalent cations, tissue of origin, sex hormones, and the level of sympathetic stimulation. Potentially, alterations in ai-adrenergic receptor affinity, independent of a change in receptor number, may play an important role in the regulation of cardiovascular tissue responsiveness to catecholamines. (Circ Res 55: 78-88, 1984)