The affinity of (?)-propranolol for ? 1- and ? 1-autoreceptors of human heart

Abstract

An appraisal of the affinity of (−)-propranolol was made for β-adrenoceptors of isolated heart preparations and myocardial membrane particles from patients undergoing open heart surgery. In order to eliminate possible distorting influences of neuronal and extraneuronal uptakes of catecholamines on the affinity estimates for (−)-propranolol, isolated tissues were pretreated once with 5 or 10 μmol/l phenoxybenzamine for 2 h. Phenoxybenzamine caused potentiation of the positive inotropic effects of (−)-noradrenaline and (−)-adrenaline but not of (−)-isoprenaline; potentiation was more pronounced in atrial than in ventricular preparations. Potentiation was greater for (−)-noradrenaline than for (−)-adrenaline. It is concluded that the concentration of physiological catecholamines at the human heart β-adrenoceptors is limited by neuronal capture but not by extraneuronal uptake. The antagonism of the positive inotropic effects of (−)-adrenaline and (−)-noradrenaline by (−)-propranolol was simple competitive in left ventricular myocardium of patients with mitral lesion. The effects of (−)-adrenaline and (−)-noradrenaline were antagonized to similar extent by (−)-propranolol. An equilibrium dissociation constant K _B (-log mol/l) of 8.6 was estimated for (−)-propranolol. In atrial preparations the inotropic effects of (−)-adrenaline were antagonized significantly more by (−)-propranolol than those of (−)-noradrenaline. K _B-Values (-log mol/l) of 8.9 [against (−)-adrenaline] and 8.5 [against (−)-noradrenaline] were estimated for (−)-propranolol. Concentration-effect curves for the stimulation of adenylate cyclase of both atrium and ventricle were biphasic for (−)-noradrenaline and monophasic for (−)-adrenaline. The high-sensitivity and low-sensitivity components of (−)-noradrenaline comprised 1/3 and 2/3, respectively, of maximum cyclase stimulation. As expected from β ₁-adrenoceptors, the high-sensitivity component of the curve for (−)-noradrenaline was selectively antagonized by (−)-bisoprolol; as expected from β ₂-adrenoceptors, the low-sensitivity component was selectively antagonized by ICI 118,551. (−)-Propranolol antagonized the effects by (−)-noradrenaline mediated by β ₂-adrenoceptors 2 to 3 times more potently than the effects mediated by β ₁-adrenoceptors. (−)-Propranolol competed with ³H-(−)-bupranolol for binding to left ventricular β-adrenoceptors. An equilibrium dissociation constant (-log mol/l) of 8.6 was estimated for (−)-propranolol. It is concluded that in human heart the positive inotropic effect of (−)-noradrenaline are mediated mostly through β ₁-adrenoceptors in left ventricle and right atrium, as manifested from the antagonism by (−)-propranolol. On left ventricle (−)-adrenaline causes most of its positive inotropic effects through β ₁-adrenoceptors, on right atrium through both β ₁- and β ₂-adrenoceptors. Adenylate cyclase stimulation by physiological catecholamines appears to be mediated predominantly through β ₂-adrenoceptors in both atrium and ventricle.