The affinity of (-)-propranolol for beta 1- and beta 2-adrenoceptors of human heart. Differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (-)-noradrenaline and (-)-adrenaline.
An appraisal of the affinity of (-)-propranolol was made for beta-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 mumol/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 beta-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 KB (-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. KB-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 beta 1-adrenoceptors, the high-sensitivity component of the curve for (-)-noradrenaline was selectively antagonized by (-)-bisoprolol; as expected from beta 2-adrenoceptors, the low-sensitivity component was selectively antagonized by ICI 118,551. (-)-Propranolol antagonized the effects of (-)-noradrenaline mediated by beta 2-adrenoceptors 2 to 3 times more potently than the effects mediated by beta 1-adrenoceptors. (-)-Propranolol competed with 3H-(-)-bupranolol for binding to left ventricular beta-adrenoceptors. An equilibrium dissociation constant (-log mol/l) of 8.6 was estimated for (-)-propranolol.(ABSTRACT TRUNCATED AT 400 WORDS)
D000262:Adenylyl Cyclases / Q000378:metabolism*; D002046:Bupranolol / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008566:Membranes / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010643:Phenoxybenzamine / Q000494:pharmacology; D011433:Propranolol / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013237:Stereoisomerism; D013268:Stimulation, Chemical
D002395:Catecholamines; D011943:Receptors, Adrenergic, beta; D010643:Phenoxybenzamine; D002046:Bupranolol; D011433:Propranolol; D000262:Adenylyl Cyclases; D009638:Norepinephrine; D004837:Epinephrine