Summary
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.
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1.
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.
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2.
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.
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3.
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.
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4.
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.
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5.
(−)-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.
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6.
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.
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Gille, E., Lemoine, H., Ehle, B. et al. The affinity of (−)-propranolol for β 1- and β 1-autoreceptors of human heart. Naunyn-Schmiedeberg's Arch. Pharmacol. 331, 60–70 (1985). https://doi.org/10.1007/BF00498852
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DOI: https://doi.org/10.1007/BF00498852