Characteristic Effects of .ALPHA.1-.BETA.1,2-Adrenergic Blocking Agent, Carvedilol, on [Ca2+]i in Ventricular Myocytes Compared With Those of Timolol and Atenolol.

Abstract

Beta-adrenergic stimulation and the resultant Ca(2+) load both seem to be associated with progression of heart failure as well as hypertrophy. Because the alpha(1)-, beta(1,2)-blocker, carvedilol, has been shown to be outstandingly beneficial in the treatment of heart failure, its direct effects on intracellular calcium ion concentration ([Ca(2+)](i)), including antagonism to isoproterenol, in ventricular myocytes were investigated and then compared with a selective beta(1)-blocker, atenolol, and a non-selective beta(1,2)-blocker, timolol. At 1-300 nmol/L, carvedilol decreased the amplitude of [Ca(2+)] (i) by approximately 20% independently of its concentration, which was a similar effect to timolol. All the beta-blockers at 10 nmol/L decreased the amount of cAMP, but atenolol had the least effect. Carvedilol in the micromol/L order further diminished the amplitude of [Ca(2+)](i) transients, and at 10 micromol/L increased the voltage threshold for pacing myocytes. These effects were not observed with timolol or atenolol. L-type Ca2+ currents (I(Ca)) were decreased by carvedilol in the micromol/L order in a concentration dependent manner. As for the beta-antagonizing effect, the concentrations of carvedilol, timolol, and atenolol needed to prevent the effect of isoproterenol by 50% (IC(50)) were 1.32, 2.01, and 612 nmol/L, respectively. Furthermore, the antagonizing effect of carvedilol was dramatically sustained even after removal of the drug from the perfusate. Carvedilol exerts negative effects on [Ca(2+)](i), including inhibition of the intrinsic beta-activity, reduction of I(Ca) in the micromol/L order, and an increase in the threshold for pacing at > or =10 micromol/L. Data on the IC(50) for the isoproterenol effect suggest that carvedilol could effectively inhibit the [Ca(2+)](i) load induced by catecholamines under clinical conditions.