Abstract
Beta-adrenergic stimulation and the resultant Ca2+ load both seem to be associated with progression of heart failure as well as hypertrophy. Because the α1-, β1,2-blocker, carvedilol, has been shown to be outstandingly beneficial in the treatment of heart failure, its direct effects on intracellular calcium ion concentration ([Ca2+]i), including antagonism to isoproterenol, in ventricular myocytes were investigated and then comapred with a selective β1-blocker, atenolol, and a non-selective β1,2-blocker, timolol. At 1-300 nmol/L, carvedilol decreased the amplitude of [Ca2+] i by ~20% independently of its concentration, which was a similar effect to timolol. All the β-blockers at 10 nmol/L decreased the amount of cAMP, but atenolol had the least effect. Carvedilol in the μmol/L order further diminished the amplitude of [Ca2+]i transients, and at 10 μmol/L increased the voltage threshold for pacing myocytes. These effects were not observed with timolol or atenolol. L-type Ca2+ currents (ICa) were decreased by carvedilol in the μmol/L order in a concentration dependent manner. As for the β-antagonizing effect, the concentrations of carvedilol, timolol, and atenolol needed to prevent the effect of isoproterenol by 50% (IC50) 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 [Ca2+]i, including inhibition of the intrinsic β-activity, reduction of ICa in the μmol/L order, and an increase in the threshold for pacing at ≥10 μmol/L. Data on the IC50 for the isoproterenol effect suggest that carvedilol could effectively inhibit the [Ca2+]i load induced by catecholamines under clinical conditions. (Circ J 2003; 67: 83 - 90)
