Characteristic effects of alpha1-beta1,2-adrenergic blocking agent, carvedilol, on [Ca2+]i in ventricular myocytes compared with those of timolol and atenolol.
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.
Yao
Atsushi
A
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan. atsushiyao@aol.com
Kohmoto
Osami
O
Oyama
Tomomi
T
Sugishita
Yasuyuki
Y
Shimizu
Tatsuya
T
Harada
Kazumasa
K
Matsui
Hiroshi
H
Komuro
Issei
I
Nagai
Ryozo
R
Matsuo
Hiroshi
H
Serizawa
Takashi
T
Maruyama
Takashi
T
Takahashi
Toshiyuki
T
D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D006168:Guinea Pigs; D006352:Heart Ventricles; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009994:Osmolar Concentration; D011412:Propanolamines / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013999:Timolol / Q000494:pharmacology*
D018674:Adrenergic Antagonists; D000319:Adrenergic beta-Antagonists; D020746:Calcium Channels, L-Type; D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D001262:Atenolol; D013999:Timolol; D002118:Calcium