Carvedilol blocks the repolarizing K+ currents and the L-type Ca2+ currentin rabbit ventricular myocytes

Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino] -2-propanol), a beta-adrenoceptor-blocking agent with vasodilator propertie s, has been reported to produce dose-related improvements in left ventricul ar function and reduction in mortality in patients with chronic heart failu re. However, its electrophysiological effects have not been elucidated. We studied ion channel and action potential modulation by carvedilol in rabbit ventricular preparations using whole-cell voltage-clamp and standard micro electrode techniques. In ventricular myocytes, carvedilol blocked the rapid ly activating component of the delayed rectifier K+ current (I-Kr) in a con centration-dependent manner (IC50 = 0.35 mu M). This block was voltage- and time-independent; a prolongation of the depolarizing pulses from a holding potential of -50 mV to +10 mV within the range of 100-3000 ms did not affe ct the extent of I-Kr block. Carvedilol also inhibited the L-type Ca2+ curr ent (I-Ca), the transient outward K+ current (I-to) and the slowly activati ng component of the delayed rectifier K+ current (I-Ks) with IC50 of 3.59, 3.34, and 12.54 mu M, respectively. Carvedilol (0.3-30 mu M) had no signifi cant effects on the inward rectifier K+ current. In papillary muscles from rabbits pretreated with reserpine, action potential duration was prolonged by 7-12% with 1 mu M and by 12-24% with 3 mu M carvedilol at stimulation fr equencies of 0.1-3.0 Hz. No further action potential duration prolongation was observed at concentrations higher than 3 mu M. These results suggest th at concomitant block of K+ and Ca2+ currents by carvedilol resulted in a mo derate prolongation of action potential duration with minimal reverse frequ ency-dependence. Such electrophysiological effects of carvedilol would be b eneficial in the treatment of ventricular tachyarrhythmias. (C) 1999 Elsevi er Science B.V. All rights reserved.