Carvedilol blocks the repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes.
Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]am ino]-2-propanol), a beta-adrenoceptor-blocking agent with vasodilator properties, has been reported to produce dose-related improvements in left ventricular function and reduction in mortality in patients with chronic heart failure. 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 microelectrode techniques. In ventricular myocytes, carvedilol blocked the rapidly activating component of the delayed rectifier K+ current (I(Kr)) in a concentration-dependent manner (IC50 = 0.35 microM). 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 affect the extent of I(Kr) block. Carvedilol also inhibited the L-type Ca2+ current (I(Ca)), the transient outward K+ current (I(to)) and the slowly activating component of the delayed rectifier K+ current (I(Ks)) with IC50 of 3.59, 3.34, and 12.54 microM, respectively. Carvedilol (0.3-30 microM) had no significant 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 microM and by 12-24% with 3 microM carvedilol at stimulation frequencies of 0.1-3.0 Hz. No further action potential duration prolongation was observed at concentrations higher than 3 microM. These results suggest that concomitant block of K+ and Ca2+ currents by carvedilol resulted in a moderate prolongation of action potential duration with minimal reverse frequency-dependence. Such electrophysiological effects of carvedilol would be beneficial in the treatment of ventricular tachyarrhythmias.
Cheng
J
J
School of Life Science and Medical Engineering, Tongji University, Shanghai, China.
Niwa
R
R
Kamiya
K
K
Toyama
J
J
Kodama
I
I
D000200:Action Potentials; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D020746:Calcium Channels, L-Type; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D051668:Delayed Rectifier Potassium Channels; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits
D000319:Adrenergic beta-Antagonists; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002227:Carbazoles; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D011412:Propanolamines; D000077261:Carvedilol