Pharmacological effects of carvedilol on T-type calcium current in murine HL-1 cells

Abstract Carvedilol is widely used in the treatment of cardiovascular diseases including atrial fibrillation. T-type Ca 2+ channels have been recognized recently in the mechanisms underlying atrial arrhythmias. However, it is unclear whether carvedilol may affect the T-type Ca 2+ channel. The present study evaluated the pharmacological effects of carvedilol on T-type calcium current ( I Ca,T ) in the murine HL-1 cell line. I Ca ,T was recorded by the whole-cell patch–clamp technique. Calcium transient was monitored by the fluorescent dye Fluo-4/AM and confocal laser scanning microscopy. Carvedilol reversibly inhibited I Ca ,T in a concentration-dependent manner, with an IC50 of 2.1 µM. 3 µM carvedilol was found to decrease the peak I Ca ,T amplitude at − 20 mV from 20.1 ± 1.8 pA/pF to 10.9 ± 2.1 pA/pF. Carvedilol significantly shifted the steady-state inactivation curve of I Ca ,T towards more negative potential by 12.8 mV, while the activation curve was not significantly altered. Carvedilol delayed recovery from inactivation of I Ca ,T , time constant ( τ ) was 112.4 ± 3.5 ms in control and 270.1 ± 4.7 ms in carvedilol. Carvedilol-induced inhibition rate in I Ca ,T was enhanced with the increase in stimuli frequency, the inhibitory rate was 23.2 ± 4.1% at 0.2 Hz and 47.2 ± 0.6% at 2 Hz. Carvedilol still produced the significant decrease in the amplitude of I Ca ,T in the presence of H-89, PKA inhibitor. Carvedilol significantly inhibited the amplitude of the calcium transient in a concentration-dependent manner. These findings indicate that carvedilol inhibits I Ca ,T in atrial cells by mechanisms involving preferential interaction with the inactivated state of T-type Ca 2+ channel.