title: 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 microM. 3 microM carvedilol was found to decrease the peak I(Ca)(,T) amplitude at -20 mV from 20.1+/-1.8pA/pF to 10.9+/-2.1pA/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 (tau) 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.
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangzhou, PR China.
authors.forename: Chunyu
authors.initials: C
authors.lastname: Deng
authors.forename: Fang
authors.initials: F
authors.lastname: Rao
authors.forename: Shulin
authors.initials: S
authors.lastname: Wu
authors.forename: Sujuan
authors.initials: S
authors.lastname: Kuang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Liu
authors.forename: Zhiling
authors.initials: Z
authors.lastname: Zhou
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Shan
authors.forename: Qiuxiong
authors.initials: Q
authors.lastname: Lin
authors.forename: Weimin
authors.initials: W
authors.lastname: Qian
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Geng
authors.forename: Youyi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiyong
authors.initials: X
authors.lastname: Yu
authors.forename: Shuguang
authors.initials: S
authors.lastname: Lin
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002460:Cell Line; D004553:Electric Conductivity; D007546:Isoquinolines / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D018408:Patch-Clamp Techniques; D011412:Propanolamines / Q000494:pharmacology*; D013449:Sulfonamides / Q000378:metabolism
chemical_list: D020747:Calcium Channels, T-Type; D002227:Carbazoles; D007546:Isoquinolines; D011412:Propanolamines; D013449:Sulfonamides; D000077261:Carvedilol; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium