Dexmedetomidine exhibits antiarrhythmic effects on human-induced pluripotent stem cell-derived cardiomyocytes through a Na/Ca channel-mediated mechanism.

BACKGROUND

Ventricular-like human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibit the electrophysiological characteristics of spontaneous beating. Previous studies demonstrated that dexmedetomidine (DMED), a highly selective and widely used α-adrenoceptor agonist for sedation, analgesia, and stress management, may induce antiarrhythmic effects, especially ventricular tachycardia. However, the underlying mechanisms of the DMED-mediated antiarrhythmic effects remain to be fully elucidated.

METHODS

A conventional patch-clamp recording method was used to investigate the direct effects of DMED on spontaneous action potentials, pacemaker currents ( ), potassium (K) channel currents ( and ), sodium (Na) channel currents ( ), and calcium (Ca) channel currents ( ) in ventricular-like hiPSC-CMs.

RESULTS

DMED dose-dependently altered the frequency of ventricular-like spontaneous action potentials with a half-maximal inhibitory concentration (IC) of 27.9 µM (n=6) and significantly prolonged the action potential duration at 90% repolarization (APD). DMED also inhibited the amplitudes of the and without affecting the activation and inactivation curves of these channels. DMED decreased the time constant of the Na and Ca channel activation at potential -40 to -20 mv, and -20 mv. DMED increased the time constant of inactivation of the Na and Ca channels. However, DMED did not affect the , , , and their current-voltage relationship. The ability of DMED to decrease the spontaneous action potential frequency and the Na and Ca channel amplitudes, were not blocked by yohimbine, idazoxan, or phentolamine.

CONCLUSIONS

DMED could inhibit the frequency of spontaneous action potentials and decrease the and of hiPSC-CMs via mechanisms that were independent of the α-adrenoceptor, the imidazoline receptor, and the α-adrenoceptor. These inhibitory effects on hiPSC-CMs may contribute to the antiarrhythmic effects of DMED.