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(2)-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 (I(f)), potassium (K(+)) channel currents (I(K1) and I(Kr)), sodium (Na(+)) channel currents (I(Na)), and calcium (Ca(2+)) channel currents (I(Ca)) 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(50)) of 27.9 µM (n=6) and significantly prolonged the action potential duration at 90% repolarization (APD(90)). DMED also inhibited the amplitudes of the I(Na) and I(Ca) without affecting the activation and inactivation curves of these channels. DMED decreased the time constant of the Na(+) and Ca(2+) channel activation at potential –40 to –20 mv, and –20 mv. DMED increased the time constant of inactivation of the Na(+) and Ca(2+) channels. However, DMED did not affect the I(K1), I(Kr), I(f), and their current-voltage relationship. The ability of DMED to decrease the spontaneous action potential frequency and the Na(+) and Ca(2+) channel amplitudes, were not blocked by yohimbine, idazoxan, or phentolamine. CONCLUSIONS: DMED could inhibit the frequency of spontaneous action potentials and decrease the I(Na) and I(Ca) of hiPSC-CMs via mechanisms that were independent of the α(2)-adrenoceptor, the imidazoline receptor, and the α(1)-adrenoceptor. These inhibitory effects on hiPSC-CMs may contribute to the antiarrhythmic effects of DMED.