TY - JOUR T1 - Ionic Mechanism of Ibutilide in Human Atrium: Evidence for a Drug-Induced Na<sup>+</sup> Current Through a Nifedipine Inhibited Inward Channel JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 9 LP - 22 VL - 286 IS - 1 AU - Kai S. Lee AU - Esther W. Lee Y1 - 1998/07/01 UR - http://jpet.aspetjournals.org/content/286/1/9.abstract N2 - This study examined the ionic mechanism of ibutilide, a class III antiarrhythmic in clinical use, on freshly isolated human atrial cells. Cells had resting potentials of −71.4 ± 2.4 mV, action potentials with overshoot of 36.8 ± 1.8 mV, duration of 265 ± 89 msec at 90% repolarization and slow repolarization (n = 16). Ibutilide, at 10−7 M, markedly increased action potential duration. Four types of outward currents were detected: Ito, Iso, a delayed rectifier and IK1. Ibutilide had no inhibitory effect on these outward currents at 10−7 M (n = 28). In K+-free solutions and −40 mV holding potential, mean peak inward current at 20 mV was −1478 ± 103 pA (n = 12). Ibutilide increased this current to −2347 ± 75 pA at 10−7 M, with half maximal effect (Kd) of 0.1 to 0.9 nM between −10 and +40 mV (n = 21). At similar concentrations, the drug increased APD, withKd of 0.7 and 0.23 nM at 70 and 90% repolarization, respectively (n = 8). Ibutilide shifted the mid-point of the steady-state inactivation curve from −21 to −12.2 mV (n = 6), and reduced current decline during repetitive depolarization (n = 5). The drug induced inward current was carried by Na+o through a nifedipine inhibited inward channel because Na+o removal eliminated the effect, and nifedipine abolished the inward current and the drug induced APD prolongation. We propose that a Na+ current through the L-type Ca++ channel mediates ibutilide’s potent clinical class III antiarrhythmic action. The American Society for Pharmacology and Experimental Therapeutics ER -