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Vol. 286, Issue 1, 9-22, July 1998

Ionic Mechanism of Ibutilide in Human Atrium: Evidence for a Drug-Induced Na+ Current Through a Nifedipine Inhibited Inward Channel

Kai S. Lee and Esther W. Lee

Department of Pharmacology, Pharmacia And Upjohn, Kalamazoo, Michigan

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- 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- 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- 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, with Kd 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.

0022-3565/98/2861-0009$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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