Effect of 4-Aminopyridine on Action Potential Parameters in Isolated Dog Purkinje Fibers

INTRODUCTION: 4-Aminopyridine (fampridine), a potassium channel blocker, has demonstrated efficacy in improving lower extremity strength and walking speed in patients with multiple sclerosis. Since in vitro electrophysiologic studies are recommended for evaluating a drug's potential to prolong the QT interval and induce such cardiac arrhythmias as Torsades de Pointes, we examined the electrophysiologic effects of 4-aminopyridine (0.5, 5.0, 50, and 500 microM) on isolated canine Purkinje fibers. METHODS: Microelectrodes monitored the resting membrane potential, overshoot, amplitude of action potential (AP), and maximal rate of depolarization of the AP upstroke in Purkinje fibers stimulated at 0.5 and 1.0 Hz. RESULTS: None of the above variables were altered in the presence of 4-aminopyridine. The AP duration at 30%, 50%, and 90% repolarization was also monitored, with only the 500-microM concentration at the 1.0-Hz frequency significantly increasing these values with respect to baseline (P < 0.05). However, the small sample size (N = 4) was small. The proportional increases, and their 95% confidence intervals, were 90.8% (-36.4%, 218.0%), 25.8% (11.9%, 39.7%), and 22.0% (14.9%, 29.1%) for APD 30%, 50%, and 90% repolarization, respectively. Reverse rate dependence was not observed, suggesting inhibition of ion channels other than those contributing to QT interval prolongation.