Repercussions of pharmacologic reduction in ionic currents on action potential configuration in rabbit Purkinje fibers: Are they indicative of proarrhythmic potential?

The evaluation of the cardiac safety of newly developed drugs by electrophysiological studies are today mandatory in several countries. A number of experimental models performed either on multicellular preparations or on native or cloned ionic channels have been used but the predictivity of the results remains a matter of debate, particularly if a drug exerts mixed ionic channel-blocking effects. The present study was designed to scrutinize the repercussions of selectively decreasing the main ionic currents which play a role in the repolarization process. Using conventional microelectrodes, action potentials were recorded from rabbit Purkinje fibers stimulated at 1 Hz and 0.2 Hz and exposed to a broad range of cumulative and increasing concentrations. The compounds used were 1) potassium channel blockers (4-aminopyridine, dofetilide, terikalant, and indapamide), 2) chloride current blocker (4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid), and 3) calcium channel antagonists (nifedipine, verapamil, and cadmium). It appears from our results that the modifications observed in the repolarization phase and in the spike-and-dome aspect showed that the antagonists evaluated were not as specific as one would expected and that they affected action potential profiles as a result of additional nonspecific effects which may influence the incidence of proarrhythmic events. In conclusion, we propose the use of rabbit Purkinje fibers as an in vitro model adequate for the evaluation of the cardiac safety of newly developed drugs. Drug Dev. Res. 47:63–76, 1999. © 1999 Wiley-Liss, Inc.