Comparative frequency-dependent effects of three class Ic agents, Org 7797, flecainide, and propafenone, on ventricular action potential duration.
The frequency-dependent electrophysiological effects of three class Ic agents, Org 7797 (0.5-5 microM), flecainide (1-20 microM), and propafenone (1-10 microM), were investigated using isolated guinea pig papillary muscle. Transmembrane cellular action potentials were recorded using conventional microelectrode techniques at driving frequencies of 0.3, 1.0, and 2.0 Hz. In concentrations inducing similar frequency-dependent decreases in Vmax, both flecainide and propafenone shortened action potential duration (APD) at the two lower stimulation frequencies, whereas increasing the driving frequency to 2 Hz attenuated drug-induced APD shortening. In contrast, Org 7797 did not shorten APD at any stimulation frequency, and indeed APD lengthening was observed at 2.0 Hz. Increases in the effective refractory period (ERP) were seen at 1.0 and 2.0 Hz in the presence of Org 7797 and at 2.0 Hz in the presence of flecainide, but ERP was either unchanged (2.0 Hz) or shortened by propafenone. The rate of onset of sodium channel block was faster in response to propafenone compared to Org 7797 and flecainide. It was concluded that all three drugs may inhibit outward repolarising potassium currents, especially at higher stimulation frequencies. However, the concentrations of Org 7797 necessary to influence repolarisation may be closer to those required to induce sodium channel block compared to flecainide and especially propafenone. These differences may influence drug-induced effects on wavelength resulting in differences in antifibrillatory efficacy.
Winslow
E
E
Department of Pharmacology, Organon Laboratories Limited, Newhouse, Lanarkshire, Scotland.
Campbell
J K
JK
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004963:Estrenes / Q000494:pharmacology*; D005424:Flecainide / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D011405:Propafenone / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D004963:Estrenes; D015222:Sodium Channels; D011405:Propafenone; C061028:Org 7797; D005424:Flecainide