In vitro cardiac electrophysiological effects of prenylamine.

In order to get information on some of the effects of prenylamine (bradycardic effect, negative inotropic effect, triggering of "torsade de pointes"), we studied with intracellular microelectrodes its electrophysiological actions on guinea-pig sinus node and papillary muscle, on sheep Purkinje fibers and rabbit sino-atrial node isolated myocytes. Prenylamine (10(-6)-10(-5) M) reduced the firing rate of sinus node preparations. This effect was associated with a slowing of the rates of diastolic depolarization, of depolarization and of repolarization, and with a slight depolarization of the maximum diastolic potential. A dose-dependent decrease of the slope of the first 100 msec of the diastolic depolarization was observed. Prenylamine (10(-6) M) also reduced the amplitude of the pacemaker current (If) recorded using the patch-clamp technique from rabbit sino-atrial node cells. Prenylamine (3 x 10(-7)-3 x 10(-6) M) dose-dependently reduced contractility of Purkinje fibers; the effect was associated with a lowering of the plateau, a decrease of the maximum rate of depolarization and a shortening of the action potential duration. Prenylamine was also able to abolish early and delayed after-depolarizations which are two kinds of calcium-dependent electrical activities relevant for the genesis of triggered arrhythmias, such as "torsade de pointes". It is concluded that prenylamine, a nonselective calcium antagonist, presents an intriguing in vitro electrophysiological profile which makes any extrapolation to its in vivo pharmacology extremely complex.