Transient outward current inhibition by propafenone and 5-hydroxypropafenone in cultured neonatal rat ventricular myocytes

The antiarrhythmic agent propafenone and its primary electropharmacologically active metabolite, 5-hydroxypropafenone, are known inhibitors of cardiac myocyte repolarizing currents. We recently documented potent propafenone inhibition of the transient outward potassium current (I-to) in human atrial myocytes from patients in the newborn and infant age range. In the current study we characterized ventricular Ito inhibition by propafenone and 5-hydroxypropafenone in neonatal myocytes enzymatically isolated from 2-day-old Sprague-Dawley rat pups. Using the whole-cell patch-clamp technique in ventricular myocytes kept in primary culture for 1-4 days, we observed comparably potent I-to inhibition by both agents, yielding 50% maximal inhibitory concentration (IC50) values of 2.1 +/- 0.5 and 1.5 +/- 0.2 muM for propafenone and 5-hydroxypropafenone, respectively. Ito blockade by both of these agents was time. concentration, and voltage dependent, but use independent. There was no drug effect on steady-state voltage dependence of I-to inactivation, or on the time course of I-to recovery from inactivation. These findings are consistent with an open channel-blocking mechanism as suggested by other models. We conclude that both propafenone and 5-hydroxypropafenone are potent I-to inhibitors in neonatal rat ventricular myocytes, with potencies exceeding those demonstrated for propafenone in adult rat ventricular myocytes or in human atrial myocytes from patients of all ages.