PRAJMALIUM, AN ANTIARRHYTHMIC WITH POSITIVE INOTROPIC EFFECT - MECHANISM OF ACTION IN RABBIT SINGLE CARDIOMYOCYTES

The propyl derivative of ajmaline, N-n-propylajmaline (prajmalium), is an antiarrhythmic compound that lacks the commonly reported negative inotropic effects of all others under clinical use. The present study was undertaken to establish and understand its effects at the cellular level in mammalian preparations. Electrical and mechanical activities were recorded from right ventricular strips and Na and L-type Ca currents (I(Na) and I(CaL), respectively) were recorded with the whole-cell patch-clamp technique in right ventricular myocytes freshly dissociated from rabbit hearts. Prajmalium decreased the maximal rate of depolarization of the action potential in a dose-dependent manner with an EC50 of 3-mu-M. This effect was use and frequency dependent. Action potential duration was increased by 1-mu-M prajmalium but decreased on applying higher concentrations. The force of contraction was slightly (15%) increased at 0.1-mu-M, not affected at all at 1-mu-M and depressed by 30% at 20-mu-M. In single cardiomyocytes maintained at negative holding potentials, I(Na) was slightly depressed by prajmalium at 10 nM and reduced by 75% at 10-mu-M. I(caL) was increased by 30 and 20% on applying prajmalium at 1 and 10-mu-M, respectively; on the other hand, I(CaL) was reduced by these two concentrations of prajmalium at less negative holding potentials. A higher prajmalium concentration (100-mu-M) decreased I(CaL) at all holding potentials studied and this effect was enhanced with depolarization. The increase in I(CaL) induced by prajmalium (1-mu-M) was also observed after I(CaL) had been fully beta-adrenergic and P2-purinergic stimulated by isoproterenol (1-mu-M) in the presence of IBMX (100-mu-M and ATP (10-mu-M). It is concluded that prajmalium is able to increase I(CaL) in rabbit ventricular cells in a voltage-dependent manner, an effect that could account in part for the observed lack of negative inotropism of this antiarrhythmic in clinics.