Molecular basis of the different effects of procainamide and N-acetylprocainamide on the maximum upstroke velocity and half-decay time of the cardiac action potential in guinea pig papillary muscle

Abstract

Procainamide (PA) and its in vivo metabolite, N-acetylprocainamide (NAPA), display some pharmacological differences. Although it is agreed that PA is a class IA antiarrhythmic, it has been reported that NAPA is a pure class III antiarrhythmic that affects only the repolarizing phase of the cardiac action potential. This last concept, observed exclusively in dogs, gained wide acceptance, appearing in classic pharmacology textbooks. However, evidence in species such as mice and rats indicates that NAPA can affect cardiac Na+ channels, which is unexpected for a pure class III antiarrhythmic drug. To further clarify this issue, the effects of PA (used as a reference drug) and NAPA on the maximum upstroke velocity (Vmax) and half-decay time (HDT) of the cardiac action potential were examined in the isolated right papillaris magnus of the guinea pig heart. Both PA and NAPA affected Vmax at lower concentrations than required to affect HDT, and NAPA had weaker effects on both variables. Thus, NAPA displayed typical class IA antiarrhythmic behavior. Therefore, the concept that NAPA is a pure class III antiarrhythmic drug is more species-dependent than previously envisioned. In addition, we demonstrated that the differential pharmacology of PA and NAPA is explainable, in molecular terms, by steric hindrance of the effects of NAPA and the greater number of potent aromatic-aromatic and cation π interactions with Na+ or K+ cardiac channels for PA.

Figure 1. Chemical structures of procainamide (A) and N-acetylprocainamide (B).

Figure 2. Digitized recordings of typical action potentials recorded intracellularly in the right papillary muscle of a guinea pig. In the control situation, the values of the corresponding electrophysiological variables were as follows: maximum upstroke velocity of the action potential (Vmax): 134 V/s; half-decay time of the action potential (HDT): 187 ms; and resting membrane potential (RMP): -83 mV. In the presence of procainamide (PA, 7 mM) the values were: Vmax: 42 V/s, HDT: 578 ms, and RMP: -86 mV. In the presence of N-acetylprocainamide (NAPA, 7 mM) the values were: Vmax: 48 V/s, HDT: 420 ms, and RMP: -82 mV. Vm: membrane potential.

Figure 3. Effects of procainamide (PA) and N-acetylprocainamide (NAPA) on the maximum upstroke velocity (Vmax) of action potentials in guinea pig papillary muscle. Data are reported as means±SE of Vmax of action potentials recorded in 5-8 cells under each condition (*P<0.05, ANOVA followed by Tukey's test) for the difference in Vmax induced by PA and NAPA at similar concentrations of 3.5 or 7.0 mM.

Figure 4. Effects of procainamide (PA) and N-acetylprocainamide (NAPA) on the half-decay time (HDT) of action potentials in guinea pig papillary muscle. Data are reported as means±SE of HDT of action potentials recorded in 5-8 cells for each condition (*P<0.05, ANOVA followed by Tukey's test) for difference in HDT induced by PA and NAPA at a similar concentration of 7.0 mM.