EFFECTS OF HYPERKALEMIA, ACIDOSIS, AND HYPOXIA ON THE DEPRESSION OF MAXIMUM RATE OF DEPOLARIZATION BY CLASS-I ANTIARRHYTHMIC DRUGS IN GUINEA-PIG MYOCARDIUM - DIFFERENTIAL ACTIONS OF CLASS-IB AND CLASS-IC AGENTS

Standard microelectrode methods were used to record intracellular action potentials from strips of guinea pig right ventricular myocardium superfused with either standard physiological saline (pH 7.3; PO2 > 650 mm Hg; [K+] = 5.6 mM) or the same solution modified to produce either hyperkalemia ([K+] = 11.2 mM), acidosis (pH = 6.3), or hypoxia (PO2 = 60 mm Hg). The effects on action potential parameters of three therapeutic concentration of lidocaine, flecainide, and encainide were studied under all four conditions at four different drive rates (interstimulus interval = 2,400, 1,200, 600, and 300 ms). Hyperkalemia in the absence of drugs produced reductions in resting potential (-87.9 +/- 3.8 to -74.6 +/- 3.3 mV), maximum rate of depolarization (316 +/- 68 to 240 +/- 12 V/s), and action potential duration (178 +/- 21 to 165 +/- 27 ms). All three drugs produced increased depression of V(max) in hyperkalemia compared to control conditions but, at all three concentrations and all four rates, this enhancement of effect was greater for lidocaine than for either of the other two agents (which did not differ significantly from each other; p < 0.001). Similar though less marked effects were produced by acidosis (3.5 mV depolarization and 19% reduction in V(max)), and once again the depression of V(max) by lidocaine was enhanced more by this intervention than were the actions of encainide or flecainide (p < 0.01). Hypoxia had no effect on action potential parameters other than duration and no significant modulation of drug actions was seen for this intervention. It is concluded that of the electrophysiological changes induced by ischemia, those due to hyperkalemia are the most important in causing enhanced depression of V(max) by class I antiarrhythmic agents and that lidocaine (subclass Ib) is significantly more selective under such conditions than encainide or flecainide (subclass Ic).