EFFECT OF INTRACELLULAR AND EXTRACELLULAR ACIDOSIS ON SODIUM CURRENT IN VENTRICULAR MYOCYTES

Conduction slowing is an essential element in the generation of ischem ic ventricular arrhythmias and is determined in part by the inward Na current (I-Na). Because intracellular acidosis is an early consequenc e of ischemia, we hypothesized that lowering intracellular pH (pH(i)) would reduce or kinetically modulate I-Na and thus affect cardiac cond uction. To test this hypothesis, the whole cell patch-clamp method was used to measure I-Na in neonatal rat ventricular myocytes exposed to varying extracellular pH (pH(o) 6.4-7.4), while perfusing the cells wi th acidic solutions (pH(i) 6.2-7.2). With simultaneous acidification o f pH(o) and pH(i) there was a progressive increase in time to peak cur rent, a 31% decrease in peak I-Na (298 +/- 18 to 206 +/- 16 pA/pF), an d a complex slowing of inactivation kinetics. At the most extreme leve ls of acidification, there was a 5-mV hyperpolarizing shift in steady- state inactivation and a 6-mV depolarizing shift in activation. Indepe ndent changes of pH(o) and pH(i) indicate that the reduction of peak I -Na is a function of pH(o). However, steady-state inactivation is modu lated by pH(i). The time course of activation and inactivation appears to depend on both pH(o) and pH(i). We conclude that both intracellula r and extracellular acidosis are significant but distinct modulators o f I-Na amplitude and kinetics in cardiac myocytes.