pH-dependent actions of 4-aminopyridine on atrial repolarization: effects on the transient outward current

Abstract

Effects of extracellular pH (pHo) were examined on the changes in atrial repolarization induced by 4-aminopyridine (4AP), which is a selective blocker of the transient outward potassium channel, I(to). Action potential parameters were measured, using the conventional microelectrode technique, in the absence and presence of 4AP (0.1-3.0 mM) at pHo 6.5, 7.25, and 8.0. Phase 1 amplitude served as an index of I(to). The onset and recovery kinetics of phase 1 amplitude were assessed at a basic cycle length of 0.5 s, and time constants (tau on and tau r) were computed. Both onset and recovery kinetics had monoexponential functions. Tonic blockade was influenced by external pH, and Kd for half block was 0.19, 0.44, and 2.43 mM for pHo 8.0, 7.25, and 6.5, respectively. Phasic block was defined and exhibited cycle length dependence. Phasic block was also modified by external pH with the greatest effect at pHo 8.0. 4AP (0.3 mM) accelerated tau on, 0.62 +/- 0.2, 0.55 +/- 0.1, and 2.0 +/- 0.8 beats for pHo 8.0, 7.25, and 6.5 compared with control 6.8 +/- 1.9, 6.3 +/- 1.9, and 5.1 +/- 1.4 beats. In contrast, 4AP slowed tau r by about 1 s from control value to 1.5 +/- 0.5 s at pHo 6.5, 4.8 +/- 1.5 s at pHo 7.25 (p < 0.05), and 5.7 +/- 2.0 s at pHo 8.0. We conclude that an increase in extracellular pH enhances block of Ito induced by 4AP, whereas low pHo attenuates the block.