Proton inhibition of transient outward potassium current in rat ventricular myocytes

Acidosis elicited during myocardial ischemia is a significant pathophysiological condition markedly affecting the electrical and contractile properties of heart muscle. We examined the effects of protons on K channel activity in rat ventricular myocytes by recording transient outward (Ito) and inward rectifier (IKl) K+ currents using the whole cell, voltage clamp technique. Proton concentration was controlled by independently varying the pH of HEPES-buffered external (pHo) or pipette (pHp) solutions. Mean Ito density in myocytes preconditioned in acidic external solution (pHo 6.0) for 15-20 min was significantly less than control cells equilibrated at physiological pHo. In contrast, IKl was not changed during this period of acidosis. External acidification did not decrease Ito when initiated after intracellular dialysis with standard pHp 7.2. However, when myocytes were dialyzed with acidic pHp, Ito density was significantly less than control, while alkaline pHp had little effect. Despite marked reduction in current density produced by low pHp solutions, steady-state activation and inactivation parameters of Ito were not significantly altered. In addition, the reversal potential of this current, kinetics of inactivation, and recovery from inactivation were not significantly affected by acidic or alkaline pHp solutions. Acidic pHp alone did not change IKl density compared with control, but when combined with Na+/H+ exchange blockade with 5-(N,N-dimethyl)-amiloride or Na(+)-free external solution, IKl density was significantly reduced. Our data suggest that protons inhibit Ito predominantly from the intracellular side of the channel, possibly by altering its conductance or gating properties. Moreover, intracellular protons differentially affect Ito and IKl channels, with the former exhibiting greater sensitivity for a given level of acidosis.