Drug-Induced hERG Current Enhancement is Modulated by Extracellular Proton and Potassium

Abstract

Acid-base disturbances and hypokalemia or hyperkalemia are frequently encountered in a variety of clinical scenarios. Extracellular proton and potassium concentrations are important modulators of hERG channel functions and biophysical properties such as deactivation and inactivation. Slowing deactivation and inactivation kinetics of hERG channel are two important components for drug-induced hERG current enhancement. This study examined if drug-induced hERG current enhancement is affected by acid-base and electrolyte aberrations at physiological temperature (37° C). Whole-cell voltage clamp technique was used to measure hERG current (step-ramp protocol: initial 1-sec depolarization step to 0 mV from −80 mV (VH) followed by a 2-sec repolarization ramp back to VH) and a typical hERG activator A-935142 was used as a tool drug. Drug-induced hERG current enhancement was potentiated by extracellular acidification (% increase for step current: 132 ± 5 vs. 58.4 ± 4.2, pH 6.8 vs. 7.4, P < 0.01; % increase for tail current: 115 ± 3 vs. 43.2 ± 3.2, P < 0.01). In contrast, alkalosis (pH 8.4) weakened the drug-induced hERG current enhancement (% increase for step: 30.3 ± 3.1 vs. 58.4 ± 4.2, pH 8.4 vs 7.4, P < 0.01; % increase for tail: 21.9 ± 2.3 vs. 43.2 ± 3.2, P < 0.01). The measured bath drug concentrations were the same at normal pH, acidosis, and alkalosis. Hypokalemia (1 mM K+) did not affect drug-induced hERG current enhancement but hyperkalemia (10 mM K+) attenuated the drug-induced hERG current enhancement (increase for step: 41.1 ± 1.6% vs. 58.4 ± 4.2%, 10 mM vs. 5 mM K+, P < 0.01; increase for tail: 31.5 ± 1.3 % vs. 43.2 ± 3.2 %, P < 0.05). These results demonstrate that hERG current enhancement by A-935142 is modulated by extracellular proton concentrations and hyperkalemia.