Acidosis Impairs the Protective Role of hERG K⁺ Channels Against Premature Stimulation

Abstract

During acidosis the contribution of I(hERG) to action potential repolarization is reduced and hERG may be less effective in counteracting proarrhythmogenic depolarizing stimuli.

Effects of pH on Nifekalant-Induced Electrophysiological Change Assessed in the Langendorff Heart Model of Guinea Pigs

“…2B. This decrease in phase 2 amplitude of MAP is consistent with previous reports (9,19,20), which has been ascribed to a decrease in plateau-phase Ca 2+ influx (19,21). Meanwhile, with regard to the shortening of MAP duration, some studies reported that a decrease in extracellular pH shortens the action potential duration (22 -25), but the others described opposite results (26,27).…”

“…Meanwhile, with regard to the shortening of MAP duration, some studies reported that a decrease in extracellular pH shortens the action potential duration (22 -25), but the others described opposite results (26,27). It has been reported that under acidic condi- tions, H + directly binds to I Kr and I Ca channels, resulting in their current inhibitions (11,19,20,28). Inhibition of I Kr channels causes the prolongation of MAP duration, whereas inhibition of I Ca channels leads to its shortening.…”

hERG K+Channels: Structure, Function, and Clinical Significance

“…Multiple groups have also reported that the changes in deactivation and suppression of G max had different pH sensitivities (26,64,262), and this likely explains some of the discrepancies between studies in which different pH ranges were used. Nevertheless, the overall effect is to cause a reduction of the amount of I Kr that will flow during the action potential (152), which contributes to the action potential prolongation observed during acidosis (63).…”

Proton block of the pore underlies the inhibition of hERG cardiac K+ channels during acidosis

“…Investigations into the effects of acidosis on hERG channel function demonstrate an extracellular proton-induced reduction in peak current amplitude (1,4,27,54,57) and an acceleration of deactivation (1,2,4,25,27,54,57); action potential simulation studies suggest that these actions cause a predisposition to arrhythmia by reducing the protection against premature stimulation (13). Furthermore, extracellular acidosis has recently been shown to reduce the binding affinity of some antiarrhythmic drugs (15).…”