Acidic extracellular pH-activated outwardly rectifying chloride current in mammalian cardiac myocytes

Abstract

Extracellular acidic pH was found to induce an outwardly rectifying Cl−current ( ICl,acid) in mouse ventricular cells, with a half-maximal activation at pH 5.9. The current showed the permeability sequence for anions to be SCN−> Br−> I−> Cl−> F−> aspartate, while it exhibited a time-dependent activation at large positive potentials. Similar currents were also observed in mouse atrial cells and in atrial and ventricular cells from guinea pig. Some Cl−channel blockers (DIDS, niflumic acid, and glibenclamide) inhibited ICl,acid, whereas tamoxifen had little effect on it. Unlike volume-regulated Cl−current ( ICl,vol) and CFTR Cl−current ( ICl,CFTR), ICl,acidwas independent of the presence of intracellular ATP. Activation of ICl,acidappeared to be also independent of intracellular Ca2+and G protein. ICl,acidand ICl,volcould develop in an additive fashion in acidic hypotonic solutions. Isoprenaline-induced ICl,CFTRwas inhibited by acidification in a pH-dependent manner in guinea pig ventricular cells. Our results support the view that ICl,acidand ICl,volstem from two distinct populations of anion channels and that the ICl,acidchannels are present in cardiac cells. ICl,acidmay play a role in the control of action potential duration or cell volume under pathological conditions, such as ischemia-related cardiac acidosis.