title: Inhibitory effects of glibenclamide on cystic fibrosis transmembrane regulator, swelling-activated, and Ca(2+)-activated Cl- channels in mammalian cardiac myocytes.
abstract: Recent studies have provided evidence that sulfonylureas, in addition to blocking ATP-sensitive K+ (KATP) channels, also inhibit cystic fibrosis transmembrane regulator (CFTR) Cl- channels in epithelial and cardiac cells. The purpose of this study was to test whether the sulfonylurea glibenclamide might also inhibit other types of cardiac Cl- channels. Whole-cell patch-clamp techniques were used to compare the effects of glibenclamide on CFTR Cl- currents in guinea pig ventricular myocytes, swelling-activated Cl- currents in guinea pig atrial myocytes, and Ca(2+)-activated Cl- currents in canine ventricular myocytes. Glibenclamide markedly inhibited CFTR Cl- currents in a voltage-independent manner at 22 degrees C, with estimated IC50 values of 12.5 and 11.0 mumol/L at +50 and -100 mV, respectively. The outwardly rectifying swelling-activated Cl- current in atrial cells was less sensitive to glibenclamide, and the block exhibited voltage dependence. At 22 degrees C, the estimated IC50 values were 193 and 470 mumol/L at +50 and -100 mV, respectively, and block was enhanced at 35 degrees C. Macroscopic Cl- currents activated by a rise in intracellular Ca2+, induced by either Ca(2+)-induced Ca2+ release or by external application of the Ca2+ ionophore A23187, were also markedly inhibited at 22 degrees C by glibenclamide in a voltage-independent manner. The estimated IC50 values were 61.5 and 69.9 mumol/L at +50 and -100 mV, respectively. These results suggest that glibenclamide, an inhibitor of cardiac CFTR Cl- channels, also inhibits swelling-activated and Ca(2+)-activated Cl- channels at higher concentrations. The results also suggest that studies attributing the beneficial or deleterious effects of sulfonylurea compounds in the heart solely to blockade of KATP channels should use submicromolar concentrations of these agents to minimize possible secondary interactions with cardiac Cl- channels.
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno 89557-0046, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yamazaki
authors.forename: J R
authors.initials: JR
authors.lastname: Hume
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018118:Chloride Channels / Q000187:drug effects*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects*; D004285:Dogs; D004594:Electrophysiology; D005905:Glyburide / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D016015:Logistic Models; D008564:Membrane Potentials; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D013997:Time Factors
chemical_list: D018118:Chloride Channels; D007004:Hypoglycemic Agents; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005905:Glyburide; D002118:Calcium