title: DCPIB is a novel selective blocker of I(Cl,swell) and prevents swelling-induced shortening of guinea-pig atrial action potential duration.
abstract: 1. We identified the ethacrynic-acid derivative DCPIB as a potent inhibitor of I(Cl,swell), which blocks native I(Cl,swell) of calf bovine pulmonary artery endothelial (CPAE) cells with an IC(50) of 4.1 microM. Similarly, 10 microM DCPIB almost completely inhibited the swelling-induced chloride conductance in Xenopus oocytes and in guinea-pig atrial cardiomyocytes. Block of I(Cl,swell) by DCPIB was fully reversible and voltage independent. 2. DCPIB (10 microM) showed selectivity for I(Cl,swell) and had no significant inhibitory effects on I(Cl,Ca) in CPAE cells, on chloride currents elicited by several members of the CLC-chloride channel family or on the human cystic fibrosis transmembrane conductance regulator (hCFTR) after heterologous expression in Xenopus oocytes. DCPIB (10 microM) also showed no significant inhibition of several native anion and cation currents of guinea pig heart like I(Cl,PKA), I(Kr), I(Ks), I(K1), I(Na) and I(Ca). 3. In all atrial cardiomyocytes (n=7), osmotic swelling produced an increase in chloride current and a strong shortening of the action potential duration (APD). Both swelling-induced chloride conductance and AP shortening were inhibited by treatment of swollen cells with DCPIB (10 microM). In agreement with the selectivity for I(Cl,swell), DCPIB did not affect atrial APD under isoosmotic conditions. 4. Preincubation of atrial cardiomyocytes with DCPIB (10 microM) completely prevented both the swelling-induced chloride currents and the AP shortening but not the hypotonic cell swelling. 5. We conclude that swelling-induced AP shortening in isolated atrial cells is mainly caused by activation of I(Cl,swell). DCPIB therefore is a valuable pharmacological tool to study the role of I(Cl,swell) in cardiac excitability under pathophysiological conditions leading to cell swelling.
authors.affiliation: Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, 65926 Frankfurt am Main, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Decher
authors.forename: H J
authors.initials: HJ
authors.lastname: Lang
authors.forename: B
authors.initials: B
authors.lastname: Nilius
authors.forename: A
authors.initials: A
authors.lastname: Brüggemann
authors.forename: A E
authors.initials: AE
authors.lastname: Busch
authors.forename: K
authors.initials: K
authors.lastname: Steinmeyer
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D016275:Atrial Function; D048429:Cell Size / Q000502:physiology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D003517:Cyclopentanes / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects*; D007189:Indans / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D012680:Sensitivity and Specificity; D051672:Shal Potassium Channels; D013997:Time Factors; D014981:Xenopus
chemical_list: C443139:4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-one-5-yl)oxybutyric acid; D018118:Chloride Channels; D003517:Cyclopentanes; D007189:Indans; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator