DCPIB is a novel selective blocker of I-Cl,I-swell and prevents swelling-induced shortening of guinea-pig atrial action potential duration

1 We identified the ethacrynic-acid derivative DCPIB as a potent inhibitor of I-Cl,I-swell, which blocks native I-Cl,I-swell of calf bovine pulmonary artery endothelial (CPAE) cells with an IC50 of 4.1 muM. Similarly, 10 (muM ) DCPIB almost completely inhibited the swelling-induced chloride conductan ce in Xenopus oocytes and in guinea-pig atrial cardiomyocytes. Block of I-C l,I-swell by DCPIB was fully reversible and voltage independent. 2 DCPIB (10 muM) showed selectivity for I-Cl,I-swell and had no significant inhibitory effects on I-Cl,I-Ca in CPAE cells, on chloride currents elicit ed by several members of the CLC-chloride channel family or on the human cy stic fibrosis transmembrane conductance regulator (hCFTR) after heterologou s expression in Xenopus oocytes. DCPIB (10 muM) also showed no significant inhibition of several native anion and cation currents of guinea pig heart like I-Cl,I-PKA, I-Kr, I-Ks, I-Kl, 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 durati on (APD). Both swelling-induced chloride conductance and AP shortening were inhibited by treatment of swollen cells with DCPIB (10 muM). In agreement with the selectivity for I-Cl,I-swell, DCPIB did not affect atrial APD unde r isoosmotic conditions. 4 Preincubation of atrial cardiomyocytes with DCPIB (10 muM) completely pre vented both the swelling-induced chloride currents and the AP shortening bu t 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,I-swell. DCPIB therefore is a valuab le pharmacological tool to study the role of I-Cl,I-swell in cardiac excita bility under pathophysiological conditions leading to cell swelling.