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.

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I Ks channels are composed of I sK and KvLQT1 subunits and underly the slowly activating, voltagedependent I Ks conductance in heart. Although it appears clear that the I sK protein aects both the biophysical properties and regulation of I Ks channels, its role in channel pharmacology is unclear. In the present study we demonstrate that KvLQT1 homopolymeric K + channels are inhibited by the I Ks blockers 293B, azimilide and 17-b-oestradiol. However, I Ks channels induced by the coexpression of I sK and KvLQT1 subunits have a 6 ± 100 fold higher anity for these blockers. Moreover, the I Ks activators mefenamic acid and DIDS had little eect on KvLQT1 homopolymeric channels, although they dramatically enhanced steady-state currents through heteropolymeric I Ks channels by arresting them in an open state. In summary, the I sK protein modulates the eects of both blockers and activators of I Ks channels. This ®nding is important for the action and speci®city of these drugs as I sK protein expression in heart and other tissues is regulated during development and by hormones.