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In this study we investigated the effects of the putative cardioselective sulphonylurea derivative HMR 1098 on ATP-sensitive potassium (K(ATP)) channels from cardiac ventricular myocytes, the INS-1 beta-cell line and from recombinant K(ATP) channels composed of SUR2A/Kir6.2, SUR1/Kir6.2, SUR1/Kir6.1 an Kir6.2,DeltaC26. Recombinant channels were expressed in tsA201 or COS-1 cells. The effects of HMR 1098 on single channel and whole-cell currents were recorded using the patch-clamp technique. At the single channel level, using excised inside-out membrane patches, HMR 1098 inhibited K(ATP) channels from ventricular cells and INS-1 cells with IC(50)s of 0.88 and 720 microM respectively. Similar results to those in cardiac cells were obtained using recombinant SUR2A/Kir6.2 K(ATP) channels. HMR 1098 inhibition of SUR2A/Kir6.2 K(ATP) channels was unaffected by the presence of internal ADP. In whole-cell recordings, HMR 1098 inhibited SUR2A/Kir6.2 and SUR1/Kir6.2 currents with IC(50)s of 2.1 and 860 microM respectively. HMR 1098 was without effect on currents either from the Kir6.2,DeltaC26 truncation mutant or from Kir2.1. Our results demonstrate that HMR 1098 is a selective inhibitor of cardiac K(ATP) channels, showing a 400 - 800-fold selectivity over beta-cell K(ATP) channels. The non-aromatic substitutions in the sulphonylurea moiety greatly increase the cardioselectivity of this compound while reducing the overall blocking potency of this sulphonylurea derivative.

In this study we investigated the effects of the putative cardioselective sulphonylurea derivative HMR 1098 on ATP-sensitive potassium (K(ATP)) channels from cardiac ventricular myocytes, the INS-1 beta-cell line and from recombinant K(ATP) channels composed of SUR2A/Kir6.2, SUR1/Kir6.2, SUR1/Kir6.1 an Kir6.2,DeltaC26. Recombinant channels were expressed in tsA201 or COS-1 cells. The effects of HMR 1098 on single channel and whole-cell currents were recorded using the patch-clamp technique. At the single channel level, using excised inside-out membrane patches, HMR 1098 inhibited K(ATP) channels from ventricular cells and INS-1 cells with IC(50)s of 0.88 and 720 microM respectively. Similar results to those in cardiac cells were obtained using recombinant SUR2A/Kir6.2 K(ATP) channels. HMR 1098 inhibition of SUR2A/Kir6.2 K(ATP) channels was unaffected by the presence of internal ADP. In whole-cell recordings, HMR 1098 inhibited SUR2A/Kir6.2 and SUR1/Kir6.2 currents with IC(50)s of 2.1 and 860 microM respectively. HMR 1098 was without effect on currents either from the Kir6.2,DeltaC26 truncation mutant or from Kir2.1. Our results demonstrate that HMR 1098 is a selective inhibitor of cardiac K(ATP) channels, showing a 400 - 800-fold selectivity over beta-cell K(ATP) channels. The non-aromatic substitutions in the sulphonylurea moiety greatly increase the cardioselectivity of this compound while reducing the overall blocking potency of this sulphonylurea derivative.