Effect of repaglinide on cloned beta cell, cardiac and smooth muscle typesof ATP-sensitive potassium channels

Aims/hypothesis. The carbamoylbenzoic acid derivative repaglinide is a pote nt short-acting insulin secretagogue that acts by closing ATP-sensitive pot assium (K-ATP) channels in the plasma membrane of the pancreatic beta cell. In this paper we investigated the specificity of repaglinide for three typ es of cloned (K-ATP) channel composed of the inwardly rectifying potassium channel Kir6.2 and either the sulphonylurea receptor SUR1, SUR2A or SUR2B, corresponding to the beta cell, cardiac and either smooth muscle types of K -ATP channel, respectively. Methods. The action of the drug was studied by whole-cell current recording s of K-ATP channels expressed either in Xenopus oocytes or mammalian cells (HEK293). We also used inside-out macropatches excised from Xenopus oocytes for detailed analysis of repaglinide action. Results. The drug blocked all three types of K-ATP channel with similar pot ency, by interacting with a low-affinity site on the pore-forming subunit o f the channel (Kir6.2: half-maximal inhibition 230 mu mol/l) and with a hig h-affinity site on the regulatory subunit, the sulphonylurea receptor (SUR: half-maximal inhibition 2-8 nmol/l). There was no difference in potency be tween channels containing SUR1, SUR2A or SUR2B. MgADP potentiated the inhib itory effect of repaglinide on Kir6.2/SUR1 and (to a lesser extent) Kir6.2/ SUR2B, but not on Kir6.2/ SUR2A. Conclusion/interpretation. Repaglinide interacts with a site common to all three types of sulphonylurea receptor leading to inhibition of the K-ATP ch annel. The fact that MgADP potentiated this effect in the case of the beta cell, but not cardiac, type of channel could help explain why the drug show s no adverse cardiovascular side-effects in vivo.