Block of human aorta Kir6.1 by the vascular K-ATP channel inhibitor U37883A

1 A human aorta cDNA library was screened at low stringency with a rat panc reatic Kir6.1 cDNA probe and a homologue of Kir6.1 (hKir6.1) was isolated a nd sequenced. 2 Metabolic poisoning of Xenopus laevis oocytes with sodium azide and appli cation of the K+ channel opener drug diazoxide induced Kf channel currents in oocytes co-injected with cRNA for hKir6.1 and hamster sulphonylurea rece ptor (SUR1), but not in oocytes injected with water or cRNA for hKir6.1 or SUR1 alone. 3 K+ channel currents due to hKir6.1+SUR1 or mouse Kir6.2+ SUR1 were strong ly inhibited by 1 mu M glibenclamide. K+-current carried by hKir6.1+SUR1 wa s inhibited by the putative vascular-selective K-ATP channel inhibitor U378 83A (IC50 32 mu M) whereas current carried by Kir6.2+SUR1 or Shaker K+ chan nels was unaffected. 4 The data support the hypothesis that hKir6.1 is a component of the vascul ar K-ATP channel, although the lower sensitivity of hKir6.1+SUR1 to U37883A compared with native vascular tissues suggests the need for another factor or subunit. Furthermore, the data suggest that pharmacology of K-ATP chann els can be determined by the pore-forming subunit as well as the sulphonylu rea receptor and point to a molecular basis for the pharmacological distinc tion between vascular and pancreatic/cardiac K-ATP channels.