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ENDOCRINE AND DIABETES

Iptakalim, a Vascular ATP-Sensitive Potassium (K_ATP) Channel Opener, Closes Rat Pancreatic -Cell K_ATP Channels and Increases Insulin Release

Department of Physiology, Hirosaki University School of Medicine, Zaifucho, Japan (N.M., S.S., M.W.); Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, California (X.M., Y.-F.L.); Divisions of Neurology (G.-H.L., Q.L., J.W.) and Neurobiology (Y.C.), Barrow Neurological Institute, Phoenix, Arizona; and Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China (H.W., J.W.)

Sulfonylureas have been the leading oral antihyperglycemic agents, and they presently continue to be the most popular antidiabetic drugs prescribed for treatment of type 2 diabetes. However, concern has arisen over the side effects of sulfonylureas on the cardiovascular system. Here, we tested the hypothesis that iptakalim, a novel vascular ATP-sensitive potassium (K_ATP) channel opener, closes rat pancreatic -cell K_ATP channels and increases insulin release. Rat pancreatic -cell K_ATP channels and heterologously expressed K_ATP channels in both human embryonic kidney (HEK) 293 cells and Xenopus oocytes were used to test the pharmacological effects of iptakalim. Patch-clamp recordings, Ca²⁺ imaging, and measurements of insulin release were applied. Patch-clamp whole-cell recordings revealed that iptakalim depolarized -cells, induced action potential firing, and reduced K_ATP channel-mediated currents. Single-channel recordings revealed that iptakalim reduced the open probability of K_ATP channels without changing channel sensitivity to ATP. By closing -cell K_ATP channels, iptakalim elevated intracellular Ca²⁺ concentrations and increased insulin release. In addition, iptakalim decreased the open probability of recombinant Kir6.2FL4A (a trafficking mutant of the Kir6.2) K_ATP channels heterologously expressed in HEK 293 cells, suggesting that iptakalim suppressed the function of -cell K_ATP channels by directly inhibiting the Kir6.2 subunit. Finally, iptakalim inhibited Kir6.2/SUR1, but it activated Kir6.1/SUR2B (vascular-type), K_ATP channels heterologously expressed in Xenopus oocytes. Iptakalim bidirectionally regulated pancreatic-type and vascular-type K_ATP channels, and this unique pharmacological property suggests the potential use of iptakalim as a new therapeutic strategy for treating type 2 diabetes with the additional benefit of alleviating vascular disorders.

Address correspondence to: Dr. Jie Wu, Neurology Research, Barrow Neurological Institute, 350 West Thomas Rd., Phoenix, AZ 85013-4496. E-mail: jie.wu{at}chw.edu