Iptakalim A Vascular Atp-Sensitive Potassium (Katp) Channel Opener Closes Rat Pancreatic Î²-Cell Katp Channels And Increases Insulin Release
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 (KATP) channel opener, closes rat pancreatic Î²-cell KATP channels and increases insulin release. Rat pancreatic Î²-cell KATP channels and heterologously expressed KATP 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 Î²-cells, induced action potential firing, and reduced KATP channel-mediated currents. Single-channel recordings revealed that iptakalim reduced the open probability of KATP channels without changing channel sensitivity to ATP. By closing Î²-cell KATP 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) KATP channels heterologously expressed in HEK 293 cells, suggesting that iptakalim suppressed the function of Î²-cell KATP channels by directly inhibiting the Kir6.2 subunit. Finally, iptakalim inhibited Kir6.2/SUR1, but it activated Kir6.1/SUR2B (vascular-type), KATP channels heterologously expressed in Xenopus oocytes. Iptakalim bidirectionally regulated pancreatic-type and vascular-type KATP 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. Copyright Â© 2007 by The American Society for Pharmacology and Experimental Therapeutics.
Journal of Pharmacology and Experimental Therapeutics
Digital Object Identifier (DOI)
Misaki, Naoko; Mao, Xia; Lin, Yu Fung; Suga, Sechiko; Li, Guo Hui; Liu, Qiang; Chang, Yongchang; Wang, Hai; Wakui, Makoto; and Wu, Jie, "Iptakalim A Vascular Atp-Sensitive Potassium (Katp) Channel Opener Closes Rat Pancreatic Î²-Cell Katp Channels And Increases Insulin Release" (2007). Neurobiology. 153.