CLOSURE BY IPTAKALIM, A CARDIOVASCULAR KATP CHANNEL OPENER, OF RAT PANCREATIC β-CELL KATP CHANNELS AND ITS MOLECULAR BASIS

4) Abstract　Diabetes mellitus is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production insulin action or both. Diabetes patients usually have accompanying cardiovascular disorders. Sulfonylureas have been the leading oral antihyperglycemic agents for type 2 diabetes treatment which currently still constitute the most popular anti‑diabetic drugs. Nevertheless concern has arisen over the side eff ects of sulfonylureas on the cardiovascular system. Here we report that iptakalim a novel cardiovascular ATP‑sensitive potassium (KATP) channel opener closed rat pancreatic β‑cell KATP channels and increased insulin release. Using whole‑cell patch‑clamp recordings iptakalim depolarized β‑cells induced action potential fi ring and reduced pancreatic KATP channel currents. Using single‑channel recordings iptakalim reduced KATP channel open‑probability independently of intracellular ATP concentrations. We demonstrated that iptakalim elevated intracellular Ca 2+ concentrations and increased insulin release as revealed by fl uorescence imaging (fura‑2) and biochemical measurements respectively. In addition iptakalim signifi cantly inhibited the open‑probability of recombinant Kir6.2/SUR1 and Kir6.2FL4A (a traffi cking mutant of the Kir6.2) channels expressed in transfected human embryonic kidney (HEK) 293 cells. Collectively iptakalim a cardiovascular KATP channel opener closes rat pancreatic β‑cell KATP channels which may result from direct inhibition of the Kir6.2 subunit. Therefore iptakalim bi‑directionally regulates KATP channels in cardiovascular and pancreatic tissues and this unique pharmacological property suggests iptakalim could be used as a new therapeutic strategy for the treatment of type 2 diabetes with the potential benefi t in alleviating cardiac and/or vascular disorders frequently associated with diabetes. Hirosaki Med.J.　59 Supplement:S89―S100,2007