Iptakalim, a vascular ATP-sensitive potassium (KATP) channel opener, closes rat pancreatic beta-cell KATP channels and increases insulin release. 2007

Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
Department of Physiology, Hirosaki University School of Medicine, Zaifucho, Japan.

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 beta-cell K(ATP) channels and increases insulin release. Rat pancreatic beta-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, Ca(2+) imaging, and measurements of insulin release were applied. Patch-clamp whole-cell recordings revealed that iptakalim depolarized beta-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 beta-cell K(ATP) channels, iptakalim elevated intracellular Ca(2+) 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 beta-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.

UI MeSH Term Description Entries
D007328 Insulin A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1). Iletin,Insulin A Chain,Insulin B Chain,Insulin, Regular,Novolin,Sodium Insulin,Soluble Insulin,Chain, Insulin B,Insulin, Sodium,Insulin, Soluble,Regular Insulin
D008564 Membrane Potentials The voltage differences across a membrane. For cellular membranes they are computed by subtracting the voltage measured outside the membrane from the voltage measured inside the membrane. They result from differences of inside versus outside concentration of potassium, sodium, chloride, and other ions across cells' or ORGANELLES membranes. For excitable cells, the resting membrane potentials range between -30 and -100 millivolts. Physical, chemical, or electrical stimuli can make a membrane potential more negative (hyperpolarization), or less negative (depolarization). Resting Potentials,Transmembrane Potentials,Delta Psi,Resting Membrane Potential,Transmembrane Electrical Potential Difference,Transmembrane Potential Difference,Difference, Transmembrane Potential,Differences, Transmembrane Potential,Membrane Potential,Membrane Potential, Resting,Membrane Potentials, Resting,Potential Difference, Transmembrane,Potential Differences, Transmembrane,Potential, Membrane,Potential, Resting,Potential, Transmembrane,Potentials, Membrane,Potentials, Resting,Potentials, Transmembrane,Resting Membrane Potentials,Resting Potential,Transmembrane Potential,Transmembrane Potential Differences
D009543 Nifedipine A potent vasodilator agent with calcium antagonistic action. It is a useful anti-anginal agent that also lowers blood pressure. Adalat,BAY-a-1040,Bay-1040,Cordipin,Cordipine,Corinfar,Fenigidin,Korinfar,Nifangin,Nifedipine Monohydrochloride,Nifedipine-GTIS,Procardia,Procardia XL,Vascard,BAY a 1040,BAYa1040,Bay 1040,Bay1040,Monohydrochloride, Nifedipine,Nifedipine GTIS
D009865 Oocytes Female germ cells derived from OOGONIA and termed OOCYTES when they enter MEIOSIS. The primary oocytes begin meiosis but are arrested at the diplotene state until OVULATION at PUBERTY to give rise to haploid secondary oocytes or ova (OVUM). Ovocytes,Oocyte,Ovocyte
D011437 Propylamines Derivatives of propylamine (the structural formula NH2CH2CH2CH3).
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D003981 Diazoxide A benzothiadiazine derivative that is a peripheral vasodilator used for hypertensive emergencies. It lacks diuretic effect, apparently because it lacks a sulfonamide group. Hyperstat,Proglycem
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response

Related Publications

Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
December 2011, Acta pharmacologica Sinica,
Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
September 2010, Journal of cardiovascular pharmacology,
Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
March 2000, Kidney international,
Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
January 2012, Journal of pharmacology & pharmacotherapeutics,
Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
January 2005, Cardiovascular drug reviews,
Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
May 2013, Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology,
Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
November 2011, Journal of biomedical research,
Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
September 2004, Life sciences,
Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
June 2006, Acta pharmacologica Sinica,
Naoko Misaki, and Xia Mao, and Yu-Fung Lin, and Sechiko Suga, and Guo-Hui Li, and Qiang Liu, and Yongchang Chang, and Hai Wang, and Makoto Wakui, and Jie Wu
September 2010, The Journal of physiology,
Copied contents to your clipboard!