Iptakalim, a Vascular Atp-sensitive Potassium (Katp) Channel Opener, Closes Rat Pancreatic Beta-cell Katp Channels and Increases Insulin Release.
From: Department of Physiology, Hirosaki University School of Medicine, Zaifucho, Japan.
The Journal of pharmacology and experimental therapeutics
- Publish Date: Aug 2007
- ISSN: 0022-3565
- Volume: 322
- Issue: 2
- Pages: 871-8
- Medium: Print
- Language: English
- Citation (JAMA): Misaki Naoko, Mao Xia, Lin Yu-Fung, et al. Iptakalim, a Vascular Atp-sensitive Potassium (Katp) Channel Opener, Closes Rat Pancreatic Beta-cell Katp Channels and Increases Insulin Release.. J. Pharmacol. Exp. Ther. Aug 2007;322:871-8
Abstract
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.
Mesh Headings (Keywords): Animals, Calcium, Cell Line, Cells, Cultured, Diazoxide, Dose-Response Relationship, Drug, Female, Glucose, Humans, Insulin, Insulin-Secreting Cells, Ion Channel Gating, Membrane Potentials, Nifedipine, Oocytes, Potassium Channel Blockers, Potassium Channels, Inwardly Rectifying, Propylamines, Rats, Tolbutamide, Xenopus laevis
Check for Full Text / PubMed Unique Identifier (PMID): 17522344
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