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Iptakalim, a vascular ATP-sensitive potassium (KATP) channel opener, closes rat pancreatic beta-cell KATP channels and increases insulin release.
J Pharmacol Exp Ther. 2007 Aug; 322(2):871-8.JP

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.

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Authors+Show Affiliations

Misaki N
Department of Physiology, Hirosaki University School of Medicine, Zaifucho, Japan.
Mao X
No affiliation info available
Lin YF
No affiliation info available
Suga S
No affiliation info available
Li GH
No affiliation info available
Liu Q
No affiliation info available
Chang Y
No affiliation info available
Wang H
No affiliation info available
Wakui M
No affiliation info available
Wu J
No affiliation info available

MeSH

AnimalsCalciumCell LineCells, CulturedDiazoxideDose-Response Relationship, DrugFemaleGlucoseHumansInsulinInsulin-Secreting CellsIon Channel GatingKATP ChannelsMembrane PotentialsNifedipineOocytesPotassium Channel BlockersPotassium Channels, Inwardly RectifyingPropylaminesRatsTolbutamideXenopus laevis

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17522344

Citation

Misaki, Naoko, et al. "Iptakalim, a Vascular ATP-sensitive Potassium (KATP) Channel Opener, Closes Rat Pancreatic Beta-cell KATP Channels and Increases Insulin Release." The Journal of Pharmacology and Experimental Therapeutics, vol. 322, no. 2, 2007, pp. 871-8.
Misaki N, Mao X, Lin YF, 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. 2007;322(2):871-8.
Misaki, N., Mao, X., Lin, Y. F., Suga, S., Li, G. H., Liu, Q., Chang, Y., Wang, H., Wakui, M., & Wu, J. (2007). Iptakalim, a vascular ATP-sensitive potassium (KATP) channel opener, closes rat pancreatic beta-cell KATP channels and increases insulin release. The Journal of Pharmacology and Experimental Therapeutics, 322(2), 871-8.
Misaki N, 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. 2007;322(2):871-8. PubMed PMID: 17522344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Iptakalim, a vascular ATP-sensitive potassium (KATP) channel opener, closes rat pancreatic beta-cell KATP channels and increases insulin release. AU - Misaki,Naoko, AU - Mao,Xia, AU - Lin,Yu-Fung, AU - Suga,Sechiko, AU - Li,Guo-Hui, AU - Liu,Qiang, AU - Chang,Yongchang, AU - Wang,Hai, AU - Wakui,Makoto, AU - Wu,Jie, Y1 - 2007/05/23/ PY - 2007/5/25/pubmed PY - 2007/9/21/medline PY - 2007/5/25/entrez SP - 871 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 322 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/17522344/Iptakalim_a_vascular_ATP_sensitive_potassium__KATP__channel_opener_closes_rat_pancreatic_beta_cell_KATP_channels_and_increases_insulin_release_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17522344 DB - PRIME DP - Unbound Medicine ER -