Iptakalim, a vascular ATP-sensitive potassium (KATP) channel opener, closes rat pancreatic beta-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 (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.
Misaki
Naoko
N
Department of Physiology, Hirosaki University School of Medicine, Zaifucho, Japan.
Mao
Xia
X
Lin
Yu-Fung
YF
Suga
Sechiko
S
Li
Guo-Hui
GH
Liu
Qiang
Q
Chang
Yongchang
Y
Wang
Hai
H
Wakui
Makoto
M
Wu
Jie
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015640:Ion Channel Gating / Q000187:drug effects; D054086:KATP Channels; D008564:Membrane Potentials / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D014044:Tolbutamide / Q000494:pharmacology; D014982:Xenopus laevis; D000099161:Kcnj11 Channel
D002118:Calcium; D003981:Diazoxide; D005947:Glucose; D007328:Insulin; D054086:KATP Channels; D009543:Nifedipine; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011437:Propylamines; D014044:Tolbutamide; D000099161:Kcnj11 Channel; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; C092520:uK-ATP-1 potassium channel