TY - JOUR
T1 - Iptakalim, a vascular ATP-sensitive potassium (KATP) channel opener, closes rat pancreatic β-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
PY - 2007/8
Y1 - 2007/8
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 (KATP) channel opener, closes rat pancreatic β-cell KATP channels and increases insulin release. Rat pancreatic β-cell KATP channels and heterologously expressed KATP channels in both human embryonic kidney (HEK) 293 cells and Xenopus oocytes were used to test the pharmacological effects of iptakalim. Patch-clamp recordings, Ca2+ imaging, and measurements of insulin release were applied. Patch-clamp whole-cell recordings revealed that iptakalim depolarized β-cells, induced action potential firing, and reduced KATP channel-mediated currents. Single-channel recordings revealed that iptakalim reduced the open probability of KATP channels without changing channel sensitivity to ATP. By closing β-cell KATP channels, iptakalim elevated intracellular Ca2+ concentrations and increased insulin release. In addition, iptakalim decreased the open probability of recombinant Kir6.2FL4A (a trafficking mutant of the Kir6.2) KATP channels heterologously expressed in HEK 293 cells, suggesting that iptakalim suppressed the function of β-cell KATP channels by directly inhibiting the Kir6.2 subunit. Finally, iptakalim inhibited Kir6.2/SUR1, but it activated Kir6.1/SUR2B (vascular-type), KATP channels heterologously expressed in Xenopus oocytes. Iptakalim bidirectionally regulated pancreatic-type and vascular-type KATP 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.
AB - 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 (KATP) channel opener, closes rat pancreatic β-cell KATP channels and increases insulin release. Rat pancreatic β-cell KATP channels and heterologously expressed KATP channels in both human embryonic kidney (HEK) 293 cells and Xenopus oocytes were used to test the pharmacological effects of iptakalim. Patch-clamp recordings, Ca2+ imaging, and measurements of insulin release were applied. Patch-clamp whole-cell recordings revealed that iptakalim depolarized β-cells, induced action potential firing, and reduced KATP channel-mediated currents. Single-channel recordings revealed that iptakalim reduced the open probability of KATP channels without changing channel sensitivity to ATP. By closing β-cell KATP channels, iptakalim elevated intracellular Ca2+ concentrations and increased insulin release. In addition, iptakalim decreased the open probability of recombinant Kir6.2FL4A (a trafficking mutant of the Kir6.2) KATP channels heterologously expressed in HEK 293 cells, suggesting that iptakalim suppressed the function of β-cell KATP channels by directly inhibiting the Kir6.2 subunit. Finally, iptakalim inhibited Kir6.2/SUR1, but it activated Kir6.1/SUR2B (vascular-type), KATP channels heterologously expressed in Xenopus oocytes. Iptakalim bidirectionally regulated pancreatic-type and vascular-type KATP 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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U2 - 10.1124/jpet.107.121129
DO - 10.1124/jpet.107.121129
M3 - Article
C2 - 17522344
AN - SCOPUS:34547122225
SN - 0022-3565
VL - 322
SP - 871
EP - 878
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -