Abstract
The effects of a novel vasorelaxant agent, MCC-134 (1-[4-(1H-imidazol-1-yl)benzoyl]-N-methyl-cyclobutanecarbothioamide), were examined on reconstituted ATP-sensitive K+(KATP) channels, which are composed of an inwardly rectifying K+ channel, Kir6.2, and three types of sulfonylurea receptors (SUR): SUR1, SUR2A, and SUR2B. Each type of KATP channel was heterologously expressed in human embryonic kidney 293T cells. The expressed KATP channel currents were measured with the whole-cell configuration of the patch-clamp method. MCC-134 activated the SUR2B/Kir6.2 channel, was a weak activator of the SUR2A/Kir6.2 channel, but did not activate the SUR1/Kir6.2 channel. MCC-134 suppressed SUR1/Kir6.2 channel currents that had been fully activated by either diazoxide or NaCN, whereas it did not affect the fully activated SUR2A/Kir6.2 or SUR2B/Kir6.2 channel currents. Thus, MCC-134, which is a relatively effective opener of the vascular smooth muscle type (SUR2B) of KATP channel, is an antagonist of the pancreatic type (SUR1) of KATP channel. Therefore, depending on the subtype of SUR, a pharmacological agent can cause either activation or inhibition of KATP channel activity.
Footnotes
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Send reprint requests to: Dr. Yoshihisa Kurachi, Department of Pharmacology II, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail:ykurachi{at}pharma2.med.osaka-u.ac.jp
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↵1 This work was supported by the Research Grant for Cardiovascular Disease (IIC-I) from the Ministry of Health and Welfare; grants from the Ministry of Education, Science, Sports and Culture of Japan; the “Research for the Future” Program from The Japan Society for the Promotion of Science (JSPS-RFTF96L00302); and the Human Frontier Science Program (RG0158/1997-B).
- Abbreviations:
- KATP channel
- ATP-sensitive K+ channel
- KNDP
- NDP-sensitive K+channel
- KCO
- K+ channel opener
- HEK
- human embryonic kidney
- SUR
- sulfonylurea receptor
- Kir
- inwardly rectifying K+ channel
- Received May 13, 1999.
- Accepted September 14, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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