MCC-134, a novel vascular relaxing agent, is an inverse agonist for the pancreatic-type ATP-sensitive K(+) channel.
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(+) (K(ATP)) 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 K(ATP) channel was heterologously expressed in human embryonic kidney 293T cells. The expressed K(ATP) 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 K(ATP) channel, is an antagonist of the pancreatic type (SUR1) of K(ATP) channel. Therefore, depending on the subtype of SUR, a pharmacological agent can cause either activation or inhibition of K(ATP) channel activity.
Shindo
T
T
Department of Pharmacology II, Graduate School of Medicine, Osaka University, Osaka, Japan.
Katayama
Y
Y
Horio
Y
Y
Kurachi
Y
Y
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D019976:Cloning, Organism; D003981:Diazoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000196:embryology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D010179:Pancreas / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D011955:Receptors, Drug / Q000145:classification / Q000235:genetics; D012966:Sodium Cyanide / Q000494:pharmacology; D064233:Sulfonylurea Receptors; D013854:Thioamides / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; C577508:Abcc8 protein, mouse; C577509:Abcc8 protein, rat; C577511:Abcc9 protein, mouse; D007093:Imidazoles; C403079:MCC 134; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D013854:Thioamides; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; D003981:Diazoxide; D012966:Sodium Cyanide