Vol. 292, Issue 1, 131-135, January 2000

MCC-134, a Novel Vascular Relaxing Agent, Is an Inverse Agonist for the Pancreatic-Type ATP-Sensitive K⁺ Channel¹

Takashi Shindo, Yusuke Katayama, Yoshiyuki Horio and Yoshihisa Kurachi

Department of Pharmacology II, Graduate School of Medicine, Osaka University, Osaka, Japan

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.