Electrophysiological actions of a novel K + channel opener MCC-134 on rabbit portal vein smooth muscle

Abstract

The effects of a newly synthesized K + channel opener, 1-[4-(1 H-imidazol-1-yl)benzoyl]- N-methylcyclobutane-carbothioamide (MCC-134) on membrane currents and intracellular Ca 2+ mobilization were investigated in rabbit portal vein smooth muscle cells. Under voltage-clamped conditions, MCC-134 dose-dependently induced K +-selective currents ( I MCC; EC 50 5.3 μM) showing little desensitization but fast deactivating properties on washout of drugs. I MCC was completely blocked by 10 μM glibenclamide, not affected by iberiotoxin (500 nM), charybdotoxin (200 nM) or apamin (500 nM), and inhibited by nonspecific K + channel blockers, tetraethylammonium (1–10 mM), 4-aminopyridine (0.1–1 mM) and Ba 2+ (0.01–0.1 mM). Intracellularly applied nucleotide diphosphates (1 mM) were effective at maintaining I MCC (apparent potency; ADP≦GDP≒IDP<UDP), whereas intracellular ATP exhibited a biphasic, i.e., augmentative and inhibitory effect(s) on I MCC. Single channel activities of about 15 pS (40/140 mM extra-/intracellular K +) fully accountable for macroscopic I MCC were activated by MCC-134. MCC-134, at a concentration as high as 100 μM, suppressed voltage-dependent Ca 2+ and noradrenaline-induced cation currents, and concomitant elevations in the intracellular Ca 2+ concentration ([Ca 2+] i).