Electrophysiological actions of a novel K(+) channel opener MCC-134 on rabbit portal vein smooth muscle.
The effects of a newly synthesized K(+) channel opener, 1-[4-(1H-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 microM) showing little desensitization but fast deactivating properties on washout of drugs. I(MCC) was completely blocked by 10 microM 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 falling dotsIDP<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 microM, suppressed voltage-dependent Ca(2+) and noradrenaline-induced cation currents, and concomitant elevations in the intracellular Ca(2+) concentration ([Ca(2+)](i)).
Morita
H
H
Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yamada
K
K
Abe
K
K
Ito
Y
Y
Inoue
R
R
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018999:Charybdotoxin / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007290:Inosine Diphosphate / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D011169:Portal Vein / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D013854:Thioamides / Q000494:pharmacology*; D014530:Uridine Diphosphate / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D007093:Imidazoles; C403079:MCC 134; D010455:Peptides; D015221:Potassium Channels; D013854:Thioamides; D014665:Vasodilator Agents; D019806:Cromakalim; D018999:Charybdotoxin; D001030:Apamin; D014530:Uridine Diphosphate; D000244:Adenosine Diphosphate; C064719:iberiotoxin; D007290:Inosine Diphosphate; D000255:Adenosine Triphosphate; D005905:Glyburide; D002118:Calcium; D009638:Norepinephrine