Action of KC-399, a newly synthesized potassium channel opener, on mechanical activity and 86Rb efflux in rat aorta.
To clarify the characteristics of KC-399, a newly synthesized potassium channel opener, we investigated the effects of KC-399 and lemakalim on the contractions induced by norepinephrine (NE 1 microM) and K+ (30 and 90 mM) and on 86Rb efflux in rat thoracic aorta. KC-399 (0.01-10 nM) and lemakalim (0.001-10 microM) induced relaxation in aortic rings precontracted with 30 mM K+ or NE, but not with 90 mM K+. The vasorelaxant effect of KC-399 was almost 500 times more potent than that of lemakalim. The vasorelaxation with KC-399 developed more slowly and was more resistant to washout than that induced by lemakalim. Glibenclamide (0.1-1 microM), a blocker of ATP-sensitive K-channels, produced concentration-dependent inhibition of the relaxant action of KC-399 in aorta treated with 30 mM K+. KC-399 (3-100 nM) and lemakalim (0.3-10 microM) stimulated 86Rb efflux in rat aorta; the potency of KC-399 was approximately 100 times greater than that of lemakalim. The effects of KC-399 on 86Rb efflux persisted after an 18-min washout period, but those of lemakalim did not. The stimulatory effects of KC-399 (10 and 30 nM) and lemakalim (1 and 3 microM) on 86Rb efflux were also significantly reduced by glibenclamide (1 microM). These results suggest that KC-399 is a potent and long-lasting vasodilator in vitro and that opening of the ATP-sensitive K+ channel may be involved in its mechanism of action.
Tamura
K
K
Research Laboratories, Chugai Pharmaceutical, Shizuoka, Japan.
Suzuki
Y
Y
Yoshida
S
S
Nabata
H
H
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018999:Charybdotoxin; D019806:Cromakalim; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012414:Rubidium Radioisotopes; D012604:Scorpion Venoms / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D012414:Rubidium Radioisotopes; D012604:Scorpion Venoms; D019806:Cromakalim; D018999:Charybdotoxin; C085685:KC 399; D000255:Adenosine Triphosphate; D005905:Glyburide; D009638:Norepinephrine