Effects of lemakalim on changes in Ca2+ concentration and mechanical activity induced by noradrenaline in the rabbit mesenteric artery.
1. Effects of (-)-cromakalim (lemakalim) on tension and Ca2+ mobilization induced by noradrenaline (NA) were investigated by measuring intracellular Ca2+ concentration ([Ca2+]i) isometric tension and production of inositol-1,4,5-trisphosphate (IP3) in smooth muscle strips of the rabbit mesenteric artery. 2. In thin smooth muscle strips, 10 microM NA produced a large phasic, followed by a small tonic increase in [Ca2+]i, which correlated well with the evoked phasic and tonic contractions, respectively. Lemakalim (0.1-10 microM) lowered the resting [Ca2+]i without a decrease in the resting tension, and also inhibited the increased [Ca2+]i and tension induced by 10 microM NA, all in a concentration-dependent manner. Glibenclamide (1 microM) inhibited these actions of lemakalim. 3. In Ca(2+)-free solution containing 2 mM EGTA, NA (10 microM) transiently increased [Ca2+]i, tension and synthesis of IP3. Lemakalim (over 0.01 microM) inhibited these actions of NA in Ca(2+)-free solution containing 5.9 mM K+, but not in Ca(2+)-free solution containing 128 mM K+. These actions of lemakalim were prevented by glibenclamide (1 microM). Lemakalim (1 microM) did not modify the increases in [Ca2+]i and tension induced by 10 mM caffeine. 4. In beta-escin-skinned strips, 10 microM NA increased [Ca2+]i in Ca(2+)-free solution containing 50 microM EGTA, 3 microM guanosine triphosphate (GTP) and 2 microM Fura 2 after the storage sites were loaded by application of 0.3 microM Ca2+ for 2 min, suggesting that Ca2+ is released from intracellular storage sites following activation of the alpha-adrenoceptor. Lemakalim (1 microM) did not inhibit the Ca2+ release from storage sites induced by NA. 5. We conclude that lemakalim inhibits NA-induced Ca2 + release due to inhibition of NA-induced 'P3 production in a manner dependent on the membrane potential and causes inhibition of the phasic contraction induced by NA.
Ito
S
S
Department of Pharmacology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Kajikuri
J
J
Itoh
T
T
Kuriyama
H
H
D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D019806:Cromakalim; D004928:Escin / Q000494:pharmacology; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009186:Myelin Sheath / Q000502:physiology; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D009467:Neuromuscular Depolarizing Agents; D011758:Pyrroles; D014665:Vasodilator Agents; D019806:Cromakalim; D004928:Escin; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium; D009638:Norepinephrine