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-mu-M 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-mu-M) lowered the resting [Ca2+]i without a decrease in the resting tension, and also inhibited the increased [Ca2+]i and tension induced by 10-mu-M NA, all in a concentration-dependent manner. Glibenclamide (1-mu-M) inhibited these actions of lemakalim. 3 In Ca2+-free solution containing 2 mM EGTA, NA (10-mu-M) transiently increased [Ca2+]i, tension and synthesis of IP3. Lemakalim (over 0.01-mu-M) inhibited these actions of NA in Ca2+-free solution containing 5.9 mM K+, but not in Ca2+-free solution containing 128 mM K+. These actions of lemakalim were prevented by glibenclamide (1-mu-M). Lemakalim (1-mu-M) did not modify the increases in [Ca2+]i and tension induced by 10 mM caffeine. 4 In beta-escin-skinned strips, 10-mu-M NA increased [Ca2+]i in Ca2+-free solution containing 50-mu-M EGTA, 3-mu-M guanosine triphosphate (GTP) and 2-mu-M Fura 2 after the storage sites were loaded by application of 0.3-mu-M Ca2+ for 2 min, suggesting that Ca2+ is released from intracellular storage sites following activation of the alpha-adrenoceptor. Lemakalim (1-mu-M) 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 IP3 production in a manner dependent on the membrane potential and causes inhibition of the phasic contraction induced by NA.