Effects of lemakalim on changes in Ca2+concentration and mechanical activity induced by noradrenaline in the rabbit mesenteric artery

Abstract

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. In thin smooth muscle strips, 10 μm 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 μm) lowered the resting [Ca2+]i without a decrease in the resting tension, and also inhibited the increased [Ca2+]i and tension induced by 10 μm NA, all in a concentration‐dependent manner. Glibenclamide (1 μm) inhibited these actions of lemakalim. In Ca2+‐free solution containing 2 mm EGTA, NA (10 μm) transiently increased [Ca2+]i, tension and synthesis of IP3. Lemakalim (over 0.01 μm) 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 μm). Lemakalim (1 μm) did not modify the increases in [Ca2+]i and tension induced by 10 mm caffeine. In β‐escin‐skinned strips, 10 μm NA increased [Ca2+]i in Ca2+‐free solution containing 50 μm EGTA, 3 μm guanosine triphosphate (GTP) and 2 μm Fura 2 after the storage sites were loaded by application of 0.3 μm Ca2+for 2 min, suggesting that Ca2+is released from intracellular storage sites following activation of the α‐adrenoceptor. Lemakalim (1 μm) did not inhibit the Ca2+release from storage sites induced by NA. 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. 1991 British Pharmacological Society