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Effects of glibenclamide on cytosolic calcium concentrations and on contraction of the rabbit aorta

1 Using fluorometry of fura‐2 and rabbit aortic strips, we studied the effects of glibenclamide (GLB), a sulphonylurea anti‐diabetic drug and an inhibitor of opening of K+ channels, on cytosolic calcium concentrations ([Ca2+]i) and on force development. 2 Both high K+‐depolarization and noradrenaline (NA) increased [Ca2+]i and force, in a concentration‐dependent manner, in the presence of extracellular Ca2+ (1.25 mm). However, force development in relation to [Ca2+]i ([Ca2+]i‐force relationship) observed with NA was much greater than that observed with K+‐depolarization. 3 Pretreatment with GLB (10−6–10−4 m) for 10 min partially inhibited, in a concentration‐dependent manner, both [Ca2+]i elevation and the force development induced by 118 mm K+‐depolarization or NA 10−5 m in the presence of extracellular Ca2+. The [Ca2+]i‐force relationship induced by both 118 mm K+ physiological salt solutions and by NA 10−5 m in the GLB‐treated strips overlapped that obtained in the non‐treated strips, thereby suggesting that GLB has no effect on the Ca2+‐sensitivity of the intracellular contractile apparatus. Only high concentrations (10−4 m) of GLB decreased [Ca2+]i and the force, when applied after the force induced by 118 mm K+ PSS or NA 10−5 m reached the maximum level. 4 In the absence of extracellular Ca2+, NA induced a transient increase in [Ca2+]i and in the force and these increases were inhibited when the vascular strips were pretreated with GLB for 10 min. The [Ca2+]i‐force relationship obtained in the GLB‐treated strips overlapped that in the non‐treated ones. 5 An ATP‐sensitive K+ channel opener, cromakalim (10−5 m) reduced the increased [Ca2+]i and force induced by 25 mm K+‐depolarization and NA 10−5 m. Subsequent application of GLB concentration‐dependently reversed this relaxant effect of cromakalim on the NA‐induced contraction (IC50 = 2 × 10−7 m). Complete reversal of the effect was observed with 10−5 m GLB. 6 We suggest that GLB inhibits both high K+‐depolarization‐ and NA‐induced contraction of the rabbit aorta, by decreasing [Ca2+]i and with no effect on the [Ca2+]i‐force relationship. However, when NA‐induced contractions were inhibited by a K+‐channel opener, GLB reversed this inhibitory effect by inhibiting K+‐channel opening and increasing [Ca2+]i.