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Effects of pinacidil on contractile proteins in high K + ‐treated intact, and in β‐escin‐treated skinned smooth muscle of the rabbit mesenteric artery
Author(s) -
Itoh Takeo,
Suzuki Satoshi,
Kuriyama Hirosi
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb09849.x
Subject(s) - pinacidil , contraction (grammar) , muscle contraction , chemistry , calmodulin , guanosine , biophysics , medicine , anatomy , calcium , endocrinology , biochemistry , biology , glibenclamide , diabetes mellitus
1 The effects of pinacidil were investigated on changes in cellular Ca 2+ concentration ([Ca 2+ ] i ) and tension in intact and chemically skinned smooth muscle strips of the rabbit mesenteric artery. 2 High K + (128 m m ) produced a large phasic followed by a tonic increase in [Ca 2+ ] i and tension in intact muscle strips. Pinacidil at 10 μ m but not 1 μ m , inhibited the phasic and tonic contractions induced by 128 m m K + without a corresponding change in [Ca 2+ ] i . 3 In β‐escin‐treated skinned smooth muscle, the minimum Ca 2+ concentration that produced contraction was 0.1 μ m and the maximum contraction was obtained at 10 μ m . Pinacidil at 10 μ m but not 1 μ m , shifted the pCa‐tension relation curve to the right and also inhibited the maximum contraction induced by Ca 2+ . The concentrations of Ca 2+ required for half maximal tension were 0.9 μ m in control and 1.5 μ m in the presence of 10 μ m pinacidil. Calmodulin (2 μ m ) increased the contraction induced by 0.3 μ m Ca 2+ (but not by 10 μ m Ca 2+ ) in the skinned strips. Pinacidil (10 μ m ) inhibited the contraction induced by 0.3 μ m or 10 μ m Ca 2+ in the presence of 2 μ m calmodulin. 4 Noradrenaline (NA, 10 μ m ) with guanosine triphosphate (GTP, 3 μ m ), guanosine 5′‐0‐(3‐thiotriphosphate) (GTPγS, 3 μ m ) or 12–0‐tetradecanoylphorbol‐13‐acetate (TPA, 0.1 μ m ) all enhanced the contraction induced by 0.3 μ m Ca 2+ . Pinacidil (10 μ m ) inhibited the contraction induced by 0.3 μ m Ca 2+ more strongly in the presence of the above agents than in their absence. 5 Following application of 2 m m adenosine‐5′‐0‐(3‐thiotriphosphate) (ATPγS) with 0.3 μ m Ca 2+ , 4 m m MgATP produced contraction in skinned strips in Ca 2+ ‐free solution containing 4 m m EGTA (‘Ca 2+ ‐independent contraction’). The amplitude of the Ca 2+ ‐independent contraction was almost the same as that obtained with 10 μ m Ca 2+ . Pinacidil (10 μ m ) had no effect on the amplitude of the Ca 2+ ‐independent contraction nor did it have any effect on the contraction induced by a solution containing no MgATP (‘rigor contraction’). 6 It is concluded that pinacidil (10 μ m ) acts directly on the contractile apparatus to inhibit Ca 2+ ‐induced contraction in smooth muscle of the rabbit mesenteric artery. The site of action of pinacidil may be between Ca 2+ ‐calmodulin complex formation and phosphorylation of the myosin light chain.