収縮蛋白Ca^<2+>感受性増強薬(Ca^<2+>sensitizer) Org 30029の作用機序 : acidosisおよびBDMによる心筋収縮抑制に対する拮抗効果 Mechanisms of action of Ca^<2+> sensitizer Org 30029 : effects on the contractile depression induced by acidosis and 2,3-butanedione monoxime

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Effects of a novel Ca<SUP>2+</SUP> sensitizer Org 30029 [N-hydroxy-5, 6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride] (ORG) on the myocardial contractile depression induced by acidosis and 2, 3-butanedione monoxime (BDM) were investigated in aequorin-loaded dog right ventricular trabeculae. The maximal positive inotropic effect (PIE) of ORG was about 150% of the isoproterenol-induced maximum (ISO<SUB>max</SUB>), while the maximal response of the Ca<SUP>2+</SUP> transient (CaT) to ORG was only 30% of ISO<SUB>max</SUB>. Elevation of [Ca<SUP>2+</SUP>]o elicited PIE equivalent to ISO<SUB>max</SUB> in association with an increase in CaT to 55% of ISO<SUB>max</SUB>. Acidosis (pH 6.6) depressed the contraction markedly to 30% of the basal force with a small increase in the amplitude of CaT. Acidosis abbreviated the twitch but prolonged CaT. BDM (3 mM) depressed the contraction markedly to 40% of the basal force with only a slight change in the amplitude of CaT. BDM abbreviated the twitch without changing the duration of CaT. Elevation of [Ca<SUP>2+</SUP>]<SUB>o</SUB> increased CaT to the same extent as control but reversed the force only to 50% of ISO<SUB>max</SUB>. In contrast, ORG completely reversed the contractile depression induced by acidosis or BDM, and elicited PIE to the same extent as control with only a small change in the amplitude of CaT. In addition, ORG prolonged the twitch that had been shortened previously by acidosis or BDM, to a level equivalent to the control in association with prolongation of CaT. This action of ORG may be mainly due to an increase in Ca<SUP>2+</SUP> sensitivity of myofibrils. Furthermore, it is evident that the Ca<SUP>2+</SUP> sensitizing effect of ORG is exerted also in pathophysiological situation where the Ca<SUP>2+</SUP> sensitivity of myofibrils has been decreased by acidosis or BDM. Thus, ORG may be an effective cardiotonic agent capable of reversing the myocardial depression induced by decrease in Ca<SUP>2+</SUP> sensitivity of myofibrils occurring in pathophysiological situation, such as acidosis in cardiac ischemia.

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  • 日本薬理学雑誌

    日本薬理学雑誌 106, 187-191, 1995-09-01

    公益社団法人 日本薬理学会

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