Inhibitory action of OKY-046HCl, a specific TXA2 synthetase inhibitor, on platelet activating factor(PAF)-induced airway hyperresponsiveness of guinea pigs: Role of TXA2 in development of PAF-induced nonspecific airway hyperresponsiveness.
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概要
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We studied a role of TXA<SUB>2</SUB> in the development of PAF-induced nonspecific airway hyperresponsiveness in guinea pigs using a TXA<SUB>2</SUB> synthetase inhibitor (OKY-046·HCI) and a stable TXA<SUB>2</SUB> mimetic agent (STA<SUB>2</SUB>). Inhalation of PAF (1 μg/ml) and STA<SUB>2</SUB> (1 or 10 ng/ml) increased the airway response to acetylcholine (ACh), histamine, leukotriene D<SUB>4</SUB> and electrical vagal stimulation. Intraduodenal administration (i.d.) of OKY-046·HCI (100 mg/kg) inhibited PAF-induced airway hyperresponsiveness. However, OKY-046·HCI (30 mg/kg, i.v.) did not suppress STA<SUB>2</SUB>-induced airway hyperresponsiveness. Neither hexamethonium (1 mg/ kg, i.v.) nor hemicholinium-3(10 mg/kg, i.v.) prevented the increase in the airway response to ACh after inhalation of PAF and STA<SUB>2</SUB>. In the presence of atropine (0.5 mg/kg, i.p.), PAF-induced airway hyperresponsiveness to histamine did not change. OKY-046·HCI (100 mg/kg, i.d.) inhibited the increase in ACh (10<SUP>-8</SUP> M)-induced <SUP>45</SUP>Ca uptake into the lung tissue from PAF-inhalated guinea pigs. Inhalation of STA<SUB>2</SUB> increased the number (B<SUB>max</SUB>) of muscarinic and H<SUB>1</SUB>-histaminergic receptors in the lung tissue from guinea pigs, but no changes were found on β-adrenoceptors. These results suggest that TXA<SUB>2</SUB> should act on the smooth muscle cells or alter functions of muscarinic and H<SUB>1</SUB>-histaminergic receptors, except β-adrenoceptors, and then increase the membrane permeability to extracellular Ca<SUP>2+</SUP>. We also assume that OKY-046·HCI can inhibit PAF-induced nonspecific airway hyperresponsiveness by suppressing the generation of TXA<SUB>2</SUB>.
- 公益社団法人 日本薬理学会の論文
著者
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Kikuchi Shinji
Central Research Laboratory Kissei Pharmaceutical Company Ltd.
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Takehana Yasuo
Central Research Laboratory Kissei Pharmaceutical Co. Ltd.
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Hamano Shuichiro
Central Research Laboratories Kissei Pharmaceutical Co. Ltd.
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Okegawa Tadao
Minase Research Institute, Ono Pharmaceutical Co., Ltd.
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KOMATSU Hidetada
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd.
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IKEDA Shigeru
Central Research Laboratories, Kissei Pharmaceutical Cc., Ltd.
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KOMATSU Hidetada
Central Research Laboratories, Kissei Pharmaceutical Cc., Ltd.
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