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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Abstract
We studied a role of TXA2 in the development of PAF-induced non-specific airway hyperrespoinsiveness in guinea pigs using a TXA2 synthetase inhibitor (OKY-046.cntdot.HCl) and a stable TXA2 mimetic agent (STA2). Inhalation of PAF (1 .mu.g/ml) and STA2 (1 or 10 ng/ml) increased the airway response to acetylcholine (ACh), histamine, leukotriene D4 and electrical vagal stimulation. Intraduodenal administration (i.e.) of OKY-046.cntdot.HCl (100 mg/kg) inhibited PAF-induced airway hyperresponsiveness. However, OKY-046.cntdot.HCl (30 mg/kg. i.v.) did not suppress STA2-induced airway hyperresponsiveness. Neitehr 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 STA2. In the presence of atropine (0.5 mg/kg, i.p.), PAF-induced airway hyperresponsiveness to histamine did not change. OKY-046.cntdot.HCl (100 mg/kg, i.d.) inhibited the increase in ACh (10-8 M)-induced 45Ca uptake into the lung tissue from PAF-inhalated guinea pigs. Inhalation of STA2 increased the number (Bmax) of muscarinic and H2-histaminergic receptors in the lung tissue from guinea pigs, but no changes were found on .beta.-adrenoceptors. These results suggest that TXA2 should act on the smooth muscle cells or alter functions of muscarinic and H2-histaminergic receptors, except .beta.-adrenoceptors, and then increase the membrane permeability to extracellular Ca2+. We also assume that OKY-046.cntdot.HCl can inhibit PAF-induced nonspecific airway hyperresponsiveness by suppressing the generation of TXA2.