Inhibitory Action of OKY-046·HCI, 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

We studied a role of TXA2 in the development of PAF-induced nonspecific airway hyperresponsiveness in guinea pigs using a TXA2 synthetase inhibitor (OKY-046·HCI) and a stable TXA2 mimetic agent (STA2). Inhalation of PAF (1 μg/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.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 STA2-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 STA2. 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 (10-8 M)-induced 45Ca uptake into the lung tissue from PAF-inhalated guinea pigs. Inhalation of STA2 increased the number (Bmax) of muscarinic and H1-histaminergic receptors in the lung tissue from guinea pigs, but no changes were found on β-adrenoceptors. These results suggest that TXA2 should act on the smooth muscle cells or alter functions of muscarinic and H1-histaminergic receptors, except β-adrenoceptors, and then increase the membrane permeability to extracellular Ca2+. We also assume that OKY-046·HCI can inhibit PAF-induced nonspecific airway hyperresponsiveness by suppressing the generation of TXA2.