Inhibitory action of OKY-O46.HCl, 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-O46.HCl) and a stable TXA2 mimetic agent (STA2). Inhalation of PAF (1 microgram/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-O46.HCl (100 mg/kg) inhibited PAF-induced airway hyperresponsiveness. However, OKY-046.HCl (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.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 H1-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 H1-histaminergic receptors, except beta-adrenoceptors, and then increase the membrane permeability to extracellular Ca2+. We also assume that OKY-046.HCl can inhibit PAF-induced nonspecific airway hyperresponsiveness by suppressing the generation of TXA2.
Takehana
Y
Y
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Nagano, Japan.
Hamano
S
S
Kikuchi
S
S
Komatsu
H
H
Okegawa
T
T
Ikeda
S
S
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001341:Autonomic Nervous System / Q000187:drug effects; D002132:Calcium Radioisotopes; D006168:Guinea Pigs; D006426:Hemicholinium 3 / Q000494:pharmacology; D006584:Hexamethonium Compounds / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects; D012137:Respiratory System / Q000187:drug effects*; D013928:Thromboxane A2 / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000179:Acrylates; D002132:Calcium Radioisotopes; D006584:Hexamethonium Compounds; D008689:Methacrylates; D010972:Platelet Activating Factor; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D006426:Hemicholinium 3; D013928:Thromboxane A2; D001285:Atropine; D013930:Thromboxane-A Synthase; C034364:ozagrel