Effect of a thromboxane A2 synthetase inhibitor (OKY-046.HCl) on airway hyperresponsiveness in guinea pigs.
We studied the effect of (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046.HCl), a specific thromboxane (TX) A2 synthetase inhibitor, on airway hyperresponsiveness of guinea pigs. OKY-046.HCl (30-100 mg/kg, intraduodenally (i.d.) or orally (p.o.)) suppressed dose dependently the airway hyperresponsiveness to acetylcholine (ACh) induced by formyl-methionyl-leucyl-phenylalanine (FMLP), platelet activating factor (PAF) and repetitive antigen. OKY-046.HCl (100 mg/kg) also inhibited the increase in TXB2 in bronchoalveolar lavage fluid (BALF) induced by FMLP, PAF and antigen. Aspirin 10 or 30 mg/kg i.d. or p.o.) suppressed the airway hyperresponsiveness induced by FMLP and PAF but not by antigen. Azelastine (10 mg/kg i.d.) was ineffective on PAF- and antigen-induced airway hyperresponsiveness. TXA2 mimetic drugs caused airway hyperresponsiveness that was not inhibited by OKY-046.HCl (30 mg/kg i.v.). Furthermore, OKY-046.HCl showed no effect on propranolol- and physostigmine-induced airway hyperresponsiveness which did not accompany TXB2 generation in BALF. The number of eosinophils in BALF increased after FMLP exposure, an effect which was not inhibited by OKY-046.HCl. These results suggest that OKY-046.HCl inhibits airway hyperresponsiveness by suppressing TXA2 generation. We suggest that OKY-046.HCl will be a new antiasthmatic drug.
Komatsu
H
H
Central Research Laboratories, Kissel Pharmaceutical Co., Ltd., Nagano, Japan.
Takehana
Y
Y
Kikuchi
S
S
Kojima
M
M
Hamano
S
S
Kusama
H
H
Okegawa
T
T
Ikeda
S
S
D015121:6-Ketoprostaglandin F1 alpha / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology*; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D000941:Antigens / Q000276:immunology; D001241:Aspirin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D006168:Guinea Pigs; D017999:Leukotriene E4; D008689:Methacrylates / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects*; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology; D013929:Thromboxane B2 / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000941:Antigens; D008689:Methacrylates; D010793:Phthalazines; D010972:Platelet Activating Factor; D013189:SRS-A; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine; D017999:Leukotriene E4; D010830:Physostigmine; D011433:Propranolol; D013930:Thromboxane-A Synthase; C034364:ozagrel; D000109:Acetylcholine; D001241:Aspirin; C020976:azelastine