In vitro effect of DP-1904, a novel anti-asthma agent, against antigen-induced constriction and TXB2 release from the isolated guinea-pig lung parenchymal tissue.
The contractile activity and mobilisation of arachidonic acid metabolites in response to the antigen challenge were studied in isolated lung parenchymal tissue from the actively sensitised guinea pig. The sustained constriction of the lung tissue was evoked by the antigen, associated with significant liberation of TXB2, histamine and p-LTs. Other prostanoids (PGF2 alpha, PGD2, PGE2 and 6-keto-PGF1 alpha) were also released by the antigen challenge. DP-1904, an inhibitor of TX synthetase, significantly suppressed the late phase of the antigen-induced constriction. DP-1904 was potent to inhibit the production of TXB2, while DP-1904 accelerated the formation of PGF2 alpha, PGE2 and 6-keto-PGF1 alpha, presumably indicating the alternative changes of dilatory metabolites to the spasmogenic component. Mepyramine and FPL-77512 augmented the effect of DP-1904. AA-861 inhibited the antigen-induced constriction of the lung parenchymal tissue by inhibiting the release of p-LTs and TXB2. Pretreatment of the lung parenchymes with anti-guinea pig platelet serum, in order to deplete the platelets, did not affect the generation of TXB2 both in resting and also in the antigen-stimulated status, indicating that TXA2 is produced in the topical pulmonary tissue. It is concluded that DP-1904 inhibits the parenchymal contraction through potent inhibition of TXA2 generation, associated with significant elevation in PGE2 and PGI2.
Takami
M
M
Exploratory Research Laboratories III, Drug Safety Administration, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Tsukada
W
W
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000941:Antigens / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D016084:Bronchoconstriction / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011738:Pyrilamine / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000378:metabolism; D013929:Thromboxane B2 / Q000378:metabolism*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D018927:Anti-Asthmatic Agents; D000941:Antigens; D016227:Benzoquinones; D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D013764:Tetrahydronaphthalenes; D013929:Thromboxane B2; D013928:Thromboxane A2; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; C006312:FPL 55712; C056295:nafagrel; D013930:Thromboxane-A Synthase; D011738:Pyrilamine