Studies in the guinea-pig with ICI 185,282: a thromboxane A2 receptor antagonist.
The effects of ICI 185,282 (5(Z)-7-([ 2,4,5-cis]-4-O-hydroxyphenyl-2-trifluoromethyl-1, 3-dioxan-5-yl)heptenoic acid) have been studied on guinea-pig platelets and pulmonary smooth muscle in-vitro and in-vivo. When tested on guinea-pig lung parenchyma in-vitro. ICI 185,282 (1 x 10(-7) M) produced a significant shift in U-46619 response curves (concentration ratio of 13:3); the antagonist (1 x 10(-5) M) did not modify histamine responses. When tested on guinea-pig trachea in-vitro ICI 185,282 (1 x 10(-7) M) caused significant inhibition of U-46619 and PGD2 responses (concentration ratios of 8.3 and 14.1, respectively); the antagonist (1 x 10(-5) M proved less effective against contractions of PGF2 alpha, LTD4 and histamine (concentration ratios of 7.0, 1.5 and 1.6). When added to guinea-pig platelet rich plasma in-vitro, ICI 185,282 (x 10(-6), 1 x 10(-5) M) caused concentration-dependent parallel shifts to the right of U-46619 aggregation curves, yielding concentration ratios of 13.6 and 141.9, respectively. In-vitro, addition of ICI 185,282 (x 10(-5) M) to indomethacin-treated pulmonary smooth muscle did not modify resting tone, neither did it induce aggregation or swelling in platelet-rich plasma preparations. When administered orally to guinea-pigs ICI 185,282 (0.1, 0.5 mg kg-1) caused a significant inhibition of U-46619-induced platelet aggregation ex-vivo which persisted greater than or equal to 8 h. In-vivo, a single oral dose of ICI 185,282 (1 mg kg-1) inhibited bronchospasm induced by U-46619, PGD2, PGF2 alpha, arachidonic acid, LTD4 and PAF; responses to histamine were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)
Birch
J
J
ICI Pharmaceuticals, Macclesfield, Cheshire, UK.
Brown
E
E
Calnan
C
C
Jessup
C L
CL
Jessup
R
R
Wayne
M
M
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D001986:Bronchial Spasm / Q000139:chemically induced / Q000188:drug therapy; D004146:Dioxanes / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects*; D008297:Male; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D012119:Respiration / Q000187:drug effects; D012129:Respiratory Function Tests; D012132:Respiratory Muscles / Q000187:drug effects
D004146:Dioxanes; D004147:Dioxins; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C059061:ICI 185282