Studies In The Guinea-pig With ICI 185,282: A Thromboxane A2 Receptor Antagonist

AbstractThe 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 × 10−7 M) produced a significant shift in U-46619 response curves (concentration ratio of 13.3); the antagonist (1 × 10−5 M) did not modify histamine responses. When tested on guinea-pig trachea in-vitro ICI 185,282 (1 × 10−7 M) caused significant inhibition of U-46619 and PGD2 responses (concentration ratios of 8.3 and 14.1, respectively); the antagonist (1 × 10−5 M) proved less effective against contractions of PGF2α, 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 (× 10−6, 1 × 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 (× 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 ≥8 h. In-vivo, a single oral dose of ICI 185,282 (1 mg kg−1) inhibited bronchospasm induced by U-46619, PGD2, PGF2α, arachidonic acid, LTD4 and PAF; responses to histamine were unaffected. When dosed intravenously to lightly anaesthetized spontaneously breathing guinea-pigs ICI 185,282 (25 mg kg−1) failed to modify Cdyn and Raw. We conclude that ICI 185,282 is a potent, selective, orally active antagonist, which expresses activity at platelet and pulmonary TXA2 receptors.