Actions of the novel thromboxane A2 antagonists, ONO-1270 and ONO-3708, on smooth muscle cells of the guinea-pig basilar artery

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Abstract
The effects of the novel thromboxane A2 (TXA2) antagonists. ONO-1270 and ONO-3708, on the electrical and mechanical responses evoked by various agents, and in particular 9, 11-epithio-11, 12-methano-thromboxane A2 (STA2), were investigated in the guinea-pig artery. STA2 (up to 0.3 μM), and ONO-1270 and ONO-3708 (up to 1.0 μM) dit not modify the membrane potential in smooth muscle cells. Perivascular nerve stimulation induced an excitatory junction potential (e.j.p.), and with frequencies over 0.25 Hz, depression of e.j.ps occurred. STA2 (0.1 μM) and both ONO-1270 and ONO-3708 had no effect on these electrical events. STA2 (over 0.1 μM) produced phasic and tonic contractile responses, in a concentration dependent manner. Both ONO-1270 and ONO-3708 competitively inhibited the phasic contraction induced by STA2 as estimated from parallel shifts in the dose-response curve, and from the Lineweaver-Burk and Schild plots (the PA2 values were 8.22 for ONO-1270 and 8.70 for ONO-3708), but both agents inhibited non-competitively the PGF2α -induced contraction. ONO-1270 and ONO-3708 (up to 0.1 μM) had no effect on contractions induced by K+ and caffeine, but did slightly inhibited contractions induced by 5-hydroxytryptamine (5-HT). Following application of indomethacin, neither agent modified the 5-HT-induced contraction. In Ca2+-free solution, 10 nM STA2 produced a phasic but not a tonic contractile response. ONO-1270 and ONO-3708 (over 1 nM) inhibited this phasic contractile response. We conclude that ONO-1270 and ONO-3708 possess the properties of potent and selective antagonists for the TXA2 (STA2)-receptor in smooth muscle cells of the guinea-pig basilar artery.