Some effects of leukotriene D4 on the mechanical properties of the guinea-pig basilar artery.

1. The effects of leukotriene D4 (LTD4) on the mechanical properties of smooth muscle cells from the guinea-pig basilar artery were investigated in whole and chemically skinned muscle strips. 2. In strips with an intact endothelium, 5-hydroxytryptamine (5-HT; 10 microM), LTD4 and LTC4 (1 microM), STA2 (1 nM-10 nM) and high K+ (30 mM-128 mM) generated contractions. These comprised an initial phasic and subsequently generated tonic response with different amplitudes. Acetylcholine (ACh, 0.1-10 microM) inhibited and methylene blue (1-10 microM) enhanced the tonic component of these contractions in endothelium-intact muscle strips. In endothelium-denuded tissues, methylene blue had no effect on mechanical responses and ACh produced a further contraction in the presence of LTD4. 3. When the endothelium was removed, the amplitude of contractions induced by all tested stimulants markedly increased. In intact muscle strips, the order of potency for the production of a maximum response was; 128 mM K+ greater than STA2 greater than LTD4 = LTC4 = 5-HT. Following removal of the endothelium; STA2 greater than 128 mM K+ greater than LTD4 = LTC4 much greater than 5-HT. 4. In endothelium-denuded strips, the selective LTD4 antagonists, ONO-RS-411 and FPL 55712 inhibited the LTD4-induced contraction. In contrast, guanethidine, prazosin, yohimbine, atropine and mepyramine had no effect. Indomethacin and a thromboxane A2(TXA2) antagonist, ONO-3708 also had no effect on LTD4-induced contractions in endothelium-denuded strips. 5. In endothelium-denuded strips, nifedipine inhibited the tonic contraction induced by LTD4 but not the phasic component. In Ca2+-free solution containing 2 mM EGTA, LTD4 produced only the phasic contractions. 6. In saponin-treated chemically skinned muscle strips, LTD4 had no effect on either the pCa-tension relationship or on the release of Ca2+ from intracellular stores. However, inositol 1,4,5-triphosphate released Ca2+ from the stores and 1,2-diolein, an activator of protein kinase C, enhanced the contractions induced by 0.3 microM Ca2+. 7. It was concluded that LTD4 acts on both the endothelium and on the smooth muscle cells of the guinea-pig basilar artery. It stimulates the release of endothelium-derived relaxing factor (EDRF) which tends to inhibit the LTD4-induced contraction. It also interacts with receptors on the smooth muscle and produces a contraction as a result of an increase in both voltage-dependent and receptor-activated Ca2+ influx and, in part, the release of Ca2+ from cellular storage sites.