Vasoactive intestinal peptide (VIP, 10 nM) inhibited the release of cyclo-oxygenase products, detected by both bioassay and radioimmunoassay, induced by leukotriene (LT) D4 (3–30 pmol) and bradykinin (BK, 3–30 nmol) from guinea-pig isolated perfused lung. Helodermin (10 nM), a peptide that is structurally related to VIP, and salbutamol (10 nM), a β2-adrenoceptor agonist, evoked a similar inhibitory effect on LTD4-induced release of cyclo-oxygenase products. The generation of TxB2 and 6-keto-PGF1α following stimulation with exogenously administered arachidonic acid (30–300 nmol) was not significantly attenuated in the presence of either VIP, helodermin or salbutamol. These results show that VIP, helodermin and salbutamol are potent inhibitors of the release of cyclo-oxygenase products induced by agonists known to activate endogenous arachidonic acid metabolism in guinea-pig lung. Since the metabolism of exogenously administered arachidonic acid was not inhibited these results suggest that the inhibitory effect may be exerted on events preceding the mobilisation of arachidonic acid and may involve cyclic AMP.

Platelet-activating factor (PAF, 10-1000 pmol) induced dose-dependent relaxations of the basal tone of superfused strips of epithelium-intact guinea-pig trachea. Indomethacin (1.4 microM) completely inhibited and WEB 2086 (1 and 10 nM) effectively antagonised these relaxations. Following epithelial removal PAF evoked a single contraction. These results show that the PAF-induced relaxations of guinea-pig trachea are dependent on an intact epithelial layer and are mediated by a cyclo-oxygenase product.

The formation of leukotrienes (LTs) from arachidonic acid derived from phospholipids of the cell membrane is initially catalysed by 5-lipoxygenasel. Metabolism of the unstable epoxide LTA4 leads to the formation of LTB4 and the cysteinyl-containing LTs C4, D4 and E4. All these LTs have potent, although different, biological activities. LTB4 is a powerful chemotactic agent for leukocytes whereas LTs C4, D4 and E4 have potent smooth muscle stimulating actions and account for the biological activity of the allergic mediator previously known as slow-reacting substance of anaphylaxis (SRS-A)2. Leukotriene B4 has pro-inflammatory actions but little smooth muscle stimulating activity of its own whereas cysteinyl-containing LTs have potent actions in the cardiovascular system and in the airways in vitro and in vivo (see3,4).

Actions of leukotrienes (LTs) B4, C4, D4 and E4 were found to be largely mediated via formationformitisn of cyclo-oxygenase products in guinea-pig isolated perfused lung and parenchymal strips. In contrast, LTs exerted a direct contractile effect on human isolated parenchymal and bronchial strips. An LT-like substance which had similar biological actions to LTD4 was generated from porcine and guinea-pig vascular tissue. The highest concentration of this material was formed by coronary and pulmonary arteries and the surrounding adventitia, as well as from the lung parenchyma.

Slow-reacting substances are formed from arachidonic acid by the action of a lipoxygenase, which leads to the formation of 5-hydroperoxy,6,8,11,14 eicosatetraenoic acid.

Slow Reacting Substances have been produced from RBL-l cells by calcium ionophore A23187 and purified to homogeneity by high pressure liquid chromatography (HPLC). The structure of the major biologically active species has been determined by mass spectrometric examination of the intact molecule as a derivative, together with amino-acid analysis and sequence determination. The characteristic triene chromophore which we originally identified in immunologically generated SRS-A is present in RBL-l SRS, and we determine the structure of this SRS as the thio-substituted dipeptide, 5-hydroxy-6-cysteinylglycinyl-7,9,11,14-eicosatetraenoic acid.