The role of leukotrienes and other mediators of vascular changes in anaphylaxis were studied in rats sensitized with monoclonal anti-DNP IgE and challenged with DNP-BSA. Microvascular changes in the mesentery were followed by intravital fluorescent microscopy and in the skin by exudation of Evans blue dye. Administration of Ag i.v. caused a marked increase in the peristaltic movement of the intestine, plasma exudation, and arteriolar constriction in the mesentery. The microvascular changes were accompanied by a profound fall in blood pressure, which was biphasic. The first phase lasted for approximately 2 min. The second phase was very prolonged and the hypotension was still maintained 40 min after Ag challenge. The changes observed were dose dependent with regard to Ag. Intradermal application of Ag resulted in dose-dependent extravasation of Evans blue dye in the skin. Plasma exudation was partially inhibited by pyrilamine and methysergide. However, their effect seemed to be more pronounced in the skin than in the mesentery. The leukotriene D4-R antagonist L-649,923 and the 5-lipoxygenase inhibitor ONO-LP-049, alone or in combination with other inhibitors, did not alter the plasma leakage in the skin. In the mesentery, the leukotriene antagonists alone had a moderate effect on vascular permeability. However, the combination of these agents with pyrilamine completely inhibited macromolecular extravasation. The hypotension was modulated by the antihistamines as well as the leukotriene and serotonin antagonists. Pyrilamine inhibited the first phase and the second phase. The major effect of methysergide was a decrease in the duration of the hypotension. This was especially evident when it was administered in combination with other inhibitors. The leukotriene antagonists when given alone had moderate effects on the blood pressure changes. However, in combination with pyrilamine, the hypotension was substantially reduced. Leukotrienes appeared to be important mediators of the vascular changes in the mesentery but not in the skin (passive cutaneous anaphylaxis). They markedly potentiated the action of histamines.