Leukotrienes B4, C4, and D4, members of a recently discovered family of substances biosynthesized from arachidonic acid, were found to have potent microvascular actions in the hamster cheek pouch. When applied topically to the vascular network, leukotrienes C4 and D4 caused an intense constriction of arterioles, being similar to angiotensin in potency in this respect. The vasoconstriction induced by leukotrienes C4 and D4 was short-lived, and it was consistently followed by a marked and dosedependent extravasation of macromolecules from postcapillary venules. Histamine did not constrict arterioles, but it elicited leakage of plasma, although on a molar basis it was no more than 1/ 1000th as potent as the leukotrienes. When used in the same concentration range as leukotrienes C4 and D4, leukotriene B4 did not evoke vasoconstriction or promote plasma leakage. On the other hand, leukotriene B4 caused a conspicuous and reversible adhesion ofleukocytes to the endothelium in postcapillary venules. Our findings that leukotrienes induce microcirculatory alterations in vivo, closely resembling the early events in the acute inflammatory response, imply that leukotrienes, formed in several blod-borne and tissue-bound cells, may mediate important microcirculatory adjustments to noxious stimuli.

Leukotriene B4 (LTB4), a metabolite of arachidonic acid, is known to be a potent chemotactic and chemokinetic substance. We have used the hamster cheek pouch microcirculation model to study the effect of LTB4 on vascular permeability and the involvement of neutrophil granulocytes in this response. Intravascular fluorescein-labeled dextran (mol wt 150,000) was used as a tracer of macromolecular permeability. Topical application of LTB4 (150 nM-5 microM) to the hamster cheek pouch resulted in an immediate increase in adhering leukocytes in postcapillary venules and later venules. Leukocyte accumulation was reversible, but continued longer the higher the dose of LTB4 used. Subsequently, a dose-dependent increase in vascular permeability was seen at post-capillary and larger venules, with a maximum 10-20 min after application; the maximum occurred later the higher the dose of LTB4. Depletion of neutrophil granulocytes by pretreatment of the animals with antineutrophil serum obtained from immunized rabbits significantly decreased the permeability response to LTB4, whereas the response to histamine was unaffected. These results suggest that neutrophil granulocytes play a role in LTB4-mediated permeability increase. LTB4 may be of importance both for the leukocyte accumulation and for the edema formation seen in inflammatory reactions.

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Lipoxin A ([5S,6R,15S]-5,6,15-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid), a recently characterized lipoxygenation product of arachidonic acid, in submicromolar concentrations elicited long-lasting contractions of the guinea-pig lung strip. The response to lipoxin A was not due to release of acetylcholine, histamine, noradrenaline or cyclo-oxygenase products. 15-hydroperoxyeicosatetraenoic acid (15-HPETE), one precursor of lipoxin A, also contracted the lung strip, but 15-HPETE was less potent on the guinea-pig trachea whereas 15-HPETE relaxed this preparation. Lipoxin A was also inactive on the guinea-pig ileum. Intravital microscopy of the hamster cheek pouch disclosed that lipoxin A, as well as 15-HPETE, induced arteriolar dilation but had no effects on microvascular permeability or leucocyte adherence to venular endothelium. Taken together, the leucocyte product lipoxin A displayed a pattern of activity in spasmogenic assays and on the microvasculature that was distinct from those known for prostaglandins, thromboxanes and leukotrienes. The findings indicate that lipoxin A is an additional arachidonic acid derived autacoid with biological actions on smooth muscle in vitro and in vivo.