The effect of leukotrienes C4 and D4 on the microvasculature of guinea-pig skin

Abstract

The effects of chemically-synthesised leukotrienes C4 and D4 (5(S) hydroxy-6(R)-gamma-glutamylcysteinylglycinyl-7,9,11,14-eicosa-4 tetraenoic acid, LTC4; 5(S) hydroxy-6(R)-cysteinylglycinyl-7,9,11,14-eicosatetraenoic acid, LTD4 on the microvasculature have been measured in guinea-pig skin using [125I]-albumin accumulation to measure plasma exudation and 133Xe clearance to measure blood flow changes. As previously shown using biosynthetic material, LTD4 caused vasoconstriction resulting in reduced blood flow. Similarly, LTC4 was found to have vasoconstrictor activity but was more potent and had a steeper dose-response curve than LTD4. There was no evidence of conversion of exogenous arachidonic acid to vasoconstrictor activity in the skin in vivo (in the absence of another stimulus): intradermally injected arachidonic acid produced vasodilatation, but induced little change in blood flow in animals pretreated with indomethacin. The vasodilator effect of arachidonic acid is presumed to be due to conversion to either PGE2 or PGI2. These results suggest that cyclo-oxygenase is normally active in the skin, whilst lipoxygenase requires activation in some way. As reported in a previous study, LTD4 induced plasma exudation when injected into the skin, but pronounced responses could only be induced by LTD4 mixed with a vasodilator prostaglandin such as PGE2. In contrast, LTC4 induced no exudation when tested alone and little when PGE2 was added. However, evidence was obtained that LTC4 has some permeability-increasing activity which is masked by its potent vasoconstrictor activity.