The action of chemically pure SRS-A on the microcirculation in vivo

Abstract

The purification of SRS-A for the purpose of structure determination has enabled us to investigate whether pure SRS-A has activity on the microvasculature. SRS-A from challenged sensitised lung in vitro was purified using five stages of purification. At each stage SRS-A activity was assayed against an in-house standard using the guinea-pig ileum blocked with mepyramine and hyoscine. The material obtained at each stage was then tested for its ability to induce plasma exudation (measured using the accumulation of intravenously-injected [131I]-albumin) in guinea-pig skin. It was found that vascular permeability-increasing activity corresponded with guinea-pig ileum contracting activity throughout the purification procedure. The final product, homogeneous SRS-A, at doses of 4 - 6 ng, produced a clear increase in vascular permeability. Two other lipoxygenase products which have been proposed to be derived from the same hydroperoxide intermediate as SRS-A, 5-hydroxyeicosatetraenoic acid and 5,12-dihydroxyeicosatetraenoic acid (leukotriene B), showed little effect on vascular permeability. PGE1 was found to potentiate plasma exudation induced by SRS-A to a greater extent than that induced by histamine. SRS-A, as a permeability-increasing agent in the presence of PGE1, was approximately 400 times more potent (on a molar basis) than histamine. When 133Xe was used to measure blood flow changes, chemically pure SRS-A was found to reduce flow in skin; 4 - 6 ng of SRS-A producing a 40-50% reduction. It is suggested that these actions of SRS-A may be important in pathophysiological conditions.