Endothelin-1 induces endothelial barrier failure in the cat hindlimb

Our purpose was to see whether endothelin- (ET) 1 could produce a change in the endothelial membrane barrier to protein in skeletal muscle. Previous s tudies in other tissues have suggested that ET-1 affects this barrier, but the measurement methods used could not exclude vascular protein extravasati on due to microvascular pressure changes or the effects of changes in perfu sed capillary surface area. We measured the protein sieving coefficient, a specific measure of the permeability of the membrane to protein, in the iso lated, perfused cat hindlimb preparation. The integral-mass balance method determined this coefficient from the changes in hematocrit and plasma prote in concentration induced by a period of transvascular fluid filtration. The data clearly indicate that ET-1 produces a dose (1-20 nM) dependent increa se in permeability indicative of barrier dysfunction. Hence, elevated ET le vels may contribute to the perivascular edema, hemoconcentration, and impai red tissue perfusion found in systemic inflammatory response syndromes and related diseases.