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Mystixins are synthetic peptides that inhibit plasma leakage after tissue injury. We sought to determine the mechanism of the antileakage effect of mystixins, with particular reference to the formation of endothelial gaps in postcapillary venules. Intravenous administration of mystixin-7, a prototype heptapeptide (p-anisoyl-Arg-Lys-Leu-Leu-d-Thi-Ile-d-Leu-NH2), decreased Evans blue leakage induced by substance P (5 μg/kg i.v.) with an ED50(95% confidence limits) of 130 (76–211) μg/kg in trachea and 52 (27–100) μg/kg in skin of anesthetized F344 rats. Leakage was decreased without a reduction in the number or size of endothelial gaps, visualized by silver deposits after silver nitrate staining. The number of silver deposits per tracheal endothelial cell was 11.4 ± 0.2 (mean ± S.E.) after vehicle pretreatment vs. 13.0 ± 0.8 after mystixin-7 pretreatment (100 μg/kg i.v.). Silver deposit diameter was unchanged at 1.4 ± 0.1 μm. Mean arterial blood pressure dropped by a maximum of 38% from baseline for approximately 10 min after mystixin-7 (100 μg/kg i.v.), then recovered to a plateau at about 13% below baseline. The antileakage effect of mystixin-7 pretreatment in vivowas also demonstrated in aldehyde-fixed vessels perfused in situwith Evans blue at constant flow (skin, 79% reduction; trachea, 49% reduction), which suggests that mystixin can reduce leakage independent of its hypotensive effect. We conclude that the antileakage effect of mystixin does not depend on reducing the number or size of endothelial gaps, but instead could be caused by residual hypotension, which reduces the negative interstitial fluid pressure toward zero, or clogging of endothelial gaps.