Role of endogenous nitric oxide in airway microvascular leakage induced by inflammatory mediators

This study examines the role of endogenous nitric oxide (NO) in airway microvascular leakage induced inflammatory mediators, which play an important role in asthmatic airways. Guinea-pigs were anesthetized and mechanically-ventilated with monitoring of arterial blood pressure, and airway microvascular leakage induced by intravenous injection of substance P (SP), leukotriene D4 (LTD4) and histamine was evaluated using Evans blue dye and Monastral blue dye in the presence and absence of the NO synthase inhibitors, L-NG-nitroarginine methyl ester (L-NAME) and L-NG-monomethyl arginine (L-NMMA). The effect of a soluble guanylate cyclase inhibitor, LY83583, on SP-induced dye leakage was also examined. Intravenous injection of SP (1 microgram.kg-1), LTD4 (1 microgram.kg-1) and histamine (100 micrograms.kg-1) significantly increased dye extravasation at all airway levels. Pretreatment with L-NAME (10 mg.kg-1 i.v.) and L-NMMA (100 mg.kg-1 i.v.) significantly inhibited SP-induced extravasation, and L-arginine (100 mg.kg-1 i.v.) reversed L-NAME-induced inhibition. L-NAME (10 mg.kg-1 i.v.) also significantly inhibited LTD4-induced dye extravasation only in central airways, and this inhibitory effect was abolished by a neurokinin-1 (NK1) antagonist, FK888 (10 mg.kg-1 i.v.) pretreatment. Histamine-induced dye extravasation was not affected by L-NAME. LY83583 (2.5 and 7.5 mg.kg-1 i.v.) partially but significantly reduced SP-induced dye leakage. These results suggest that endogenous nitric oxide plays a role in neurokinin-1 receptor-mediated airway microvascular leakage, and presumably involves the guanylate cyclase pathway.

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