Kageyama N, Miura M, Ichinose M, Tomaki M, Ishikawa J, Ohuchi Y, Endoh N, Shirato K
First Dept of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Eur Respir J. 1997 Jan;10(1):13-9. doi: 10.1183/09031936.97.10010013.
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.
本研究探讨内源性一氧化氮（NO）在气道微血管渗漏诱导的炎症介质中的作用，这些炎症介质在哮喘气道中起重要作用。豚鼠经麻醉并机械通气，同时监测动脉血压，在存在和不存在一氧化氮合酶抑制剂L-NG-硝基精氨酸甲酯（L-NAME）和L-NG-单甲基精氨酸（L-NMMA）的情况下，使用伊文思蓝染料和酸性铬蓝染料评估静脉注射P物质（SP）、白三烯D4（LTD4）和组胺诱导的气道微血管渗漏。还研究了可溶性鸟苷酸环化酶抑制剂LY83583对SP诱导的染料渗漏的影响。静脉注射SP（1微克·千克-1）、LTD4（1微克·千克-1）和组胺（100微克·千克-1）在所有气道水平均显著增加染料外渗。用L-NAME（10毫克·千克-1静脉注射）和L-NMMA（100毫克·千克-1静脉注射）预处理可显著抑制SP诱导的外渗，而L-精氨酸（100毫克·千克-1静脉注射）可逆转L-NAME诱导的抑制作用。L-NAME（10毫克·千克-1静脉注射）仅在中央气道显著抑制LTD4诱导的染料外渗，且这种抑制作用可被神经激肽-1（NK1）拮抗剂FK888（10毫克·千克-1静脉注射）预处理消除。组胺诱导的染料外渗不受L-NAME影响。LY83583（2.5和7.5毫克·千克-1静脉注射）部分但显著减少SP诱导的染料渗漏。这些结果表明，内源性一氧化氮在神经激肽-1受体介导的气道微血管渗漏中起作用，可能涉及鸟苷酸环化酶途径。
