title: Role of endogenous nitric oxide in airway microvascular leakage induced by inflammatory mediators.
abstract: 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.
authors.affiliation: First Dept of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kageyama
authors.forename: M
authors.initials: M
authors.lastname: Miura
authors.forename: M
authors.initials: M
authors.lastname: Ichinose
authors.forename: M
authors.initials: M
authors.lastname: Tomaki
authors.forename: J
authors.initials: J
authors.lastname: Ishikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Ohuchi
authors.forename: N
authors.initials: N
authors.lastname: Endoh
authors.forename: K
authors.initials: K
authors.lastname: Shirato
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001249:Asthma / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects*; D004396:Coloring Agents; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005070:Evans Blue; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000175:diagnosis / Q000209:etiology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000494:pharmacology*; D007275:Injections, Intravenous; D017998:Leukotriene D4 / Q000008:administration & dosage / Q000494:pharmacology; D008168:Lung / Q000098:blood supply*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009942:Organometallic Compounds; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D000634:Aminoquinolines; D004396:Coloring Agents; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007211:Indoles; D018836:Inflammation Mediators; D064729:Neurokinin-1 Receptor Antagonists; D009942:Organometallic Compounds; C078949:FK 888; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D013373:Substance P; C015445:copper phthalocyanine; D005070:Evans Blue; D017998:Leukotriene D4; D006632:Histamine; C041715:6-anilino-5,8-quinolinedione; D001120:Arginine; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D019331:NG-Nitroarginine Methyl Ester