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.
Kageyama
N
N
First Dept of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan.
Miura
M
M
Ichinose
M
M
Tomaki
M
M
Ishikawa
J
J
Ohuchi
Y
Y
Endoh
N
N
Shirato
K
K
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
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