Deficiency of nitric oxide in polycation-induced airway hyperreactivity.
Using a perfused guinea-pig tracheal tube preparation, we investigated the role of endogenous nitric oxide (NO) in polycation-induced airway hyperreactivity (AHR) to methacholine. Intraluminal (IL) administration of the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 100 microM) caused a 1.8 fold increase in the maximal contractile response (Emax) to IL methacholine compared to control, without an effect on the pEC50 (-log10 EC50). The polycation poly-L-arginine (100 microg ml(-1), IL) similarly enhanced the Emax for methacholine; however, the pEC50 value was also increased, by one log10 unit. L-NAME had no effect on the enhanced methacholine response of poly-L-arginine-treated airways, while the enhanced agonist response was completely normalized by the polyanion heparin (25 u ml(-1), IL). In addition, the effect of L-NAME was fully restored in the poly-L-arginine plus heparin treated airways. The results indicate that, in addition to enhanced epithelial permeability, a deficiency of endogenous NO contributes to polycation-induced AHR. The latter finding may represent a novel mechanism of AHR induced by eosinophil-derived cationic proteins in allergic asthma.
Meurs
H
H
Department of Molecular Pharmacology, University Centre for Pharmacy, Groningen, The Netherlands.
Schuurman
F E
FE
Duyvendak
M
M
Zaagsma
J
J
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006493:Heparin / Q000494:pharmacology; D066298:In Vitro Techniques; D016210:Methacholine Chloride / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011073:Polyamines / Q000494:pharmacology*; D000071228:Polyelectrolytes; D011108:Polymers / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology
D016085:Bronchoconstrictor Agents; D004791:Enzyme Inhibitors; D006493:Heparin; D016210:Methacholine Chloride; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D010455:Peptides; D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers; C015462:polyarginine