title: The effect of the nitric oxide synthase inhibitor, L-NMMA, on sodium metabisulphite-induced bronchoconstriction and refractoriness in asthma.
abstract: Refractoriness to indirect bronchoconstrictor stimuli, is a feature of asthma but the mechanism is poorly understood. This study tested the hypothesis that endogenous nitric oxide (NO) produced during a first bronchoconstrictor challenge protects against subsequent challenge and therefore has a role in the refractory process. The effect of an NO synthase inhibitor, N(G)-mono-methyl-L-arginine (L-NMMA), on refractoriness to sodium metabisulphite (MBS) was investigated in 20 subjects with mild asthma. On visit one, the dose of MBS which caused a 20% fall in forced expiratory volume in one second (FEV1) (PD20) was determined. On visit two, the refractory index (RI) to MBS was determined by challenging the subjects twice with their PD20 of MBS, the second challenge proceeding after recovery from the first. Those showing a refractory index of approximately 30% (10 subjects) inhaled either L-NMMA or placebo followed 5 min later by two challenges with their PD20 of MBS in a double-blind cross over study at two further visits. The dose of L-NMMA used was shown to reduce exhaled NO for a duration sufficient to cover the second MBS challenge However, no significant difference was found between L-NMMA and placebo in maximum fall in FEV1% and area under the curve (AUC) during first or second MBS challenges or in RI on the two study days. It is concluded that subjects with mild asthma show refractoriness to sodium metabisulphite, but that endogenous nitric oxide is unlikely to be involved either in the refractory process or in the response to sodium metabisulphite per se.
authors.affiliation: Dept of Respiratory Medicine, City Hospital, Nottingham, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Hamad
authors.forename: A
authors.initials: A
authors.lastname: Wisniewski
authors.forename: S P
authors.initials: SP
authors.lastname: Range
authors.forename: T
authors.initials: T
authors.lastname: Small
authors.forename: F
authors.initials: F
authors.lastname: Holland
authors.forename: A J
authors.initials: AJ
authors.lastname: Knox
mesh_terms: D001249:Asthma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D016084:Bronchoconstriction / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004342:Drug Hypersensitivity / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume; D006801:Humans; D009569:Nitric Oxide / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009819:Office Visits; D013147:Spirometry; D013447:Sulfites; D016896:Treatment Outcome; D019323:omega-N-Methylarginine / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013447:Sulfites; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C030981:metabisulfite; D019001:Nitric Oxide Synthase