title: Nitric oxide deficiency contributes to impairment of airway relaxation in cystic fibrosis mice.
abstract: The pulmonary disease of cystic fibrosis (CF) is characterized by persistent airway obstruction, which has been attributed to chronic endobronchial infection and inflammation. The levels of exhaled nitric oxide (NO) are reduced in CF patients, which could contribute to bronchial obstruction through dysregulated constriction of airway smooth muscle. Because airway epithelium from CF mice has been shown to have reduced expression of inducible NO synthase, we examined airway responsiveness and relaxation in isolated tracheas of CF mice. Airway relaxation as measured by percent relaxation of precontracted tracheal segments to electrical field stimulation (EFS) and substance P, a nonadrenergic, noncholinergic substance, was significantly impaired in CF mice. The airway relaxation in response to prostaglandin E2 was similar in CF and non-CF animals. Treatment with the NO synthase inhibitor NG-nitro-L-arginine methylester reduced tracheal relaxation induced by EFS in wild-type animals but had virtually no effect in the CF mice. Conversely, exogenous NO and L-arginine, a NO substrate, reversed the relaxation defect in CF airway. We conclude that the relative absence of NO compromises airways relaxation in CF, and may contribute to the bronchial obstruction seen in the disease.
authors.affiliation: Department of Pediatrics, Rainbow Babies and Childrens Hospital and MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-6010, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Mhanna
authors.forename: T
authors.initials: T
authors.lastname: Ferkol
authors.forename: R J
authors.initials: RJ
authors.lastname: Martin
authors.forename: I A
authors.initials: IA
authors.lastname: Dreshaj
authors.forename: A M
authors.initials: AM
authors.lastname: van Heeckeren
authors.forename: T J
authors.initials: TJ
authors.lastname: Kelley
authors.forename: M A
authors.initials: MA
authors.lastname: Haxhiu
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000503:physiopathology; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018181:Mice, Inbred CFTR; D009126:Muscle Relaxation / Q000187:drug effects; D009569:Nitric Oxide / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D004791:Enzyme Inhibitors; D019335:Nitroarginine; D009569:Nitric Oxide; D013373:Substance P; D001120:Arginine; D019001:Nitric Oxide Synthase; D015232:Dinoprostone