title: Asymmetric dimethylarginine blocks nitric oxide-mediated alcohol-stimulated cilia beating.
abstract: The airway epithelium is exposed to alcohol during drinking through direct exhalation of volatized ethanol from the bronchial circulation. Alcohol exposure leads to a rapid increase in the cilia beat frequency (CBF) of bronchial epithelial cells followed by a chronic desensitization of cilia stimulatory responses. This effect is governed in part by the nitric oxide regulation of cyclic guanosine and adenosine monophosphate-dependent protein kinases (PKG and PKA) and is not fully understood. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is implicated in the pathogenesis of several pulmonary disorders. We hypothesized that the inhibition of nitric oxide synthase by ADMA blocks alcohol-stimulated increases in CBF. To test this hypothesis, ciliated primary bovine bronchial epithelial cells (BBEC) were preincubated with ADMA (100  µM) and stimulated with 100 mM ethanol. CBF was measured and PKA assayed. By 1 hr, ethanol activated PKA, resulting in elevated CBF. Both alcohol-induced PKA activation and CBF were inhibited in the presence of ADMA. ADMA alone had no effect on PKA activity or CBF. Using a mouse model overexpressing the ADMA-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), we examined PKA and CBF in precision-cut mouse lung slices. Alcohol-stimulated increases in lung slice PKA and CBF were temporally enhanced in the DDAH mice versus control mice.
authors.affiliation: VA Nebraska-Western Iowa Health Care System Research Service, Department of Veterans Affairs Medical Center, 4101 Woolworth Avenue, Omaha, NE 68105, USA ; Department of Environmental, Agricultural, and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA ; Pulmonary, Critical Care, Sleep & Allergy Division, Department of Internal Medicine, 985300 Nebraska Medical Center, Omaha, NE 68198-5300, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Wyatt
authors.forename: S M
authors.initials: SM
authors.lastname: Wells
authors.forename: Z A
authors.initials: ZA
authors.lastname: Alsaidi
authors.forename: J M
authors.initials: JM
authors.lastname: DeVasure
authors.forename: E B
authors.initials: EB
authors.lastname: Klein
authors.forename: K L
authors.initials: KL
authors.lastname: Bailey
authors.forename: J H
authors.initials: JH
authors.lastname: Sisson
mesh_terms: D000581:Amidohydrolases / Q000737:chemistry; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001980:Bronchi / Q000166:cytology / Q000473:pathology; D002417:Cattle; D002470:Cell Survival; D002478:Cells, Cultured; D002923:Cilia / Q000187:drug effects / Q000473:pathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism*; D013997:Time Factors; D014132:Trachea / Q000473:pathology
chemical_list: D009569:Nitric Oxide; D000431:Ethanol; C018524:N,N-dimethylarginine; D001120:Arginine; D017868:Cyclic AMP-Dependent Protein Kinases; D000581:Amidohydrolases; C059999:dimethylargininase