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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Hyperosmolar Solution Effects in Guinea Pig Airways. III. Studies on the Identity of Epithelium-Derived Relaxing Factor in Isolated Perfused Trachea Using Pharmacological Agents

Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia (J.S.F., J.A.D., D.X.-Y.W., R.A.J.); Department of Pharmacology and Toxicology, Robert C. Byrd Health Sciences Center of West Virginia University, Morgantown, West Virginia (J.S.F., R.A.J.); and Department of Physiology, The Brody School of Medicine at East Carolina University, Greenville, North Carolina (M.R.V.S.)

Hyperosmolar challenge of airway epithelium stimulates the release of epithelium-derived relaxing factor (EpDRF), but the identity of EpDRF is not known. We examined the effects of pharmacological agents on relaxant responses of methacholine (3 x 10^-7 M)-contracted guinea pig perfused trachea to mucosal hyperosmolar challenge using D-mannitol. Responses were inhibited by gossypol (5 x10^-6 M), an agent with diverse actions, by the carbon monoxide (CO) scavenger hemoglobin (10^-6 M), and by the heme oxygenase (HO) inhibitor zinc (II) protoporphyrin IX (10^-4 M). The HO inhibitor chromium (III) mesoporphyrin IX (10^-4 M) was not inhibitory, and the HO activator heme-L-lysinate (3 x10^-4 M) did not evoke relaxant responses. The CO donor tricarbonyldichlororuthenium (II) dimer (2.2 x10^-4 M) elicited small relaxation responses. Other agents without an effect on responses included: apyrase, adenosine, 6-anilino-5,8-quinolinequinone (LY83583), proadifen, (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid (MK 571), diphenhydramine, glibenclamide, HgCl₂, tetrodotoxin, nystatin, -hemolysin, 8-bromoguanosine 3',5'-cyclic monophosphothioate, Rp-isomer, 12-O-tetradecanoylphorbol-13-acetate, cholera toxin, pertussis toxin, thapsigargin, nifedipine, Ca²⁺-free mucosal solution, hydrocortisone, and epidermal growth factor. Cytoskeleton inhibitors, includingerythro-9-(2-hydroxyl-3-nonyl)adenine, colchicine, nocodazole, latrunculin B, and cytochalasins B and D, had no effect on relaxation responses. The results suggest provisionally that a portion of EpDRF activity may be due to CO and that the release of EpDRF does not involve cytoskeletal reorganization.

Address correspondence to: Dr. Jeffrey S. Fedan, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Rd., Morgantown, WV 26505-2888. E-mail: jsf2{at}cdc.gov

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