Abstract
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 × 10-7 M)-contracted guinea pig perfused trachea to mucosal hyperosmolar challenge using d-mannitol. Responses were inhibited by gossypol (5 ×10-6 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 ×10-4 M) did not evoke relaxant responses. The CO donor tricarbonyldichlororuthenium (II) dimer (2.2 ×10-4 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, α-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.
Footnotes
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↵1 Hypertonic solutions are those that cause cell shrinkage. Hyperosmolar solutions have osmolarity greater than that of the physiological extracellular solution. For simplicity, in this report we do not draw distinctions between the two terms when describing general phenomena.
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This work was supported, in part, by National Institutes of Health Grant 5-T32-GM07039 (to R.A.J.). Mention of brand name does not constitute product endorsement. This article is the third one of a series of four companion articles that report the effects of hyperosmolar solutions in guinea pig airways (Fedan et al., 2003; Johnston et al., 2003; Wu et al., 2003).
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DOI: 10.1124/jpet.103.051664.
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ABBREVIATIONS: EpDRF, epithelium-derived relaxing factor; MCh, methacholine; d-M, d-mannitol; MKHS, modified Krebs-Henseleit solution; ZnPP, zinc (II) protoporphyrin IX; CrMP, chromium (III) mesoporphyrin IX; Rp-8-Br-cGMPS, 8-bromoguanosine 3',5'-cyclic monophosphothioate, Rp-isomer; CO, carbon monoxide; HO, heme oxygenase; [Ru(Co)3Cl2]2, tricarbonyldichlororuthenium (II) dimer; PK, protein kinase; TPA, 12-O-tetradecanoylphorbol-13-acetate; EGF, epidermal growth factor; LY83583, 6-anilino-5,8-quinolinequinone; MK 571, (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid.
- Received March 14, 2003.
- Accepted October 8, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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