title: Hyperosmolarity reduces the relaxing potency of nitric oxide donors in guinea-pig trachea.
abstract: 1. Non-responders to inhaled nitric oxide treatment have been observed in various patient groups. The bronchodilatory effect of inhaled nitric oxide was attenuated when the airway lumen was rendered hyperosmolar in an in vivo study on rabbits. We used a guinea-pig tracheal perfusion model to investigate the effects of increased osmolarity (450 mOsm, NaCl added) on the relaxing potency of the nitric oxide donors sodium nitroprusside (SNP) and (+/-)-S-nitroso-N-acetylpenicillamine (SNAP). 2. Under iso-osmolar conditions SNP relaxed the carbachol (CCh, 1 microM) contracted trachea by 83+/-3%. After pretreatment with intraluminal hyperosmolarity SNP relaxed the CCh-contracted trachea by only 31+/-7% (P<0.05). When the trachea was contracted to the same extent under untreated and hyperosmolar conditions, the untreated trachea was completely relaxed by SNP but, after hyperosmolar pretreatment, SNP could no longer relax the trachea. 3. SNAP relaxed the CCh contracted trachea by 27+/-5%. After pretreatment with intraluminal hyperosmolarity, SNAP relaxed the trachea by 11+/-4%, which was less than in the iso-osmolar control (P<0.05). 4. Extraluminal hyperosmolarity did not affect carbachol elicited contraction, and SNP administered externally during extraluminal hyperosmolarity was able to relax the trachea (P<0.05). 5. The cell permeable guanosine 3'5'-cyclic monophosphate analogue 8-Br-cGMP relaxed the CCh contracted trachea in both iso-osmolar (P<0.05) and hyperosmolar conditions (P<0.05). 6. The relaxant effect of nitric oxide donors on tracheal smooth muscle is markedly reduced when the airway epithelium is exposed to hyperosmolar solution.
authors.affiliation: Department of Medical Sciences, Clinical Physiology, Uppsala University, University Hospital, Sweden. josephine.hjoberg@klinfys.uu.se
authors.forename: J
authors.initials: J
authors.lastname: Hjoberg
authors.forename: M
authors.initials: M
authors.lastname: Högman
authors.forename: G
authors.initials: G
authors.lastname: Hedenstierna
mesh_terms: D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D009994:Osmolar Concentration; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D012462:Saline Solution, Hypertonic / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D018721:Muscarinic Agonists; D020030:Nitric Oxide Donors; D012462:Saline Solution, Hypertonic; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D026423:S-Nitroso-N-Acetylpenicillamine; D002217:Carbachol; D006162:Guanylate Cyclase; D010396:Penicillamine; D006152:Cyclic GMP