Hyperosmolarity reduces the relaxing potency of nitric oxide donors in guinea-pig trachea

1 Non-responders to inhaled nitric oxide treatment have been observed in va rious patient groups. The bronchodilatory effect of inhaled nitric oxide wa s attenuated when the airway lumen was rendered hyperosmolar in an in vivo study on rabbits. We used a guinea-pig tracheal perfusion model to investig ate the effects of increased osmolarity (450 mOsm, NaCl added) on the relax ing 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 mu M) cont racted trachea by 83+/-3%. After pretreatment with intraluminal hyperosmola rity 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 hyperosmo lar conditions, the untreated trachea was completely relaxed by SNP but, af ter hyperosmolar pretreatment, SNP could no longer relax the trachea. 3 SNAP relaxed the CCh contracted trachea by 27+/-5%. After pretreatment wi th 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 contractio n, and SNP administered externally during extraluminal hyperosmolarity was able to relax the trachea (P<0.05). 5 The cell permeable guanosine 3'5'-cyc lic 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 m arkedly reduced when the airway epithelium is exposed to hyperosmolar solut ion.