The hyperosmolar airway : Mechanisms of reduced response to nitric oxide
Abstract: Inhaled nitric oxide (NO) relaxes smooth muscle of the airways and of pulmonary blood vessels and is used to treat lung diseases where the pulmonary vessels are constricted. NO has also been tested as a bronchodilator in asthmatic patients. Inhaled NO is a powerful therapeutic agent, but about one-third of the patients do not respond to the treatment.It was hypothesised that variations in thedegree of airway wall oedema could account for the variable responses to inhaled NO. After creation of airway wall oedema in mechanically ventilated rabbits, by inhalation of nebulised hypertonic saline, inhaled NO could no longer dilate methacholine-constricted airways. An increase in the ionconcentration, the osmolarity, on the airway surface produced by hyperventilating the rabbits with dry air also blocked the relaxation induced by NO. The mechanism underlying this lack of response to NO in a hyperosmolar airway was further investigated with guinea pig tracheal perfusion methods in vitro.When the osmolarity was increased on the mucosal side of guinea pig trachea in vitro, the relaxation induced by the NO donor sodium nitroprusside (SNP) was diminished. Hyperosmolarity dehydrated the mucosa and submucosa, but blocking of the epithelial dehydration with amiloride did not affect the response to SNP. The decrease in response to NO in the hyperosmolar airway was not due to dysfunction of the tracheal smooth muscle and the most likely-explanation is that the NO molecule becomes bound or inactivated and does not reach the airway smooth muscle. Removal of NO scavenging superoxide anions with superoxide dismutase (SOD) increased the relaxing effect of SNP. In conclusion, increased osmolarity on the airway epithelium leads to reducedairway relaxation by NO. The suggested mechanism of this reduction is the generation of superoxide anions that inactivate the NO molecule.
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