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Habituation in nitric oxide stimulation of cyclic GMP production.
Mercer RR; Brady TC; Castranova V; Autten RL
Toxicologist 1998 Mar; 42(1-S):302
We have previously demonstrated that inhaled NO (I wk. 6ppm) reduces growth factor signaling via protein phosphorylation and in longer exposures produces atrophy of interstitial cells and matrix. These results were not expected given the role of cGMP in stimulating interstitial cell and matrix synthesis and the presumed stimulation of cGMP by inhaled NO. In this study we measured the time course of changes in pulmonary cyclic nucleotides and tyrosine kinase/phosphatase activity. For these measurements Sprague Dawley rats (275-325 gm) were exposed to clean-air or 6 ppm NO for 1 hour, 24 hours or 1 week. Lung tissue was harvested for assay of cGMP and cAMP content, total kinase activity (serine, threnine, and tyrosine), tyrosine kinase/phosphatase activity and total tyrosine phosphorylated proteins. NO exposure produced a transient elevation in cGMP. After 1hr of NO, cGMP was 5 fold greater than clean-air controls and 2 fold higher at 24 hours. However after one week of exposure, cGMP returned to control levels. No difference in total kinase activity was found. Tyrosine kinase and phosphatase activity of NO groups were not significantly different from clean-air controls. Total tyrosine phosphorylated proteins were significantly reduced at 1 week. The results demonstrate that the lungs can produce feedback inhibition of inhaled NO-stimulated cGMP production. Nitration of tyrosines in protein substrates appears to block phosphorylation and potentially suppresses an important growth factor signaling pathway.
Nitrogen-oxides; Cell-function; Cell-growth; Cell-damage; Cell-alteration; Proteins; Animal-studies; Animals; Laboratory-animals; Pulmonary-disorders; Pulmonary-function; Pulmonary-system; Pulmonary-function-tests
The Toxicologist. Society of Toxicology 37th Annual Meeting, March 1-5,1998, Seattle, Washington