February 2013

Nitric Oxide in Hyposmia

The role of nitric oxide in hyposmia was first hypothesized in patients with hyposmia after hyposmia was improved with treatment with theophylline. This therapy was found to increase nitric oxide levels similar to increases that occurred in cAMP and cGMP subsequent to detailed analysis of the theophylline treatment results.

The mechanism for this action includes the action of a cAMP elevating agent (i.e., theophylline) acting to increase an inducible type of nitric oxide such that as cAMP increases nitric oxide also increases. Nitric oxide also activates guanylate cyclase and increases cGMP in several tissues. Many prior studies have demonstrated these effects.

Our clinical studies indicate that theophylline acts as a cAMP elevating agent which corrects smell loss in patients with many causes of their smell loss and in so doing can also increase nitric oxide. This theophylline action increases stem cell activation of both taste and smell receptors, increases the generation and perpetuation of taste and smell receptors and thereby restores taste and smell function in patients with previously untreated hyposmia.

1. Henkin RI, Velicu I, Levy, LM. Congenital smell loss – a genetic disorder of decreased cell growth and increased cell death determined by biochemical measurements in nasal mucus. FASEB J. 2007;21:728.5.

2. Arnold WP, Mittal CK, Katsuki, S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3’:5’-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci USA. 1977;74:3203-3207.

3. Bredt DS, Ferris CD, Snyder SH. Nitric oxide synthase regulatory sites. Phosphorylation by cyclic AMP-dependent protein kinase, protein kinase C, and calcium/calmodulin protein kinase; identification of flavin and calmodulin binding sites. J Biol Chem. 1992;267:10976-10981.