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Published ahead of print on November 3, 2003, doi:10.1164/rccm.200211-1372OC

Am. J. Respir. Crit. Care Med., Volume 169, Number 2, January 2004, 227-234

A more recent version of this article appeared on January 15, 2004
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Submitted on December 12, 2002
Accepted on October 30, 2003

Effect of Phosphodiesterase-5 Inhibitor, Sildenafil (Viagra), in Animal Models of Airways Disease

Toby J Toward1, Nicola Smith1, and Kenneth J Broadley1*

1 Divison of Pharmacology, Welsh School of Pharmacy, Cardiff University, Cardiff, Wales, United Kingdom

* To whom correspondence should be addressed. E-mail: SmithN1{at}Cardiff.ac.uk.

Phosphodiesterase-5 degrades guanosine 3',5'cyclic monophosphate (cGMP) and its inhibitor, sildenafil citrate (Viagra) treats erectile dysfunction by smooth muscle relaxation through elevated cGMP. Sildenafil was examined in two guinea-pig models of airways disease; guinea-pigs exposed to lipopolysaccharide or atopic sensitized guinea-pigs exposed to ovalbumen. Ovalbumen exposure caused early-and late-phase bronchoconstrictor responses, measured in conscious animals by whole body plethysmography. 24h after ovalbumen exposure there was airway hyperreactivity to inhaled histamine and significantly elevated macrophages, eosinophils and nitric oxide metabolites in bronchoalveolar lavage fluid. Sildenafil treatment (1mg.kg-1 i.p.) failed to affect the early and late responses, but significantly reduced airway hyperreactivity, leukocyte influx and elevated nitric oxide. Lipopolysaccharide exposure (30 microg.ml-1) caused airway hyperreactivity to histamine at 1h and macrophage, eosinophil and neutrophil influx at 24h with raised nitric oxide. Sildenafil pretreatment inhibited lipopolysaccharide-induced airway hyperreactivity, leukocyte influx and nitric oxide generation. The effectiveness of sildenafil was not dependent upon endogenous nitric oxide since inhibition of nitric oxide synthase with N{omega}-nitro-L-arginine methyl ester did not prevent its action. Inhibition of phosphodiesterase-5 by sildenafil was confirmed by elevated S-nitroso-N-acetylpenicilliamine-induced cGMP generation in isolated lungs. These antiinflammatory actions of sildenafil in guinea-pig models suggest that phosphodiesterase-5 inhibitors may have potential in treating airways disease.
Key words: Asthma, lipopolysaccharide, PDE5 inhibitor, inflammation, airway hyperreactivity




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