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Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up-regulation of NO-cGMP signaling

Mark Kirsch^*, Barbara Kemp-Harper, Norbert Weissmann, Friedrich Grimminger and Harald H. H. W. Schmidt^,1

^* Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, Germany;

Department of Pharmacology and Centre for Vascular Health, Monash University, Melbourne, Australia; and

University of Giessen Lung Center, Medical Clinic II/V, Giessen, Germany

¹Correspondence: Department of Pharmacology & Centre for Vascular Health, Monash University, Wellington Rd., Bldg. 13e, Rm. 116, Melbourne, Victoria 3800, Australia. E-mail: harald.schmidt{at}med.monash.edu.au

The availability of inhibitors of cGMP-specific phosphodiesterase 5 (PDE 5), such as sildenafil, has revolutionized the treatment of pulmonary hypertension (PH). Sildenafil may exert its protective effects in a mechanism-based fashion by targeting a pathophysiologically attenuated NO-cGMP signaling pathway. To elucidate this, we analyzed changes in the pulmonary expression and activity of key enzymes of NO-cGMP signaling as well as the functional pulmonary responses to sildenafil in the 5 or 21 day hypoxia mouse model of PH. Surprisingly, we found doubled NO synthase (NOS) II and III levels, no evidence for attenuated NO bioaviability as evidenced by the nitrosative/oxidative stress marker protein nitro tyrosine, and no changes in the expression and activity of the NO receptor, soluble guanylyl cyclase (sGC). PDE 5 was either unchanged at day 5 or, after 21 days of hypoxia, even significantly decreased along with unchanged activity. Biochemically, these changes were mirrored by increased cGMP spillover into the lung perfusate and cGMP-dependent phosphorylation of the vasodilator-stimulated phosphoprotein, VASP. Sildenafil further augmented cGMP and phospho-VASP levels in lungs of mice exposed for 5 or 21 days and decreased pulmonary arterial pressure in mice after 5 days but not 21 days of hypoxia. In conclusion, NO-cGMP signaling is compensatorily up-regulated in the hypoxic mouse model of PH, and sildenafil further augments this pathway to functionally alleviate pulmonary vasoconstriction.—Kirsch, M., Kemp-Harper, B., Weissmann, N., Grimminger, F., Schmidt, H. H. H. W. Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up-regulation of NO-cGMP signaling.

Key Words: vascular disease • PH • lung perfusate

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