Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up-regulation of NO-cGMP signaling.
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 bioavailability 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
Mark
M
Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-University Giessen, Germany.
Kemp-Harper
Barbara
B
Weissmann
Norbert
N
Grimminger
Friedrich
F
Schmidt
Harald H H W
HH
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D015854:Up-Regulation
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D006152:Cyclic GMP