Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity.
BACKGROUND
Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil) are a novel, orally active approach to the treatment of pulmonary arterial hypertension. The role of natriuretic peptides in the response to sildenafil was examined in mice lacking NPR-A, a guanylyl cyclase-linked natriuretic peptide receptor, in which pulmonary hypertension was induced by hypoxia.


RESULTS
Mice homozygous for NPR-A (NPR-A+/+) and null mutants (NPR-A-/-) were studied. Sildenafil inhibited the pressor response to acute hypoxia in the isolated perfused lungs of both genotypes. This effect was greater in the presence of atrial natriuretic peptide in the perfusate in NPR-A+/+ mice but not NPR-A-/- animals. In vivo, NPR-A mutants had higher basal right ventricular (RV) systolic pressures (RVSPs) than did NPR-A+/+ mice, and this was not affected by 3 weeks of treatment with sildenafil (25 mg x kg(-1) x d(-1)). Both genotypes exhibited a rise in RVSP and RV weight with chronic hypoxia (10% O2 for 21 days); RVSP and RV weight were reduced by continuous sildenafil administration in NPR-A+/+ mice, but only RVSP showed evidence of a response to the drug in NPR-A-/- mice. The effect of sildenafil on hypoxia-induced pulmonary vascular muscularization and cyclic GMP levels was also blunted in NPR-A-/- mice.


CONCLUSIONS
The natriuretic peptide pathway influences the response to PDE5 inhibition in hypoxia-induced pulmonary hypertension, particularly its effects on RV hypertrophy and vascular remodeling.
Zhao
Lan
L
Section on Clinical Pharmacology, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, London, England.
Mason
Nicola A
NA
Strange
Julian W
JW
Walker
Hamish
H
Wilkins
Martin R
MR
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D006162:Guanylate Cyclase / Q000172:deficiency* / Q000235:genetics; D006720:Homozygote; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D010477:Perfusion; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency* / Q000235:genetics; D012121:Respiration, Artificial; D000068677:Sildenafil Citrate; D013450:Sulfones; D016278:Ventricular Function, Right / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009320:Atrial Natriuretic Factor; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP