Abstract | RATIONALE: OBJECTIVES: Because cGMP is inactivated by phosphodiesterase (PDE) enzymes, we hypothesized that the cGMP-specific PDE5 inhibitor sildenafil would promote angiogenesis and attenuate oxygen-induced lung injury in newborn rats. METHODS, MEASUREMENTS, AND MAIN RESULTS: In vitro, sildenafil (10(-4) M) increased endothelial capillary network formation of human pulmonary endothelial cells exposed to hyperoxia. In vivo, rat pups were randomly exposed from birth to normoxia, hyperoxia (95% O(2), BPD model), and hyperoxia+sildenafil (100 mg/kg/day subcutaneously). Rat pups exposed to hyperoxia showed fewer and enlarged air spaces as well as decreased capillary density, mimicking pathologic features seen in human BPD. These structural anomalies were associated with echographic (decreased pulmonary acceleration time) and structural ( right ventricular hypertrophy and increased medial wall thickness) signs of pulmonary hypertension. Sildenafil preserved alveolar growth and lung angiogenesis, and decreased pulmonary vascular resistance, right ventricular hypertrophy and medial wall thickness. CONCLUSIONS: Our findings suggest a role for the NO/cGMP pathway during alveolar development. Sildenafil may have therapeutic potential in diseases associated with impaired alveolar structures.
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Authors | Faruqa Ladha, Sebastien Bonnet, Farah Eaton, Kyoko Hashimoto, Greg Korbutt, Bernard Thébaud |
Journal | American journal of respiratory and critical care medicine
(Am J Respir Crit Care Med)
Vol. 172
Issue 6
Pg. 750-6
(Sep 15 2005)
ISSN: 1073-449X [Print] United States |
PMID | 15947285
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Phosphodiesterase Inhibitors
- Piperazines
- Purines
- Sulfones
- Sildenafil Citrate
- Cyclic GMP
- Oxygen
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Topics |
- Animals
- Animals, Newborn
- Cells, Cultured
- Cyclic GMP
(blood)
- Humans
- Hypertension, Pulmonary
(diagnostic imaging, physiopathology)
- Lung
(blood supply, drug effects, pathology)
- Lung Diseases
(chemically induced, pathology, physiopathology)
- Neovascularization, Physiologic
(drug effects)
- Oxygen
- Phosphodiesterase Inhibitors
(pharmacology)
- Piperazines
(pharmacology)
- Pulmonary Alveoli
(drug effects, growth & development, pathology)
- Purines
- Rats
- Rats, Sprague-Dawley
- Sildenafil Citrate
- Sulfones
- Ultrasonography, Doppler
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