Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension.
BACKGROUND
Phosphodiesterase type 5 (PDE5) is a novel therapeutic target for the treatment of pulmonary hypertension. This study examined the distribution of PDE5 in normal and hypoxic lung and the effect of chronic PDE5 inhibition with sildenafil, initiated before and during exposure to hypoxia, on pulmonary artery pressure (PAP) and structure.


RESULTS
Sprague-Dawley rats were exposed to hypoxia (10% O2) for up to 42 days. PAP, measured continuously by telemetry, increased gradually by 20 to 40 mm Hg, reaching a plateau between 10 and 14 days, and declined to normal levels on return to normoxia. PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal lung and in distal muscularized arteries (<25 microm diameter) after hypoxia-induced pulmonary hypertension. Sildenafil (25 or 75 mg x kg(-1) x d(-1)) given before hypoxia produced marked dose-dependent inhibition in the rise of PAP (60% to 90% reduction; P<0.0001) and vascular muscularization (28.4+/-5.0% reduction; P<0.001). When begun after 14 days of hypoxia, sildenafil significantly reduced PAP (30% reduction; P<0.0001) and partially reversed pulmonary artery muscularization (39.9+/-4.9% reduction; P<0.001).


CONCLUSIONS
PDE5 is found throughout the muscularized pulmonary vascular tree, including in newly muscularized distal pulmonary arteries exposed to hypoxia. PDE5 inhibition attenuates the rise in PAP and vascular remodeling when given before chronic exposure to hypoxia and when administered as a treatment during ongoing hypoxia-induced pulmonary hypertension.
Sebkhi
A
A
Section on Clinical Pharmacology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Strange
Julian W
JW
Phillips
Steven C
SC
Wharton
John
J
Wilkins
Martin R
MR
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D018660:Blood Pressure Monitoring, Ambulatory / Q000295:instrumentation; D015153:Blotting, Western; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis / Q000187:drug effects*; D010879:Piperazines / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011667:Pulmonary Veins / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones; D013686:Telemetry; D014665:Vasodilator Agents / Q000627:therapeutic use
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat