Phosphodiesterase type 5 and high altitude pulmonary hypertension.
BACKGROUND
This study explored phosphodiesterase type 5 (PDE5) inhibition as a strategy for treating high altitude pulmonary arterial hypertension (HAPH).


METHODS
689 subjects (313 men) of mean (SD) age 44 (0.6) years living above 2500 m were screened for HAPH by medical examination and electrocardiography, and 188 (27%) met the criteria for right ventricular hypertrophy. 44 underwent cardiac catheterisation and 29 (66%) had a resting mean pulmonary artery pressure (PAP) above 25 mmHg. 22 patients with a raised mean PAP were randomised to receive sildenafil (25 or 100 mg) or matching placebo taken 8 hourly for 12 weeks.


RESULTS
At 3 months, patients on sildenafil 25 mg 8 hourly (n = 9) had a significantly (p = 0.018) lower mean PAP (-6.9 mmHg) at the end of the dosing interval than those on placebo (n = 8) (95% CI -12.4 to -1.3). The treatment effect for sildenafil 100 mg 8 hourly (n = 5) compared with placebo was -6.4 mm Hg (95% CI -12.9 to 0.1). Both doses improved 6 minute walk distance, the lower dose by 45.4 m (95% CI 11.5 to 79.4; p = 0.011) and the higher dose by 40.0 m (95% CI 0.2 to 79.8; p = 0.049). Sildenafil was well tolerated. Necroscopic lung specimens from three subjects with HAPH showed abundant PDE5 in the muscular coat of remodelled pulmonary arterioles.


CONCLUSIONS
PDE5 is an attractive drug target for the treatment of HAPH and a larger study of the long term effects of PDE5 inhibition in HAPH is warranted.
Aldashev
A A
AA
Institute of Molecular Biology and Medicine, Bishkek, Kyrgyzstan.
Kojonazarov
B K
BK
Amatov
T A
TA
Sooronbaev
T M
TM
Mirrakhimov
M M
MM
Morrell
N W
NW
Wharton
J
J
Wilkins
M R
MR
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000532:Altitude Sickness / Q000188:drug therapy* / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human