Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension.
BACKGROUND
The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown.


RESULTS
We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger's syndrome; New York Heart Association class II to III). Functional class improved by > or =1 class in all patients. Pretreatment versus posttreatment values (mean+/-SEM) were as follows: 6-minute walk, 376+/-30 versus 504+/-27 m, P<0.0001; mean PA pressure, 70+/-3 versus 52+/-3 mm Hg, P<0.007; pulmonary vascular resistance index 1702+/-151 versus 996+/-92 dyne x s x cm(-5) x m(-2), P<0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels.


CONCLUSIONS
This small pilot study suggests that long-term sildenafil therapy might be a safe and effective treatment for PAH. At a monthly cost of 492 dollars Canadian, sildenafil is more affordable than most approved PAH therapies. A large multicenter trial is indicated to directly compare sildenafil with existing PAH treatments.
Michelakis
Evangelos D
ED
Vascular Biology Group and Pulmonary Hypertension Program, Department of Medicine, University of Alberta, 2C2 Walter C Mackenzie Health Sciences Centre, 8440 112th St, Edmonton, Alberta, Canada, T6G 2B7. emichela@cha.ab.ca
Tymchak
Wayne
W
Noga
Michelle
M
Webster
Linda
L
Wu
Xi-Chen
XC
Lien
Dale
D
Wang
Shao-Hua
SH
Modry
Dennis
D
Archer
Stephen L
SL
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000284:Administration, Oral; D000328:Adult; D002469:Cell Separation; D003404:Creatinine / Q000032:analysis; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D005080:Exercise Test / Q000187:drug effects; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology*; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D018408:Patch-Clamp Techniques; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis / Q000187:drug effects; D010865:Pilot Projects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use*; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011687:Purines; D000068677:Sildenafil Citrate; D013318:Stroke Volume / Q000187:drug effects; D013450:Sulfones; D013995:Time; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use*
D051036:Large-Conductance Calcium-Activated Potassium Channels; D010879:Piperazines; D024681:Potassium Channels, Calcium-Activated; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D003404:Creatinine; D000068677:Sildenafil Citrate; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human