Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide.
BACKGROUND
The prognosis of patients with severe pulmonary hypertension (PHT) is poor. To determine prognosis and guide therapy, an acute hemodynamic trial of selective pulmonary vasodilators, usually inhaled nitric oxide (iNO), was performed. We hypothesized that oral sildenafil, a phosphodiesterase-5 inhibitor, is a safe and effective alternative to iNO.


RESULTS
We studied 13 consecutive patients (mean+/-SEM, 44+/-2 years of age; 9 women) referred for consideration of heart-lung transplantation or as a guide to medical therapy. All but one were functional class III or IV. Patients had primary PHT (n=9), pulmonary arterial hypertension (n=2), or secondary PHT (n=2). Hemodynamics and serum cyclic guanosine-monophosphate levels (cGMP) were measured at baseline and at peak effects of iNO (80 ppm), sildenafil (75 mg), and their combination. The decrease in pulmonary vascular resistance was similar with iNO (-19+/-5%) and sildenafil (-27+/-3%), whereas sildenafil+iNO was more effective than iNO alone (-32+/-5%, P<0.003). Sildenafil and sildenafil+iNO increased cardiac index (17+/-5% and 17+/-4%, respectively), whereas iNO did not (-0.2+/-2.0%, P<0.003). iNO increased, whereas sildenafil tended to decrease, pulmonary capillary wedge pressure (+15+/-6 versus -9+/-7%, P<0.0007). Systemic arterial pressure was similar among groups and did not decrease with treatment. cGMP levels increased similarly with iNO and sildenafil, and their combination synergistically elevated cGMP (P<0.0001).


CONCLUSIONS
A single oral dose of sildenafil is as effective and selective a pulmonary vasodilator as iNO. Sildenafil may be superior to iNO in that it increases cardiac output and does not increase wedge pressure. Future studies are indicated to establish whether sildenafil could be effective over a longer duration.
Michelakis
Evangelos
E
Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Canada. emichela@cha.ab.ca
Tymchak
Wayne
W
Lien
Dale
D
Webster
Linda
L
Hashimoto
Kyoko
K
Archer
Stephen
S
D000284:Administration, Oral; D000328:Adult; D006152:Cyclic GMP / Q000097:blood; D004232:Diuretics / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D006261:Headache / Q000209:etiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000008:administration & dosage*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D011237:Predictive Value of Tests; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects; D014859:Warfarin / Q000627:therapeutic use
D004232:Diuretics; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D014859:Warfarin; D000068677:Sildenafil Citrate; D006152:Cyclic GMP