Inclusion criteria:

• Age > 18 years
• PAH defined as IPAH, FPAH, or PAH associated with collagen vascular disease
• Baseline 6MW > 150 meters
• PAH as defined by hemodynamics at diagnosis by right heart catheterization defined as: mean PAP > 25 mmHg with a normal PCWP < 15 mm Hg at rest and a PVR > 3 Wood units
• Receiving conventional therapy as clinically indicated (oxygen, diuretics, aldosterone antagonist, calcium channel blockers, digoxin) with dose that is unchanged in the preceding 30 days prior to enrollment. This is excluding anticoagulants (warfarin) as the patient's dose may not be stable if the patient is having a cardiac catheterization at baseline within 30 days of enrollment and warfarin is being held. The dose of warfarin needs to be stable for 7 days or therapeutic with an INR = 2.0
• If on intravenous/subcutaneous prostacyclin at a stable dose > 30 days
• If subjects are on sildenafil, must be at a stable dose > 30 days
• Must have right heart catheterization on prostacyclin + sildenafil within preceding 30 days. Subjects must be on a stable dose of medication within 30 days prior to cardiac catheterization and therefore there can be no dosage changes of the medications between catheterization and baseline
• Must have pulmonary function tests (PFT) within 90 days prior to enrollment: TLC, FEV1, FVC, DLCO
• Women of childbearing years must use adequate contraception (hormonal or barrier method of birth control) prior to enrollment. Subjects need to have a negative serum or urine pregnancy test.
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• PAH associated with all other etiologies: HIV, portopulmonary disease, congenital heart disease
• Subjects with pulmonary hypertension due to thromboembolism, significant interstitial lung disease, chronic obstructive pulmonary disease, congestive heart failure, valvular heart disease
• Subjects with (World Health Organization (WHO) functional Class IV(19)
• Subjects with scleroderma with total lung capacity (TLC) < 60% of predicted within 30 days of screening
• Subjects with significant obstructive lung disease with FEV1/FVC < 80% of predicted
• Subjects with hypotension defined as systolic arterial pressure < 90 mmHg at baseline
• Subjects with hypertension defined as systolic arterial pressure >140 mmHg at baseline or a diastolic arterial pressure > 90 mmHg
• Subjects with impaired renal function defined as creatinine clearance < 30 ml/min as defined by the

Cockcroft-Gault formula:

• Male: creatinine clearance (ml/min) = (140-age) x (body weight in kg)/ (72x serum creatinine in mg/dl);

• Female: creatinine clearance (ml/min)= 0.85 (140-age) x (body weight in kg)/ (72x serum creatinine in mg/dl)

  • Subjects with liver function tests (transaminases (AST/ALT), total bilirubin, and alkaline phosphatase) > 2X normal values
  • Subjects with acutely decompensated heart failure or hospitalization within the previous 30 days prior to screening
  • Subjects may not be receiving any other investigational agents
  • Subjects on endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan) or chronic arginine supplementation
  • Subjects with left ventricular ejection fraction < 45% or left ventricular shortening fraction < 0.2
  • Subjects with acute myocardial infarction within 90 days prior to screening
  • Subjects with limitations to performance of exercise measures (6MW) due to conditions other than PH associated dyspnea/fatigue
  • Subjects taking nitrates for any medical problem
  • Subjects taking phosphodiesterase inhibitors (any formulation) for erectile dysfunction
  • Subjects with a recent (< 180 days) history of pulmonary embolism verified by ventilation/perfusion scan, angiogram, or spiral CT scan
  • Pregnant or lactating women
  • Subjects with a history of current drug abuse including alcohol