Modulating Effects of Lisinopril on Sildenafil Activity in Pulmonary Arterial Hypertension(PAH)( MELISSA)

The broad aim of this investigation is to determine whether the modulating effect of angiotensin converting enzyme inhibition on vascular smooth muscle responsiveness to the nitric oxide pathway that we have observed in an animal model of Congestive Heart Failure(CHF) can be exploited in humans with PAH. Furthermore, we have identified a group of genes TAO kinase I, IL-10, Rho kinase, Raf1, bile acid coenzyme A and Fmr1 that are modulated by long-acting angiotensin-converting enzyme inhibitor (ACEI) in our animal model, and therefore may also be modulated by ACEI in patients with PAH

Inclusion criteria

• Age 18-75
• World Health Organization (WHO) Group I PAH with prior documentation of peripheral vascular resistance (PVR) > 3 WU and wedge(PCW) 16 or less.
• WHO Functional Class I-III
• 6 minute walk distance 150-575 meters
• Women of child bearing potential must have a negative pregnancy test and be using effective contraception
• Receiving therapy with phosphodiesterase-5 inhibitor for PAH (sildenafil or tadalafil) for at least 3 months and with stable dose for at least 30 days
• If already receiving therapy with endothelin receptor antagonists must have been on therapy for at least 3 months and on stable dose for at least 30 days

Exclusion criteria

• Allergy or intolerance to captopril or other angiotensin converting enzyme inhibitors
• Systemic systolic blood pressure less than 100 mm Hg
• Therapy with prostanoids (iloprost, treprostinil, epoprostenol) within preceding 3 months
• Pregnant or breast feeding
• Creatinine > 2.0 mg/dl
• Potassium > 5.0 meq/dl
• Unable to provide informed consent
• TLC or VC <60% predicted
• Untreated obstructive sleep apnea
• LVEF < 40%
• Hb < 10 mg/dL