Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension.
Pulmonary hypertension (PH) is a disease of various origins. Nitric oxide-a potent vasodilator-is a key player of pulmonary vasoregulation. Nitric oxide signaling is mainly mediated by the guanylate cyclase/cyclic guanylate monophosphate pathway. The effects of this second messenger system are limited by enzymatic degradation through phosphodiesterases (PDEs). Recently, beneficial effects of the oral PDE-5 inhibitor sildenafil (originally approved for the treatment of erectile dysfunction) were reported for the treatment of PH. We provide a brief overview of the experimental and clinical application of PDE inhibitors in the field of PH. In particular, studies reporting the clinical effectiveness of sildenafil are highlighted. This agent, despite oral application, displays characteristics of a pulmonary selective vasodilator. In addition, evidence shows that sildenafil is operative mainly in the vasculature of well-ventilated areas of the lung. However, to date, controlled randomized trials proving the efficacy of this approach for the treatment of pulmonary arterial hypertension are lacking. The results of such studies have to confirm the current encouraging findings before recommendations regarding the use of PDE-5 inhibitors as a new treatment for PH can be made.
Ghofrani
Hossein A
HA
Department of Internal Medicine Pulmonary Hypertension Center, University Hospital, Giessen, Germany. ardeschir.ghofrani@innere.med.uni-giessen.de
Pepke-Zaba
Joanna
J
Barbera
Joan A
JA
Channick
Richard
R
Keogh
Anne M
AM
Gomez-Sanchez
Miguel A
MA
Kneussl
Meinhard
M
Grimminger
Friedrich
F
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014665:Vasodilator Agents / Q000627:therapeutic use
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000068677:Sildenafil Citrate