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Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension

Hossein A. Ghofrani, MD^*,*, Joanna Pepke-Zaba, MD, Joan A. Barbera, MD, Richard Channick, MD, Anne M. Keogh, MD^||, Miguel A. Gomez-Sanchez, MD^¶, Meinhard Kneussl, MD and Friedrich Grimminger, MD^*

^* Department of Internal Medicine Pulmonary Hypertension Center, University Hospital, Giessen, Germany
Pulmonary Vascular Disease Unit, Papworth Hospital, Papworth Everard, Cambridge, United Kingdom
Servei de Pneumologia i Al.lèrgia Respiratòria, Unitat de Transplantament Renal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
Division of Pulmonary and Critical Care Medicine, University of California, San Diego, California, USA
^|| Xavier 4, St. Vincent's Hospital, Darlinghurst, Australia
^¶ Unidad de Insuficiencia Cardíaca e Hipertensión Pulmonar, Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain
Department of Internal Medicine V, University Hospital, Vienna, Austria

Manuscript received December 1, 2003; revised manuscript received February 6, 2004, accepted February 10, 2004.

^* Reprint requests and correspondence: Dr. Hossein-Ardeschir Ghofrani, Department of Internal Medicine, Pulmonary Hypertension Center, University Hospital, Klinikstrasse 36, 35392 Giessen, Germany.
ardeschir.ghofrani{at}innere.med.uni-giessen.de

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.

Abbreviations and Acronyms   cAMP = cyclic adenylate monophosphate   cGMP = cyclic guanylate monophosphate   GC = guanylate cyclase   HIV = human immunodeficiency virus   NO = nitric oxide   NYHA = New York Heart Association   PAH = pulmonary arterial hypertension   PDE = phosphodiesterase   PH = pulmonary hypertension   PPH = primary pulmonary hypertension

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