This Article Abstract Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ghofrani, H. A. Articles by Grimminger, F. Search for Related Content PubMed Articles by Ghofrani, H. A. Articles by Grimminger, F.

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

View larger version (22K): [in a new window]   Figure 1 Scheme of nitric oxide (NO) metabolism pathway. In this diagram the nitric oxide (NO) pathway is depicted. In presence of oxygen (O2) and/or alveolar ventilation, NO synthases (NOS) are activated and produce NO from L-arginine via L-citrulline. The NO activates soluble- and membrane-bound guanylate cyclases, which synthesize cyclic guanylate monophosphate (cGMP), which subsequently activates cGMP-kinase. This enzyme—by activation of K+-channels and subsequent Ca++-channel inhibition—evokes a reduction of intracellular Ca++ concentration, finally resulting in vasodilation. The downstream effects of NO are limited by phosphodiesterase (PDE)-induced degradation of cGMP.

View larger version (29K): [in a new window]   Figure 2 Comparison of pulmonary vasodilative potency of oral sildenafil, inhaled nitric oxide (NO), and inhaled iloprost. Comparative vasodilator testing was performed in 30 patients with precapillary pulmonary hypertension. In each group, the effect of inhaled NO on pulmonary vascular resistance (PVR) was compared with that of sildenafil, inhaled iloprost, or a combination of both. In the upper left figure, inhaled NO and iloprost were compared with a low dose of sildenafil (12.5 mg), while in the upper right figure a combination of sildenafil and iloprost was tested. The lower left figure summarizes the effects of 50 mg sildenafil compared to NO and iloprost, and the lower right figure shows the data of a combination of high-dose sildenafil with iloprost (adapted from Ghofrani et al., Ann Intern Med 2002;136:515–22).

View larger version (20K): [in a new window]   Figure 3 Hemodynamic and gas-exchange response to inhaled nitric oxide (NO), infused PGI2, and oral sildenafil in patients with lung fibrosis and pulmonary hypertension. Deviations from preintervention baseline are displayed for inhaled NO, infused prostacyclin (PGI iv), and oral sildenafil (Sil oral). CO = cardiac output; mPAP = mean pulmonary arterial pressure; mSAP = mean systemic arterial pressure; PaO 2 = partial pressure of arterial oxygen (changes in mm Hg); PVRI = pulmonary vascular resistance index; PVR/SVR ratio = ratio of pulmonary to systemic vascular resistance (adapted from Ghofrani et al., Lancet 2002;360:895–900).