ERJ
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Published online before print June 11, 2008, 10.1183/09031936.00114407
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary materials, methods and figures
Right arrow All Versions of this Article:
32/4/881    most recent
09031936.00114407v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Permissions
Right arrowRequest Permissions
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (8)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schermuly, R. T.
Right arrow Articles by Grimminger, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schermuly, R. T.
Right arrow Articles by Grimminger, F.
Eur Respir J 2008; 32:881-891
Copyright ©ERS Journals Ltd 2008

Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension

R. T. Schermuly1, J-P. Stasch2, S. S. Pullamsetti1, R. Middendorff3, D. Müller3, K-D. Schlüter4, A. Dingendorf4, S. Hackemack1, E. Kolosionek1, C. Kaulen1, R. Dumitrascu1, N. Weissmann1, J. Mittendorf2, W. Klepetko5, W. Seeger1, H. A. Ghofrani1 and F. Grimminger1

1 University of Giessen Lung Centre (UGLC), 3 Dept of Anatomy and Cell Biology, 4 Institute of Physiology, University of Giessen, Giessen, 2 Pharma Research Centre, Bayer HealthCare, Wuppertal, Germany, 5 Dept of Cardiothoracic Surgery, University of Vienna, Vienna, Austria.

CORRESPONDENCE: R. T. Schermuly, University of Giessen Lung Centre (UGLC), Klinikstrasse 36, 35392 Giessen, Germany. Fax: 49 6419942419. E-mail: ralph.schermuly{at}uglc.de

Keywords: BAY 63-2521, cardiovascular diseases, nitric oxide, pharmacology, pulmonary arterial hypertension, smooth muscle

Received: August 31, 2007
Accepted May 18, 2008

Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH.

Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg·kg–1·day–1) partially reversed the PAH, the right heart hypertrophy and the structural remodelling of the lung vasculature.

Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right heart hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension.




This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
S. de Frutos, C. H. Nitta, E. Caldwell, J. Friedman, and L. V. Gonzalez Bosc
Regulation of soluble guanylyl cyclase-{alpha}1 expression in chronic hypoxia-induced pulmonary hypertension: role of NFATc3 and HuR
Am J Physiol Lung Cell Mol Physiol, September 1, 2009; 297(3): L475 - L486.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
E. D. Michelakis
Soluble guanylate cyclase stimulators as a potential therapy for PAH: enthusiasm, pragmatism and concern
Eur. Respir. J., April 1, 2009; 33(4): 717 - 721.
[Full Text] [PDF]

Home page
 Eur Respir JHome page
F. Grimminger, G. Weimann, R. Frey, R. Voswinckel, M. Thamm, D. Bolkow, N. Weissmann, W. Muck, S. Unger, G. Wensing, et al.
First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension
Eur. Respir. J., April 1, 2009; 33(4): 785 - 792.
[Abstract] [Full Text] [PDF]

Home page
 ERRHome page
H. A. Ghofrani and F. Grimminger
Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy
Eur. Respir. Rev., March 1, 2009; 18(111): 35 - 41.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2008 by the European Respiratory Society.