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Published online before print June 11, 2008
Eur Respir J 2008, doi:10.1183/09031936.00114407
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ORIGINAL ARTICLE

Expression and Function of Soluble Guanylate Cyclase in Pulmonary Arterial Hypertension

R.T. Schermuly 1*, J-P. Stasch 2, S.S. Pullamsetti 1, R. Middendorff 3, D. Müller 3, K-D. Schlüter 4, A. Dingendorf 4, S. Hackemack 1, E. Kolosionek 1, C. Kaulen 1, R. Dumitrascu 1, N. Weissmann 1, J. Mittendorf 2, W. Klepetko 5, W. Seeger 1, H.A. Ghofrani 1, F. Grimminger 1

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

* To whom correspondence should be addressed. E-mail: ralph.schermuly{at}uglc.de.


  Abstract

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

Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs as compared to healthy donor lungs was demonstrated by immunohistochemistry. Similar to human, upregulation of sGC was detected in the structurally remodeled 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 sensitizes it to its physiological stimulator, nitric oxide (NO). Chronic treatment of hypoxic mice and MCT rats with fully established pulmonary hypertension with BAY 63-2521 (10 mg·kg-1 day) partially reversed the pulmonary hypertension, the right heart hypertrophy and the structural remodeling of the lung vasculature.

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

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




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