Johannes-Peter Stasch

Publications of Johannes-Peter Stasch

• Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease.

  Authors: Johannes-Peter Stasch, Pál Pacher, Oleg V Evgenov

  Circulation. 05/2011; 123(20):2263-73.

• Riociguat for the treatment of pulmonary hypertension.

  Authors: Ralph T Schermuly, Wiebke Janssen, Norbert Weissmann, Johannes-Peter Stasch, Friedrich Grimminger, Hossein Ardeschir Ghofrani

  Expert opinion on investigational drugs. 03/2011; 20(4):567-76.

  INTRODUCTION: Pulmonary hypertension (PH) is a severe condition with a poor prognosis despite recent treatment advances. Therapies with new mechanisms of action are needed. AREAS COVERED: This reviewINTRODUCTION: Pulmonary hypertension (PH) is a severe condition with a poor prognosis despite recent treatment advances. Therapies with new mechanisms of action are needed. AREAS COVERED: This review will help readers understand the mechanism of action of the soluble guanylate cyclase (sGC) stimulator riociguat (BAY 63-2521) and will provide a comprehensive summary regarding efficacy and safety of this drug in the management of PH. The most relevant publications up to December 2010 were used as sources for this review. EXPERT OPINION: Cyclic guanosine monophosphate (cGMP) is an important mediator of the preferential perfusion of well-ventilated regions throughout the lung. Drugs that increase cGMP levels could promote pulmonary vasorelaxation while maintaining optimal gas exchange. cGMP is generated by sGC, which can be stimulated by nitric oxide (NO). Riociguat stimulates sGC independently of NO and increases the sensitivity of sGC to NO, resulting in increased cGMP levels. Results to date suggest rapid, potent and prolonged efficacy and good tolerability in different types of PH. Phase III clinical trials are evaluating the long-term safety and clinical effectiveness of riociguat in pulmonary arterial hypertension (PAH) and chronic thromboembolic PH. Riociguat has the potential to become an important drug for the treatment of patients with PH.

• Endothelin-1 overexpression restores diastolic function in eNOS knockout mice.

  Authors: Nicolas Vignon-Zellweger, Katharina Relle, Elodie Kienlen, Markus Alter, Patrick Seider, Juliya Sharkovska, Susi Heiden, Philipp Kalk, Karima Schwab, Barbara Albrecht-Küpper, Franz Theuring, Johannes-Peter Stasch, Berthold Hocher

  Journal of hypertension. 03/2011; 29(5):961-70.

  The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascularThe cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET(+/+)) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice. eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET(+/+) mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-) , developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e.g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e.g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation. eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism.

• Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats.

  Authors: Sandra Geschka, Axel Kretschmer, Yuliya Sharkovska, Oleg V Evgenov, Bettina Lawrenz, Andreas Hucke, Berthold Hocher, Johannes-Peter Stasch

  PloS one. 01/2011; 6(7):e21853.

  A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelialA direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension. Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1. Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.

• Fluorescence dequenching makes haem-free soluble guanylate cyclase detectable in living cells.

  Authors: Linda S Hoffmann, Peter M Schmidt, Yvonne Keim, Carsten Hoffmann, Harald H H W Schmidt, Johannes-Peter Stasch

  PloS one. 01/2011; 6(8):e23596.

  In cardiovascular disease, the protective NO/sGC/cGMP signalling-pathway is impaired due to a decreased pool of NO-sensitive haem-containing sGC accompanied by a reciprocal increase in NO-insensitiveIn cardiovascular disease, the protective NO/sGC/cGMP signalling-pathway is impaired due to a decreased pool of NO-sensitive haem-containing sGC accompanied by a reciprocal increase in NO-insensitive haem-free sGC. However, no direct method to detect cellular haem-free sGC other than its activation by the new therapeutic class of haem mimetics, such as BAY 58-2667, is available. Here we show that fluorescence dequenching, based on the interaction of the optical active prosthetic haem group and the attached biarsenical fluorophor FlAsH can be used to detect changes in cellular sGC haem status. The partly overlap of the emission spectrum of haem and FlAsH allows energy transfer from the fluorophore to the haem which reduces the intensity of FlAsH fluorescence. Loss of the prosthetic group, e.g. by oxidative stress or by replacement with the haem mimetic BAY 58-2667, prevented the energy transfer resulting in increased fluorescence. Haem loss was corroborated by an observed decrease in NO-induced sGC activity, reduced sGC protein levels, and an increased effect of BAY 58-2667. The use of a haem-free sGC mutant and a biarsenical dye that was not quenched by haem as controls further validated that the increase in fluorescence was due to the loss of the prosthetic haem group. The present approach is based on the cellular expression of an engineered sGC variant limiting is applicability to recombinant expression systems. Nevertheless, it allows to monitor sGC's redox regulation in living cells and future enhancements might be able to extend this approach to in vivo conditions.

• Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models.

  Authors: Yuliya Sharkovska, Philipp Kalk, Bettina Lawrenz, Michael Godes, Linda Sarah Hoffmann, Kathrin Wellkisch, Sandra Geschka, Katharina Relle, Berthold Hocher, Johannes-Peter Stasch

  Journal of hypertension. 08/2010; 28(8):1666-75.

  The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterialThe nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low-renin and high-renin rat models of hypertension. The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage.

• Kynurenine is an endothelium-derived relaxing factor produced during inflammation.

  Authors: Yutang Wang, Hanzhong Liu, Gavin McKenzie, Paul K Witting, Johannes-Peter Stasch, Michael Hahn, Dechaboon Changsirivathanathamrong, Ben J Wu, Helen J Ball, Shane R Thomas, Vimal Kapoor, David S Celermajer, Andrew L Mellor, John F Keaney, Nicholas H Hunt, Roland Stocker

  Nature medicine. 02/2010; 16(3):279-85.

  Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cellsControl of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-gamma, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.

• Soluble Guanylate Cyclase Agonists Inhibit Expression and Procoagulant Activity of Tissue Factor.

  Authors: Mikhail A Sovershaev, Elena M Egorina, John-Bjarne Hansen, Bjarne Osterud, Pál Pacher, Johannes-Peter Stasch, Oleg V Evgenov

  Arteriosclerosis, thrombosis, and vascular biology. 08/2009;

  OBJECTIVE: Tissue factor (TF), a major initiator of blood coagulation, contributes to inflammation, atherosclerosis, angiogenesis, and vascular remodeling. Pharmacological agonists of solubleOBJECTIVE: Tissue factor (TF), a major initiator of blood coagulation, contributes to inflammation, atherosclerosis, angiogenesis, and vascular remodeling. Pharmacological agonists of soluble guanylate cyclase (sGC) attenuate systemic and pulmonary hypertension, vascular remodeling, and platelet aggregation. However, the influence of these novel pharmacophores on TF is unknown. METHODS AND RESULTS: We evaluated effects of BAY 41-2272 and BAY 58-2667 on expression and activity of TF in human monocytes and umbilical vein endothelial cells (HUVECs). Both compounds reduced expression of active TF protein in monocytes stimulated with lipopolysaccharide, as demonstrated by immunoblotting and a TF procoagulant activity assay. In-cell Western assay revealed that this effect was associated with a marked reduction of total and surface TF presentation. Furthermore, BAY 41-2272 and BAY 58-2667 decreased TF protein expression and the TF-dependent procoagulant activity in HUVECs stimulated with TNF-alpha. The sGC agonists also suppressed transcriptional activity of NF-kappaB. A siRNA-mediated knockdown of the alpha1-subunit of sGC in monocytes and HUVECs confirmed that the inhibitory effect of BAY 41-2272 and BAY 58-2667 on TF expression is mediated through the sGC-dependent mechanisms. CONCLUSIONS: Inhibition of TF expression and activity by sGC agonists might provide therapeutic benefits in cardiovascular diseases associated with enhanced procoagulant and inflammatory response.

• Increased serum levels of tissue inhibitor of metalloproteinase-1 in patients with acute myocardial infarction.

  Authors: Wilfried Dinh, Reiner Füth, Thomas Scheffold, Lars Bansemir, Till Köhler, Harald Lapp, Alexander Bufe, Werner Nickl, Johannes-Peter Stasch, Mark Lankisch

  International heart journal. 07/2009; 50(4):421-31.

  It has been suggested that matrix-metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases (TIMPs) play a major role in the regulation of myocardial remodeling.It has been suggested that matrix-metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases (TIMPs) play a major role in the regulation of myocardial remodeling. Myocardial extracellular matrix (ECM) is highly susceptible to ischemic injury in acute myocardial infarction (AMI).We measured serum levels of TIMP-1 in the early hours of AMI to study the kinetics of these enzymes in an early ischemic phase.TIMP-1 was measured in 25 patients with AMI and 116 healthy controls. Blood samples were obtained during the first 12 hours after hospital admission. Left ventricular function (LVF) and hemodynamic data were collected during coronary intervention.TIMP-1 was significantly elevated in patients with AMI within the first hours compared to controls (P < 0.05). No significant difference was observed between patients with preserved LVF and with impaired LVF. Elevated TIMP-1 levels did not correlate with increased levels of CK or CK-MB band during the first hours after AMI.Increased TIMP-1 can be detected within 12 hours in patients with AMI, suggesting early onset of remodeling. Elevation of TIMP-1 may be a surrogate marker for increased ECM-turnover. The prognostic relevance needs to be proved in long-term studies.

• Nitric Oxide-Independent Vasodilator Rescues Heme-Oxidized Soluble Guanylate Cyclase From Proteasomal Degradation.

  Authors: Sabine Meurer, Sylke Pioch, Tatjana Pabst, Nils Opitz, Peter M Schmidt, Tobias Beckhaus, Kristina Wagner, Simone Matt, Kristina Gegenbauer, Sandra Geschka, Michael Karas, Johannes-Peter Stasch, Harald H H W Schmidt, Werner Müller-Esterl

  Circulation research. 06/2009;

  Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and downregulation of its majorNitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and downregulation of its major intracellular receptor, the alphabeta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of the heme of sGC, as well as the responsiveness of sGC to NO. sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here, we show that oxidation-induced downregulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand BAY 58-2667 prevented sGC ubiquitination and stabilized both alpha and beta subunits. Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC.

• Increased levels of laminin and collagen type VI may reflect early remodelling in patients with acute myocardial infarction.

  Authors: Wilfried Dinh, Lars Bansemir, Reiner Füth, Werner Nickl, Johannes-Peter Stasch, Michael Coll Barroso, Harald Lapp, Alexander Bufe, Judith Wolfertz, Thomas Scheffold, Mark Lankisch

  Acta cardiologica. 06/2009; 64(3):329-34.

  OBJECTIVE: The development of left ventricular remodelling (LVR) after acute myocardial infarction (AMI) is a predictor of heart failure and mortality. The extracellular matrix (ECM) is highlyOBJECTIVE: The development of left ventricular remodelling (LVR) after acute myocardial infarction (AMI) is a predictor of heart failure and mortality. The extracellular matrix (ECM) is highly susceptible to ischaemic injury. Laminin and collagen type VI (CVI) contribute to ECM formation in the infarct zone. To determine whether these markers can be detected in blood samples, we measured laminin and CVI in patients with AMI and control subjects. METHODS: A total of 60 patients scheduled for coronary angiography and 31 patients with AMI were included. We subdivided the patients into three groups: (1) AMI, (2) stable coronary artery disease (CAD) and (3) exclusion of CAD. Laminin and CVI serum concentrations were recorded using the ELISA-technique. RESULTS: Laminin was significantly higher in patients with AMI than in subjects with stable CAD (36.5 vs. 23.9, P < 0.01) or without CAD (36.5 vs. 24.6 ng/ml, P < 0.05). CVI-levels were significantly elevated in patients with AMI compared to subjects without CAD (7.5 ng/ml vs. 5.4 ng/ml, P < 0.05) or stable CAD (7.5 ng/ml vs. 5.7 ng/ml, P = 0.01). Laminin and CVI were significantly higher in patients with severely reduced left ventricular function. Laminin and CVI values were significantly correlated (r = 0.6). CONCLUSION: Our data suggest that laminin and CVI serum levels can be potential surrogate parameters of ECM remodelling after AMI. We hypothesize that serum laminin reflects early ECM-remodelling involved in the process of postischaemic tissue degradation and repair, and CVI may be a marker of collagen denaturation and shifts in the collagen phenotype ratios.

• Discovery of Riociguat (BAY 63-2521): A Potent, Oral Stimulator of Soluble Guanylate Cyclase for the Treatment of Pulmonary Hypertension.

  Authors: Joachim Mittendorf, Stefan Weigand, Cristina Alonso-Alija, Erwin Bischoff, Achim Feurer, Michael Gerisch, Armin Kern, Andreas Knorr, Dieter Lang, Klaus Muenter, Martin Radtke, Hartmut Schirok, Karl-Heinz Schlemmer, Elke Stahl, Alexander Straub, Frank Wunder, Johannes-Peter Stasch

  ChemMedChem. 04/2009;

  Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis ofSoluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in the pathogenesis of cardiovascular and other diseases. Direct stimulation of sGC represents a promising therapeutic strategy particularly for the treatment of pulmonary hypertension (PH), a disabling disease associated with a poor prognosis. Previous sGC stimulators such as the pyrazolopyridines BAY 41-2272 and BAY 41-8543 demonstrated beneficial effects in experimental models of PH, but were associated with unfavorable drug metabolism and pharmacokinetic (DMPK) properties. Herein we disclose an extended SAR exploration of this compound class to address these issues. Our efforts led to the identification of the potent sGC stimulator riociguat, which exhibits an improved DMPK profile and exerts strong effects on pulmonary hemodynamics and exercise capacity in patients with PH. Riociguat is currently being investigated in phase III clinical trials for the oral treatment of PH.

• NO- and Haem-Independent Soluble Guanylate Cyclase Activators.

  Authors: Harald H H W Schmidt, Peter M Schmidt, Johannes-Peter Stasch

  Handbook of experimental pharmacology. 02/2009;

  Oxidative stress, a risk factor for several cardiovascular disorders, interferes with the NO/sGC/cGMP signalling pathway through scavenging of NO and formation of the strong intermediate oxidant,Oxidative stress, a risk factor for several cardiovascular disorders, interferes with the NO/sGC/cGMP signalling pathway through scavenging of NO and formation of the strong intermediate oxidant, peroxynitrite. Under these conditions, endothelial and vascular dysfunction develops, culminating in different cardio-renal and pulmonary-vascular diseases. Substituting NO with organic nitrates that release NO (NO donors) has been an important principle in cardiovascular therapy for more than a century. However, the development of nitrate tolerance limits their continuous clinical application and, under oxidative stress and increased formation of peroxynitrite foils the desired therapeutic effect. To overcome these obstacles of nitrate therapy, direct NO- and haem-independent sGC activators have been developed, such as BAY 58-2667 (cinaciguat) and HMR1766 (ataciguat), showing unique biochemical and pharmacological properties. Both compounds are capable of selectively activating the oxidized/haem-free enzyme via binding to the enzyme's haem pocket, causing pronounced vasodilatation. The potential importance of these new drugs resides in the fact that they selectively target a modified state of sGC that is prevalent under disease conditions as shown in several animal models and human disease. Activators of sGC may be beneficial in the treatment of a range of diseases including systemic and pulmonary hypertension (PH), heart failure, atherosclerosis, peripheral arterial occlusive disease (PAOD), thrombosis and renal fibrosis. The sGC activator HMR1766 is currently in clinical development as an oral therapy for patients with PAOD. The sGC activator BAY 58-2667 has demonstrated efficacy in a proof-of-concept study in patients with acute decompensated heart failure (ADHF), reducing pre- and afterload and increasing cardiac output from baseline. A phase IIb clinical study for the indication of ADHF is currently underway.

• sGC activators and stimulators attenuate ischemia/reperfusion injury of the lung

  Authors: Bakytbek Egemnazarov, Akylbek Sydykov, Ralph Schermuly, Norbert Weissmann, Johannes-Peter Stasch, Werner Seeger, Friedrich Grimminger, Hossain Ghofrani

  BMC Pharmacology. 01/2009;

• Novel soluble guanylyl cyclase stimulator BAY 41-2272 attenuates ischemia/reperfusion induced lung injury.

  Authors: Bakytbek Egemnazarov, Akylbek Sydykov, Ralph Theo Schermuly, Norbert Weissmann, Johannes-Peter Stasch, Akpai S Sarybaev, Werner Seeger, Friedrich Grimminger, Hossein Ardeschir Ghofrani

  American journal of physiology. Lung cellular and molecular physiology. 01/2009;

  The protective effects of nitric oxide (NO), a physiological activator of soluble guanylyl cyclase (sGC), have been reported in ischemia/reperfusion (I/R) syndrome of the lung. Therefore, we studiedThe protective effects of nitric oxide (NO), a physiological activator of soluble guanylyl cyclase (sGC), have been reported in ischemia/reperfusion (I/R) syndrome of the lung. Therefore, we studied the effects of BAY 41-2272, a novel sGC stimulator, on I/R injury of the lung in an isolated intact organ model. Lung injury was assessed by measuring weight gain and microvascular permeability (capillary filtration coefficient, Kfc). Release of reactive oxygen species (ROS) into the perfusate was measured during early reperfusion by ESR spectroscopy. Rabbit lungs were treated with BAY 41-2272, L-NMMA 400, or NO to evaluate the effects on I/R induced lung injury. In untreated lungs a dramatic rise in Kfc values and weight gain during reperfusion were observed, these results were associated with increased ROS production. Both, BAY 41-2272 and L-NMMA significantly attenuated vascular leakage and suppressed ROS release. Additional experiments showed that BAY 41-2272 diminished phorbol-12-myristrate-13-acetate induced ROS production by NADPH-oxidase. A pharmacological inhibition of the enzyme with consequent reduction in ROS levels decreased I/R injury. Nitric oxide had only marginal effect on I/R injury. Thus, BAY 41-2272 protects against I/R induced lung injury by interfering with the activation of NADPH-oxidases. Key words: acute lung injury, nitric oxide, oxidative stress, ROS.

• Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteosomal degradation

  Authors: Sabine Meurer, Sylke Pioch, Tatjana Pabst, Nils Opitz, Peter Schmidt, Tobias Beckhaus, Kristina Wagner, Simone Matt, Kristina Gegenbauer, Sandra Geschka, Michael Karas, Johannes-Peter Stasch, Harald Schmidt, Werner Müller-Esterl

  BMC Pharmacology. 01/2009;

• Cardio-renal protection of riociguat (BAY 63-2521) in low- and high-renin models of hypertension

  Authors: Philipp Kalk, Yuliya Sharkovska, Bettina Lawrenz, Michael Godes, Linda Hoffmann, Kathrin Wellkisch, Sandra Geschka, Katharina Relle, Berthold Hocher, Johannes-Peter Stasch

  BMC Pharmacology. 01/2009;

• Is kynurenine a novel and important vasodilator in human septic shock?

  Authors: Yutang Wang, Dechaboon Changsiri, Gavin McKenzie, Johannes-Peter Stasch, Michael Hahn, C Woolfe, D Rajbhandari, David Celermajer, Roland Stocker

  BMC Pharmacology. 01/2009;

• Antihypertrophic actions of NO-independent soluble guanylyl cyclase (sGC) ligands BAY 41-2272 and BAY 58-2667 in vitro

  Authors: Rebecca Ritchie, Jennifer Irvine, Jane Love, John Horowitz, Johannes-Peter Stasch, Barbara Kemp-Harper

  BMC Pharmacology. 01/2009;

• Kynurenine is a novel endothelium-derived vascular relaxing factor produced during inflammation

  Authors: Yutang Wang, Hanzhong Liu, Gavin McKenzie, Paul Witting, Johannes-Peter Stasch, Michael Hahn, Katherine Jackman, Dechaboon Changsirivathanathamrong, Ben Wu, Helen Ball, Shane Thomas, David Celermajer, Andrew Mellor, Chris Sobey, John Keaney, Nicholas Hunt, Roland Stocker

  BMC Pharmacology. 01/2009;