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Pharmacotherapy of Pulmonary Hypertension pp 279–313Cite as

Soluble Guanylate Cyclase Stimulators in Pulmonary Hypertension

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 218))

Abstract

Soluble guanylate cyclase (sGC) is a key enzyme in the nitric oxide (NO) signalling pathway. On binding of NO to its prosthetic haem group, sGC catalyses the synthesis of the second messenger cyclic guanosine monophosphate (cGMP), which promotes vasodilation and inhibits smooth muscle proliferation, leukocyte recruitment, platelet aggregation and vascular remodelling through a number of downstream mechanisms. The central role of the NO–sGC–cGMP pathway in regulating pulmonary vascular tone is demonstrated by the dysregulation of NO production, sGC activity and cGMP degradation in pulmonary hypertension (PH). The sGC stimulators are novel pharmacological agents that directly stimulate sGC, both independently of NO and in synergy with NO. Optimisation of the first sGC stimulator, YC-1, led to the development of the more potent and more specific sGC stimulators, BAY 41-2272, BAY 41-8543 and riociguat (BAY 63-2521). Other sGC stimulators include CFM-1571, BAY 60-4552, vericiguat (BAY 1021189), the acrylamide analogue A-350619 and the aminopyrimidine analogues. BAY 41-2272, BAY 41-8543 and riociguat induced marked dose-dependent reductions in mean pulmonary arterial pressure and vascular resistance with a concomitant increase in cardiac output, and they also reversed vascular remodelling and right heart hypertrophy in several experimental models of PH. Riociguat is the first sGC stimulator that has entered clinical development. Clinical trials have shown that it significantly improves pulmonary vascular haemodynamics and increases exercise ability in patients with pulmonary arterial hypertension (PAH), chronic thromboembolic PH and PH associated with interstitial lung disease. Furthermore, riociguat reduces mean pulmonary arterial pressure in patients with PH associated with chronic obstructive pulmonary disease and improves cardiac index and pulmonary vascular resistance in patients with PH associated with left ventricular systolic dysfunction. These promising results suggest that sGC stimulators may constitute a valuable new therapy for PH. Other trials of riociguat are in progress, including a study of the haemodynamic effects and safety of riociguat in patients with PH associated with left ventricular diastolic dysfunction, and long-term extensions of the phase 3 trials investigating the efficacy and safety of riociguat in patients with PAH and chronic thromboembolic PH. Finally, sGC stimulators may also have potential therapeutic applications in other diseases, including heart failure, lung fibrosis, scleroderma and sickle cell disease.

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References

  • Ahrens I, Habersberger J, Baumlin N, Qian H, Smith BK, Stasch JP, Bode C, Schmidt HH, Peter K (2011) Measuring oxidative burden and predicting pharmacological response in coronary artery disease patients with a novel direct activator of haem-free/oxidised sGC. Atherosclerosis 218:431–434

    Article  PubMed  CAS  Google Scholar 

  • Arnold WP, Mittal CK, Katsuki S, Murad F (1977) Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci USA 74:3203–3207

    Article  PubMed  CAS  Google Scholar 

  • Aytekin M, Aulak KS, Haserodt S, Chakravarti R, Cody J, Minai OA, Dweik RA (2012) Abnormal platelet aggregation in idiopathic pulmonary arterial hypertension: role of nitric oxide. Am J Physiol Lung Cell Mol Physiol 302:L512–L520

    Article  PubMed  CAS  Google Scholar 

  • Badejo AM Jr, Nossaman VE, Pankey EA, Bhartiya M, Kannadka CB, Murthy SN, Nossaman BD, Kadowitz PJ (2010) Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide. Am J Physiol Heart Circ Physiol 299:H1153–H1159

    Article  PubMed  CAS  Google Scholar 

  • Bayer (2012) Bayer’s riociguat first drug to demonstrate efficacy in patients with chronic thromboembolic pulmonary hypertension. Bayer Investor News, Leverkusen, Germany, 23 Oct 2012

    Google Scholar 

  • Bayer (2013) Bayer HealthCare Development Pipeline. http://www.bayerpharma.com/en/research-and-development/development-pipeline/index.php?phase=1. Accessed 4 June 2013

  • Becker EM, Stasch JP, Bechem M, Truebel H (2011) Comparison of different vasodilators, endothelin antagonist, PDE5 inhibitor and sGC stimulators in an animal model of secondary pulmonary hypertension: effects on “desaturation”. BMC Pharmacol 11(Suppl 1):P5 (abstract)

    Article  Google Scholar 

  • Becker C, Frey R, Hesse C, Unger S, Reber M, Mück W (2012) Absorption behavior of riociguat (BAY 632521): bioavailability, food effects, and dose-proportionality. Eur Respir Soc P951 (abstract)

    Google Scholar 

  • Beyer C, Reich N, Schindler SC, Akhmetshina A, Dees C, Tomcik M, Hirth-Dietrich C, von Degenfeld G, Sandner P, Distler O et al (2012) Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Ann Rheum Dis 71:1019–1026

    Article  PubMed  CAS  Google Scholar 

  • Bischoff E, Stasch JP (2004) Effects of the sGC stimulator BAY 41-2272 are not mediated by phosphodiesterase 5 inhibition. Circulation 110:e320–e321

    Article  PubMed  CAS  Google Scholar 

  • Black SM, Sanchez LS, Mata-Greenwood E, Bekker JM, Steinhorn RH, Fineman JR (2001) sGC and PDE5 are elevated in lambs with increased pulmonary blood flow and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 281:L1051–L1057

    PubMed  CAS  Google Scholar 

  • Bonderman D, Ghio S, Felix SB, Ghofrani HA, Michelakis E, Mitrovic V, Oudiz RJ, Boateng F, Scalise AV, Roessig L, Semigran MJ (2013) Left ventricular systolic dysfunction associated with pulmonary hypertension riociguat trial (LEPHT) study group. Circulation 128(5):502–511

    Article  PubMed  CAS  Google Scholar 

  • Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, Voelkel NF (2004) Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med 169:764–769

    Article  PubMed  Google Scholar 

  • Brockunier LL, Guo J, Parmee ER, Raghavan S, Rosauer K, Stelmach JE, Schmidt DR (2009) Soluble guanylate cyclase activators. Patent application number PCT/US2009/064570, Merck Sharp & Dohme Corporation

    Google Scholar 

  • Bryan NS, Bian K, Murad F (2009) Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci 14:1–18

    Article  CAS  Google Scholar 

  • Burney S, Caulfield JL, Niles JC, Wishnok JS, Tannenbaum SR (1999) The chemistry of DNA damage from nitric oxide and peroxynitrite. Mutat Res 424:37–49

    Article  PubMed  CAS  Google Scholar 

  • Canalli AA, Franco-Penteado CF, Saad ST, Conran N, Costa FF (2008) Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation. Haematologica 93:605–609

    Article  PubMed  CAS  Google Scholar 

  • Cary SP, Winger JA, Marletta MA (2005) Tonic and acute nitric oxide signaling through soluble guanylate cyclase is mediated by nonheme nitric oxide, ATP, and GTP. Proc Natl Acad Sci USA 102:13064–13069

    Article  PubMed  CAS  Google Scholar 

  • Cau SB, Dias-Junior CA, Montenegro MF, de Nucci G, Antunes E, Tanus-Santos JE (2008) Dose-dependent beneficial hemodynamic effects of BAY 41-2272 in a canine model of acute pulmonary thromboembolism. Eur J Pharmacol 581:132–137

    Article  PubMed  CAS  Google Scholar 

  • Cetin A, Kaya T, Demirkoprulu N, Karadas B, Duran B, Cetin M (2004) YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits the spontaneous contractions of isolated pregnant rat myometrium. J Pharmacol Sci 94:19–24

    Article  PubMed  CAS  Google Scholar 

  • Claudino MA, Franco-Penteado CF, Corat MA, Gimenes AP, Passos LA, Antunes E, Costa FF (2009) Increased cavernosal relaxations in sickle cell mice priapism are associated with alterations in the NO-cGMP signaling pathway. J Sex Med 6:2187–2196

    Article  PubMed  CAS  Google Scholar 

  • Clini E, Cremona G, Campana M, Scotti C, Pagani M, Bianchi L, Giordano A, Ambrosino N (2000) Production of endogenous nitric oxide in chronic obstructive pulmonary disease and patients with cor pulmonale. Correlates with echo-Doppler assessment. Am J Respir Crit Care Med 162:446–450

    Article  PubMed  CAS  Google Scholar 

  • Coggins MP, Bloch KD (2007) Nitric oxide in the pulmonary vasculature. Arterioscler Thromb Vasc Biol 27:1877–1885

    Article  PubMed  CAS  Google Scholar 

  • Costell MH, Ancellin N, Bernard RE, Zhao S, Upson JJ, Morgan LA, Maniscalco K, Olzinski AR, Ballard VL, Herry K et al (2012) Comparison of soluble guanylate cyclase stimulators and activators in models of cardiovascular disease associated with oxidative stress. Front Pharmacol 3:128

    Article  PubMed  CAS  Google Scholar 

  • Cracowski JL, Cracowski C, Bessard G, Pepin JL, Bessard J, Schwebel C, Stanke-Labesque F, Pison C (2001) Increased lipid peroxidation in patients with pulmonary hypertension. Am J Respir Crit Care Med 164:1038–1042

    Article  PubMed  CAS  Google Scholar 

  • Cremona G, Higenbottam T, Borland C, Mist B (1994) Mixed expired nitric oxide in primary pulmonary hypertension in relation to lung diffusion capacity. QJM 87:547–551

    PubMed  CAS  Google Scholar 

  • Derbyshire ER, Marletta MA (2012) Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 81:533–559

    Article  PubMed  CAS  Google Scholar 

  • Deruelle P, Grover TR, Abman SH (2005a) Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep. Am J Physiol Lung Cell Mol Physiol 289:L798–L806

    Article  PubMed  CAS  Google Scholar 

  • Deruelle P, Grover TR, Storme L, Abman SH (2005b) Effects of BAY 41-2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 288:L727–L733

    Article  PubMed  CAS  Google Scholar 

  • Deruelle P, Balasubramaniam V, Kunig AM, Seedorf GJ, Markham NE, Abman SH (2006) BAY 41-2272, a direct activator of soluble guanylate cyclase, reduces right ventricular hypertrophy and prevents pulmonary vascular remodeling during chronic hypoxia in neonatal rats. Biol Neonate 90:135–144

    Article  PubMed  CAS  Google Scholar 

  • Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, Stasch JP, Gnoth MJ, Seeger W, Grimminger F et al (2006) Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation 113:286–295

    Article  PubMed  CAS  Google Scholar 

  • Dunkern TR, Feurstein D, Rossi GA, Sabatini F, Hatzelmann A (2007) Inhibition of TGF-beta induced lung fibroblast to myofibroblast conversion by phosphodiesterase inhibiting drugs and activators of soluble guanylyl cyclase. Eur J Pharmacol 572:12–22

    Article  PubMed  CAS  Google Scholar 

  • Egemnazarov B, Sydykov A, Schermuly RT, Weissmann N, Stasch JP, Sarybaev AS, Seeger W, Grimminger F, Ghofrani HA (2009) Novel soluble guanylyl cyclase stimulator BAY 41-2272 attenuates ischemia-reperfusion-induced lung injury. Am J Physiol Lung Cell Mol Physiol 296:L462–L469

    Article  PubMed  CAS  Google Scholar 

  • Egemnazarov B, Amirjanians V, Kojonazarov B, Sydykov A, Stasch JP, Weissmann N, Grimminger F, Seeger W, Schermuly RT, Ghofrani HA (2010) Inhalative application of soluble guanylyl cyclase stimulator BAY 41-8543 for treatment of pulmonary arterial hypertension. Am J Respir Crit Care Med 181:A6307 (abstract)

    Google Scholar 

  • Ehret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, Chasman DI, Smith AV, Tobin MD, Verwoert GC, Hwang SJ et al (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478:103–109

    Article  PubMed  CAS  Google Scholar 

  • Erusalimsky JD, Moncada S (2007) Nitric oxide and mitochondrial signaling: from physiology to pathophysiology. Arterioscler Thromb Vasc Biol 27:2524–2531

    Article  PubMed  CAS  Google Scholar 

  • Evgenov OV, Ichinose F, Evgenov NV, Gnoth MJ, Falkowski GE, Chang Y, Bloch KD, Zapol WM (2004) Soluble guanylate cyclase activator reverses acute pulmonary hypertension and augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs. Circulation 110:2253–2259

    Article  PubMed  CAS  Google Scholar 

  • Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP (2006) NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 5:755–768

    Article  PubMed  CAS  Google Scholar 

  • Evgenov OV, Kohane DS, Bloch KD, Stasch JP, Volpato GP, Bellas E, Evgenov NV, Buys ES, Gnoth MJ, Graveline AR et al (2007) Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation. Am J Respir Crit Care Med 176:1138–1145

    Article  PubMed  CAS  Google Scholar 

  • Evgenov OV, Zou L, Zhang M, Mino-Kenudson M, Mark EJ, Buys ES, Raher MJ, Li Y, Feng Y, Jones RC et al (2011) Nitric oxide-independent stimulation of soluble guanylate cyclase attenuates pulmonary fibrosis. BMC Pharmacol 11(Suppl 1):O9 (abstract)

    Article  Google Scholar 

  • Farrow KN, Lee KJ, Perez M, Schriewer JM, Wedgwood S, Lakshminrusimha S, Smith CL, Steinhorn RH, Schumacker PT (2012) Brief hyperoxia increases mitochondrial oxidation and increases phosphodiesterase 5 activity in fetal pulmonary artery smooth muscle cells. Antioxid Redox Signal 17:460–470

    Article  PubMed  CAS  Google Scholar 

  • Freitas CF, Morganti RP, Annichino-Bizzacchi JM, De Nucci G, Antunes E (2007) Effect of BAY 41-2272 in the pulmonary hypertension induced by heparin-protamine complex in anaesthetized dogs. Clin Exp Pharmacol Physiol 34:10–14

    Article  PubMed  CAS  Google Scholar 

  • Frey R, Mück W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G (2008) Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. J Clin Pharmacol 48:926–934

    Article  PubMed  CAS  Google Scholar 

  • Frey R, Mück W, Kirschbaum N, Krätzschmar J, Weimann G, Wensing G (2011) Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study. J Clin Pharmacol 51:1051–1060

    Article  PubMed  CAS  Google Scholar 

  • Frey R, Becker C, Unger S, Schmidt A, Wensing G, Mück W (2013a) Pharmacokinetics of the soluble guanylate cyclase stimulator riociguat in individuals with hepatic impairment. Am J Respir Crit Care Med 187:A3310 (abstract)

    Google Scholar 

  • Frey R, Mück W, Unger S, Reber M, Krätzschmar J, Wensing G (2013b) Riociguat (BAY 63-2521) and aspirin: a pharmacodynamic and pharmacokinetic interaction study. J Clin Pharmacol (in submission)

    Google Scholar 

  • Friebe A, Koesling D (1998) Mechanism of YC-1-induced activation of soluble guanylyl cyclase. Mol Pharmacol 53:123–127

    PubMed  CAS  Google Scholar 

  • Friebe A, Schultz G, Koesling D (1996) Sensitizing soluble guanylyl cyclase to become a highly CO-sensitive enzyme. EMBO J 15:6863–6868

    PubMed  CAS  Google Scholar 

  • Friebe A, Mullershausen F, Smolenski A, Walter U, Schultz G, Koesling D (1998) YC-1 potentiates nitric oxide- and carbon monoxide-induced cyclic GMP effects in human platelets. Mol Pharmacol 54:962–967

    PubMed  CAS  Google Scholar 

  • Friebe A, Russwurm M, Mergia E, Koesling D (1999) A point-mutated guanylyl cyclase with features of the YC-1-stimulated enzyme: implications for the YC-1 binding site? Biochemistry 38:15253–15257

    Article  PubMed  CAS  Google Scholar 

  • Friebe A, Mergia E, Dangel O, Lange A, Koesling D (2007) Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase. Proc Natl Acad Sci USA 104:7699–7704

    Article  PubMed  CAS  Google Scholar 

  • Galiè N, Neuser D, Muller K, Scalise A, Grunig E (2013) A placebo-controlled, double-blind phase II interaction study to evaluate blood pressure following addition of riociguat to patients with symptomatic pulmonary arterial hypertension (PAH) receiving sildenafil (PATENT PLUS). Am J Respir Crit Care Med 187:A3530 (abstract)

    Google Scholar 

  • Galle J, Zabel U, Hubner U, Hatzelmann A, Wagner B, Wanner C, Schmidt HH (1999) Effects of the soluble guanylyl cyclase activator, YC-1, on vascular tone, cyclic GMP levels and phosphodiesterase activity. Br J Pharmacol 127:195–203

    Article  PubMed  CAS  Google Scholar 

  • Garg UC, Hassid A (1989) Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83:1774–1777

    Article  PubMed  CAS  Google Scholar 

  • Geschka S, Kretschmer A, Sharkovska Y, Evgenov OV, Lawrenz B, Hucke A, Hocher B, Stasch JP (2011) Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats. PLoS One 6:e21853

    Article  PubMed  CAS  Google Scholar 

  • Gheorghiade M, Marti CN, Sabbah HN, Roessig L, Greene SJ, Bohm M, Burnett JC, Campia U, Cleland JG, Collins SP et al (2013) Soluble guanylate cyclase: a potential therapeutic target for heart failure. Heart Fail Rev 18:123–134

    Article  PubMed  CAS  Google Scholar 

  • Ghio S, Bonderman D, Felix SB, Ghofrani HA, Michelakis ED, Mitrovic V, Oudiz RJ, Frey R, Roessig L, Semigran MJ (2012) Left ventricular systolic dysfunction associated with pulmonary hypertension riociguat trial (LEPHT): rationale and design. Eur J Heart Fail 14:946–953

    Article  PubMed  CAS  Google Scholar 

  • Ghofrani HA, Hoeper MM, Halank M, Meyer FJ, Staehler G, Behr J, Ewert R, Binnen T, Weimann G, Grimminger F (2010a) Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: first long-term extension data from a phase II study. Am J Respir Crit Care Med 181:A6770 (abstract)

    Google Scholar 

  • Ghofrani HA, Hoeper MM, Halank M, Meyer FJ, Staehler G, Behr J, Ewert R, Weimann G, Grimminger F (2010b) Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 36:792–799

    Article  PubMed  CAS  Google Scholar 

  • Ghofrani HA, Galiè N, Grimminger F, Grüning E, Humbert M, Jing ZC, Keogh A, Langleben D, Ochan Kilama M, Fritsch A, Neuser D, Rubin L (2013a) Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369:330–340

    Google Scholar 

  • Ghofrani HA, D’Armini AM, Grimminger F, Hoeper M, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins M, Fritsch A, Neuser D, Weimann G, Wang C (2013b) Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 369:319–329

    Google Scholar 

  • Ghofrani HA, Stähler G, Grünig E, Halank M, Mitrovic V, Unger S, Mück W, Frey R, Grimminger F, Schermuly RT et al (2013c) Riociguat in pulmonary hypertension associated with chronic obstructive pulmonary disease. Eur Resp J (in submission)

    Google Scholar 

  • Giaid A, Saleh D (1995) Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 333:214–221

    Article  PubMed  CAS  Google Scholar 

  • Girgis RE, Champion HC, Diette GB, Johns RA, Permutt S, Sylvester JT (2005) Decreased exhaled nitric oxide in pulmonary arterial hypertension: response to bosentan therapy. Am J Respir Crit Care Med 172:352–357

    Article  PubMed  Google Scholar 

  • Grimminger F, Weimann G, Frey R, Voswinckel R, Thamm M, Bolkow D, Weissmann N, Mück W, Unger S, Wensing G et al (2009) First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 33:785–792

    Article  PubMed  CAS  Google Scholar 

  • Hirst DG, Robson T (2011) Nitric oxide physiology and pathology. Methods Mol Biol 704:1–13

    Article  PubMed  CAS  Google Scholar 

  • Hoeper MM, Halank M, Wilkens H, Gunther A, Weimann G, Gebert I, Leuchte HH, Behr J (2013) Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial. Eur Respir J 41:853–860

    Article  PubMed  Google Scholar 

  • Hoshikawa Y, Ono S, Suzuki S, Tanita T, Chida M, Song C, Noda M, Tabata T, Voelkel NF, Fujimura S (2001) Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol 90:1299–1306

    PubMed  CAS  Google Scholar 

  • Huh JW, Kim SY, Lee JH, Lee YS (2011) YC-1 attenuates hypoxia-induced pulmonary arterial hypertension in mice. Pulm Pharmacol Ther 24:638–646

    Article  PubMed  CAS  Google Scholar 

  • Humbert P, Niroomand F, Fischer G, Mayer B, Koesling D, Hinsch KD, Gausepohl H, Frank R, Schultz G, Bohme E (1990) Purification of soluble guanylyl cyclase from bovine lung by a new immunoaffinity chromatographic method. Eur J Biochem 190:273–278

    Article  PubMed  CAS  Google Scholar 

  • Hwang TL, Hung HW, Kao SH, Teng CM, Wu CC, Cheng SJ (2003a) Soluble guanylyl cyclase activator YC-1 inhibits human neutrophil functions through a cGMP-independent but cAMP-dependent pathway. Mol Pharmacol 64:1419–1427

    Article  PubMed  CAS  Google Scholar 

  • Hwang TL, Wu CC, Guh JH, Teng CM (2003b) Potentiation of tumor necrosis factor-alpha expression by YC-1 in alveolar macrophages through a cyclic GMP-independent pathway. Biochem Pharmacol 66:149–156

    Article  PubMed  CAS  Google Scholar 

  • Irvine JC, Ganthavee V, Love JE, Alexander AE, Horowitz JD, Stasch JP, Kemp-Harper BK, Ritchie RH (2012) The soluble guanylyl cyclase activator bay 58-2667 selectively limits cardiomyocyte hypertrophy. PLoS One 7:e44481

    Article  PubMed  CAS  Google Scholar 

  • Joshi CN, Martin DN, Fox JC, Mendelev NN, Brown TA, Tulis DA (2011) The soluble guanylate cyclase stimulator BAY 41-2272 inhibits vascular smooth muscle growth through the cAMP-dependent protein kinase and cGMP-dependent protein kinase pathways. J Pharmacol Exp Ther 339:394–402

    Article  PubMed  CAS  Google Scholar 

  • Kaneko FT, Arroliga AC, Dweik RA, Comhair SA, Laskowski D, Oppedisano R, Thomassen MJ, Erzurum SC (1998) Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med 158:917–923

    Article  PubMed  CAS  Google Scholar 

  • Kawaguchi Y, Tochimoto A, Hara M, Kawamoto M, Sugiura T, Katsumata Y, Okada J, Kondo H, Okubo M, Kamatani N (2006) NOS2 polymorphisms associated with the susceptibility to pulmonary arterial hypertension with systemic sclerosis: contribution to the transcriptional activity. Arthritis Res Ther 8:R104

    Article  PubMed  CAS  Google Scholar 

  • Kielstein JT, Bode-Boger SM, Hesse G, Martens-Lobenhoffer J, Takacs A, Fliser D, Hoeper MM (2005) Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 25:1414–1418

    Article  PubMed  CAS  Google Scholar 

  • Kim NH, d’Armini A, Grunig E, Hoeper MM, Jansa P, Mayer E, Simonneau G, Torbicki A, Want C, Wilkins MR et al (2013) Hemodynamic assessment of patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) in the phase III CHEST-1 study. Am J Respir Crit Care Med 187:A3529 (abstract)

    Article  CAS  Google Scholar 

  • Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM (1994) YC-1, a novel activator of platelet guanylate cyclase. Blood 84:4226–4233

    PubMed  CAS  Google Scholar 

  • Krasuski RA, Warner JJ, Wang A, Harrison JK, Tapson VF, Bashore TM (2000) Inhaled nitric oxide selectively dilates pulmonary vasculature in adult patients with pulmonary hypertension, irrespective of etiology. J Am Coll Cardiol 36:2204–2211

    Article  PubMed  CAS  Google Scholar 

  • Kronas N, Peters B, Goetz AE, Kubitz JC (2011) Inhaled and intravenous application of a stimulator of the soluble guanylate cyclase (BAY 41-8543) reduces pulmonary vascular resistance in a model of septic shock. BMC Pharmacol 11(Suppl 1):P41 (abstract)

    Article  Google Scholar 

  • Lamothe M, Chang FJ, Balashova N, Shirokov R, Beuve A (2004) Functional characterization of nitric oxide and YC-1 activation of soluble guanylyl cyclase: structural implication for the YC-1 binding site? Biochemistry 43:3039–3048

    Article  PubMed  CAS  Google Scholar 

  • Lang M, Kojonazarov B, Tian X, Kalymbetov A, Weissmann N, Grimminger F, Kretschmer A, Stasch JP, Seeger W, Ghofrani HA et al (2012) The soluble guanylate cyclase stimulator riociguat ameliorates pulmonary hypertension induced by hypoxia and SU5416 in rats. PLoS One 7:e43433

    Article  PubMed  CAS  Google Scholar 

  • Laursen JB, Somers M, Kurz S, McCann L, Warnholtz A, Freeman BA, Tarpey M, Fukai T, Harrison DG (2001) Endothelial regulation of vasomotion in apoE-deficient mice: implications for interactions between peroxynitrite and tetrahydrobiopterin. Circulation 103:1282–1288

    Article  PubMed  CAS  Google Scholar 

  • Lee YC, Martin E, Murad F (2000) Human recombinant soluble guanylyl cyclase: expression, purification, and regulation. Proc Natl Acad Sci USA 97:10763–10768

    Article  PubMed  CAS  Google Scholar 

  • Lobo B, Puig-Pey R, Ferrer E, Dominguez-Fandos D, Coll N, Garcia J, Musri MM, Peinado VI, BarberÁ JA (2013) Stimulation of soluble guanylate cyclase in guinea pigs chronically exposed to cigarette smoke reduces intrapulmonary vascular remodeling and prevents emphysema. Am J Respir Crit Care Med 187:A4666

    Google Scholar 

  • Lundgren J, Kylhammar D, Hedelin P, Radegran G (2012) sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model. Acta Physiol (Oxf) 206:178–194

    Article  CAS  Google Scholar 

  • Maclean MR, Johnston ED, McCulloch KM, Pooley L, Houslay MD, Sweeney G (1997) Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat: changes in pulmonary hypertension. J Pharmacol Exp Ther 283:619–624

    PubMed  CAS  Google Scholar 

  • Malerba M, Radaeli A, Ragnoli B, Airo P, Corradi M, Ponticiello A, Zambruni A, Grassi V (2007) Exhaled nitric oxide levels in systemic sclerosis with and without pulmonary involvement. Chest 132:575–580

    Article  PubMed  CAS  Google Scholar 

  • Mam V, Tanbe AF, Vitali SH, Arons E, Christou HA, Khalil RA (2010) Impaired vasoconstriction and nitric oxide-mediated relaxation in pulmonary arteries of hypoxia- and monocrotaline-induced pulmonary hypertensive rats. J Pharmacol Exp Ther 332:455–462

    Article  PubMed  CAS  Google Scholar 

  • Mellion BT, Ignarro LJ, Ohlstein EH, Pontecorvo EG, Hyman AL, Kadowitz PJ (1981) Evidence for the inhibitory role of guanosine 3′, 5′-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood 57:946–955

    PubMed  CAS  Google Scholar 

  • Mercier O, Guihaire J, Boulate D, Nickl W, Truebel H (2012) sGC-stimulation vs. PDE5-inhibition in a model of chronic thromboembolic pulmonary hypertension (CTEPH). Am J Respir Crit Care Med 185:A4775 (abstract)

    Google Scholar 

  • Miguel LI, Almeida CB, Traina F, Canalli AA, Dominical VM, Saad ST, Costa FF, Conran N (2011) Inhibition of phosphodiesterase 9A reduces cytokine-stimulated in vitro adhesion of neutrophils from sickle cell anemia individuals. Inflamm Res 60:633–642

    Article  PubMed  CAS  Google Scholar 

  • Miller LN, Nakane M, Hsieh GC, Chang R, Kolasa T, Moreland RB, Brioni JD (2003) A-350619: a novel activator of soluble guanylyl cyclase. Life Sci 72:1015–1025

    Article  PubMed  CAS  Google Scholar 

  • Mitrovic V, Swidnicki B, Ghofrani HA, Mück W, Kirschbaum N, Mittendorf J, Stasch JP, Wensing G, Frey R, Lentini S (2009) Acute hemodynamic response to single oral doses of BAY 60-4552, a soluble guanylate cyclase stimulator, in patients with biventricular heart failure. BMC Pharmacol 9(Suppl 1):P51 (abstract)

    Article  Google Scholar 

  • Mittendorf J, Weigand S, Alonso-Alija C, Bischoff E, Feurer A, Gerisch M, Kern A, Knorr A, Lang D, Muenter K et al (2009) Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 4:853–865

    Article  PubMed  CAS  Google Scholar 

  • Mülsch A, Bauersachs J, Schafer A, Stasch JP, Kast R, Busse R (1997) Effect of YC-1, an NO-independent, superoxide-sensitive stimulator of soluble guanylyl cyclase, on smooth muscle responsiveness to nitrovasodilators. Br J Pharmacol 120:681–689

    Article  PubMed  Google Scholar 

  • Münzel T, Daiber A, Mülsch A (2005) Explaining the phenomenon of nitrate tolerance. Circ Res 97:618–628

    Article  PubMed  CAS  Google Scholar 

  • Murad F (2006) Shattuck Lecture. Nitric oxide and cyclic GMP in cell signaling and drug development. N Engl J Med 355:2003–2011

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly DA, McLaughlin BE, Marks GS, Brien JF, Nakatsu K (2001) YC-1 enhances the responsiveness of tolerant vascular smooth muscle to glyceryl trinitrate. Can J Physiol Pharmacol 79:43–48

    Article  PubMed  Google Scholar 

  • Ott IM, Alter ML, Von Websky K, Kretschmer A, Tsuprykov O, Sharkovska Y, Krause-Relle K, Raila J, Henze A, Stasch JP et al (2012) Effects of stimulation of soluble guanylate cyclase on diabetic nephropathy in diabetic eNOS knockout mice on top of angiotensin II receptor blockade. PLoS One 7(8):e42623

    Article  PubMed  CAS  Google Scholar 

  • Pan SL, Guh JH, Chang YL, Kuo SC, Lee FY, Teng CM (2004) YC-1 prevents sodium nitroprusside-mediated apoptosis in vascular smooth muscle cells. Cardiovasc Res 61:152–158

    Article  PubMed  CAS  Google Scholar 

  • Pankey EA, Badejo AM, Casey DB, Lasker GF, Riehl RA, Murthy SN, Nossaman BD, Kadowitz PJ (2012) Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension. Nitric Oxide 27:1–8

    Article  PubMed  CAS  Google Scholar 

  • Perez M, Lakshminrusimha S, Wedgwood S, Czech L, Gugino SF, Russell JA, Farrow KN, Steinhorn RH (2012) Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn. Am J Physiol Lung Cell Mol Physiol 302:L595–L603

    Article  PubMed  CAS  Google Scholar 

  • Pfeifer A, Klatt P, Massberg S, Ny L, Sausbier M, Hirneiss C, Wang GX, Korth M, Aszodi A, Andersson KE et al (1998) Defective smooth muscle regulation in cGMP kinase I-deficient mice. EMBO J 17:3045–3051

    Article  PubMed  CAS  Google Scholar 

  • Raat NJ, Tabima DM, Specht PA, Tejero J, Champion HC, Kim-Shapiro D, Baust J, Mik EG, Hildesheim M, Stasch JP et al (2013) Direct sGC activation bypasses NO scavenging reactions of intravascular free oxy-hemoglobin and limits vasoconstriction. Antioxid Redox Signal. doi:10.1089/ars.2013.5181

    PubMed  Google Scholar 

  • Radi R (2004) Nitric oxide, oxidants, and protein tyrosine nitration. Proc Natl Acad Sci USA 101:4003–4008

    Article  PubMed  CAS  Google Scholar 

  • Riley MS, Porszasz J, Miranda J, Engelen MP, Brundage B, Wasserman K (1997) Exhaled nitric oxide during exercise in primary pulmonary hypertension and pulmonary fibrosis. Chest 111:44–50

    Article  PubMed  CAS  Google Scholar 

  • Rizzo NO, Maloney E, Pham M, Luttrell I, Wessells H, Tateya S, Daum G, Handa P, Schwartz MW, Kim F (2010) Reduced NO-cGMP signaling contributes to vascular inflammation and insulin resistance induced by high-fat feeding. Arterioscler Thromb Vasc Biol 30:758–765

    Article  PubMed  CAS  Google Scholar 

  • Roger S, Badier-Commander C, Paysant J, Cordi A, Verbeuren TJ, Feletou M (2010) The anti-aggregating effect of BAY 41-2272, a stimulator of soluble guanylyl cyclase, requires the presence of nitric oxide. Br J Pharmacol 161:1044–1058

    Article  PubMed  CAS  Google Scholar 

  • Roy B, Mo E, Vernon J, Garthwaite J (2008) Probing the presence of the ligand-binding haem in cellular nitric oxide receptors. Br J Pharmacol 153:1495–1504

    Article  PubMed  CAS  Google Scholar 

  • Rubin LJ, Galiè N, Grimminger F, Grunig E, Humbert MJC, Jing ZC, Keogh AM, Langleben D, Fritsch A, Ochan Kilama M et al (2013) Riociguat for the treatment of pulmonary arterial hypertension (PAH): a phase III long-term extension study (PATENT-2). Am J Respir Crit Care Med 187:A3531 (abstract)

    Google Scholar 

  • Russwurm M, Mergia E, Mullershausen F, Koesling D (2002) Inhibition of deactivation of NO-sensitive guanylyl cyclase accounts for the sensitizing effect of YC-1. J Biol Chem 277:24883–24888

    Article  PubMed  CAS  Google Scholar 

  • Salvi E, Kutalik Z, Glorioso N, Benaglio P, Frau F, Kuznetsova T, Arima H, Hoggart C, Tichet J, Nikitin YP et al (2012) Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase. Hypertension 59:248–255

    Article  PubMed  CAS  Google Scholar 

  • Sanli C, Oguz D, Olgunturk R, Tunaoglu FS, Kula S, Pasaoglu H, Gulbahar O, Cevik A (2012) Elevated homocysteine and asymmetric dimethyl arginine levels in pulmonary hypertension associated with congenital heart disease. Pediatr Cardiol 33:1323–1331

    Article  PubMed  Google Scholar 

  • Sawada N, Itoh H, Miyashita K, Tsujimoto H, Sone M, Yamahara K, Arany ZP, Hofmann F, Nakao K (2009) Cyclic GMP kinase and RhoA Ser188 phosphorylation integrate pro- and antifibrotic signals in blood vessels. Mol Cell Biol 29:6018–6032

    Article  PubMed  CAS  Google Scholar 

  • Schermuly RT, Stasch JP, Pullamsetti SS, Middendorff R, Muller D, Schluter KD, Dingendorf A, Hackemack S, Kolosionek E, Kaulen C et al (2008) Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 32:881–891

    Article  PubMed  CAS  Google Scholar 

  • Schlossmann J, Schinner E (2012) cGMP becomes a drug target. Naunyn Schmiedebergs Arch Pharmacol 385:243–252

    Article  CAS  Google Scholar 

  • Schmidt P, Schramm M, Schroder H, Stasch JP (2003) Mechanisms of nitric oxide independent activation of soluble guanylyl cyclase. Eur J Pharmacol 468:167–174

    Article  PubMed  CAS  Google Scholar 

  • Schwappacher R, Kilic A, Kojonazarov B, Lang M, Diep T, Zhuang S, Gawlowski T, Schermuly RT, Pfeifer A, Boss GR et al (2013) A molecular mechanism for therapeutic effects of cGMP-elevating agents in pulmonary arterial hypertension. J Biol Chem. doi:10.1074/jbc.M113.458729

    PubMed  Google Scholar 

  • Schymura Y, Janssen W, Eule U, Stasch JP, Weissmann N, Ghofrani HA, Grimminger F, Seeger W, Schermuly RT (2012) Antifibrotic effects of riociguat in a murine model of chronic right ventricular pressure overload. Am J Respir Crit Care Med 185:A6850

    Google Scholar 

  • Seimetz M, Parajuli N, Pichl A, Stasch JP, Frey R, Schermuly RT, Ghofrani HA, Seeger W, Grimminger F, Weissmann N (2011) Effects of the soluble guanylate cyclase stimulator riociguat on emphysema development in tobacco-smoke exposed mice. Am J Respir Crit Care Med 183:A3107 (abstract)

    Google Scholar 

  • Seimetz M, Parajuli N, Pichl A, Stasch JP, Frey R, Schermuly RT, Seeger W, Grimminger F, Ghofrani HA, Weissmann N (2012) Prevention of cigarette smoke-induced pulmonary hypertension by the soluble guanylate cyclase stimulator riociguat. Am J Respir Crit Care Med 185:A3416

    Google Scholar 

  • Selwood DL, Brummell DG, Budworth J, Burtin GE, Campbell RO, Chana SS, Charles IG, Fernandez PA, Glen RC, Goggin MC et al (2001) Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase. J Med Chem 44:78–93

    Article  PubMed  CAS  Google Scholar 

  • Semigran M, Bonderman D, Ghio S, Felix S, Ghofrani HA, Michelakis ED, Mitrovic V, Oudiz RJ, Roessig L, Scalise AV (2012) Left ventricular systolic dysfunction associated with pulmonary hypertension riociguat trial (LEPHT). Circulation 126:2789–2790

    Google Scholar 

  • Shao Z, Wang Z, Shrestha K, Thakur A, Borowski AG, Sweet W, Thomas JD, Moravec CS, Hazen SL, Tang WHW (2012) Pulmonary hypertension associated with advanced systolic heart failure. J Am Coll Cardiol 59:1150–1158

    Article  PubMed  Google Scholar 

  • Sharkovska Y, Kalk P, Lawrenz B, Godes M, Hoffmann LS, Wellkisch K, Geschka S, Relle K, Hocher B, Stasch JP (2010) Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models. J Hypertens 28:1666–1675

    Article  PubMed  CAS  Google Scholar 

  • Skoro-Sajer N, Mittermayer F, Panzenboeck A, Bonderman D, Sadushi R, Hitsch R, Jakowitsch J, Klepetko W, Kneussl MP, Wolzt M et al (2007) Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 176:1154–1160

    Article  PubMed  CAS  Google Scholar 

  • Stasch JP, Hobbs AJ (2009) NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol 191:277–308

    Article  PubMed  CAS  Google Scholar 

  • Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Gerzer R, Minuth T, Perzborn E, Pleiss U et al (2001) NO-independent regulatory site on soluble guanylate cyclase. Nature 410:212–215

    Article  PubMed  CAS  Google Scholar 

  • Stasch JP, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Minuth T, Perzborn E, Schramm M, Straub A (2002a) Pharmacological actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vitro studies. Br J Pharmacol 135:333–343

    Article  PubMed  CAS  Google Scholar 

  • Stasch JP, Dembowsky K, Perzborn E, Stahl E, Schramm M (2002b) Cardiovascular actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vivo studies. Br J Pharmacol 135:344–355

    Article  PubMed  CAS  Google Scholar 

  • Stasch JP, Schmidt PM, Nedvetsky PI, Nedvetskaya TY, Kumar HSA, Meurer S, Deile M, Taye A, Knorr A, Lapp H et al (2006) Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels. J Clin Invest 116:2552–2561

    Article  PubMed  CAS  Google Scholar 

  • Stasch JP, Pacher P, Evgenov OV (2011) Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 123:2263–2273

    Article  PubMed  Google Scholar 

  • Straub A, Stasch JP, Alonso-Alija C, Benet-Buchholz J, Ducke B, Feurer A, Furstner C (2001) NO-independent stimulators of soluble guanylate cyclase. Bioorg Med Chem Lett 11:781–784

    Article  PubMed  CAS  Google Scholar 

  • Thoonen R, Buys ES, Cauwels A, Nimmegeers S, Geschka S, Delanghe J, Hochepied T, De Cauwer L, Rogge E, Sips P et al (2013a) A critical role for heme-free soluble guanylate cyclase in cardiovascular disease. Nat Med (under review)

    Google Scholar 

  • Thoonen R, Sips PY, Bloch KD, Buys ES (2013b) Pathophysiology of hypertension in the absence of nitric oxide/cyclic GMP signaling. Curr Hypertens Rep 15:47–58

    Article  PubMed  CAS  Google Scholar 

  • Thorsen LB, Eskildsen-Helmond Y, Zibrandtsen H, Stasch JP, Simonsen U, Laursen BE (2010) BAY 41-2272 inhibits the development of chronic hypoxic pulmonary hypertension in rats. Eur J Pharmacol 647:147–154

    Article  PubMed  CAS  Google Scholar 

  • Tonelli AR, Haserodt S, Aytekin M, Dweik RA (2013) Nitric oxide deficiency in pulmonary hypertension: pathobiology and implications for therapy. Pulm Circ 3:20–30

    PubMed  CAS  Google Scholar 

  • Tse MT (2012) Trial watch: Phase III success for first-in-class pulmonary hypertension drug. Nat Rev Drug Discov 11:896

    Article  PubMed  CAS  Google Scholar 

  • Tulis DA, Bohl Masters KS, Lipke EA, Schiesser RL, Evans AJ, Peyton KJ, Durante W, West JL, Schafer AI (2002) YC-1-mediated vascular protection through inhibition of smooth muscle cell proliferation and platelet function. Biochem Biophys Res Commun 291:1014–1021

    Article  PubMed  CAS  Google Scholar 

  • Watts JA, Gellar MA, Fulkerson MB, Kline JA (2011) Pulmonary vascular reserve during experimental pulmonary embolism: effects of a soluble guanylate cyclase stimulator, BAY 41-8543. Crit Care Med 39:2700–2704

    PubMed  CAS  Google Scholar 

  • Watts JA, Gellar MA, Fulkerson MB, Kline JA (2013) A soluble guanylate cyclase stimulator, BAY 41-8543, preserves right ventricular function in experimental pulmonary embolism. Pulm Pharmacol Ther 26:205–211

    Article  PubMed  CAS  Google Scholar 

  • Weidenbach A, Stasch JP, Ghofrani HA, Weissmann N, Grimminger F, Seeger W, Schermuly RT (2005) Inhaled NO and the guanylate cyclase stimulator BAY 41-2272 in oleic acid induced acute lung injury in rabbits. BMC Pharmacol 5:P61

    Article  Google Scholar 

  • Wharton J, Strange JW, Moller GM, Growcott EJ, Ren X, Franklyn AP, Phillips SC, Wilkins MR (2005) Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med 172:105–113

    Article  PubMed  Google Scholar 

  • Wolin MS, Wood KS, Ignarro LJ (1982) Guanylate cyclase from bovine lung. A kinetic analysis of the regulation of the purified soluble enzyme by protoporphyrin IX, heme, and nitrosyl-heme. J Biol Chem 257:13312–13320

    PubMed  CAS  Google Scholar 

  • Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, Thunnissen FB, Farver C, Hazen SL, Jennings C et al (2004) Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 18:1746–1748

    PubMed  CAS  Google Scholar 

  • Yazawa S, Tsuchiya H, Hori H, Makino R (2006) Functional characterization of two nucleotide-binding sites in soluble guanylate cyclase. J Biol Chem 281:21763–21770

    Article  PubMed  CAS  Google Scholar 

  • Zhang HQ, Zhiren X, Teodozyj K, Dinges J (2003) A concise synthesis of ortho-substituted aryl-acrylamides – potent activators of soluble guanylate cyclase. Tetrahedron Lett 44:8661–8663

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Cardiology Research, Bayer Pharma AG, Aprather Weg 18a, 42096, Wuppertal, Germany

    Johannes-Peter Stasch

  2. Institute of Pharmacy, University Halle-Wittenberg, Halle (Saale), Germany

    Johannes-Peter Stasch

  3. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Gray/Jackson 424, Boston, MA, 02114, USA

    Oleg V. Evgenov

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  1. Johannes-Peter Stasch
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  2. Oleg V. Evgenov
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Correspondence to Johannes-Peter Stasch .

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  1. Faculte´ de Me´decine, Univ Paris-Sud, Le Kremlin Bicêtre, France

    Marc Humbert

  2. Dep of Anasthesia and Critical Care, Harvard Medical School Massachusetts General Hospital, Boston, Massachusetts, USA

    Oleg V. Evgenov

  3. Cardiovascular Research, Bayer Pharma AG, Wuppertal, Germany

    Johannes-Peter Stasch

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Stasch, JP., Evgenov, O.V. (2013). Soluble Guanylate Cyclase Stimulators in Pulmonary Hypertension. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_12

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