pp 1-39 | Cite as

Soluble Guanylate Cyclase Stimulators and Activators

  • Peter SandnerEmail author
  • Daniel P. Zimmer
  • G. Todd Milne
  • Markus Follmann
  • Adrian Hobbs
  • Johannes-Peter Stasch
Part of the Handbook of Experimental Pharmacology book series


When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.

Graphical Abstract


cGMP Cyclic guanosine monophosphate Nitric oxide sGC sGC activator sGC stimulator Soluble guanylyl cyclase 



The authors would like to thank Christian Meier, Kelly Lewis, and Shalini Murali at Bayer and Jennifer Chickering, Albert Profy, Emmanuel Buys, Joon Jung, Paul Renhowe, Yueh-tyng Chien, Regina Graul, and Chris Winrow at Ironwood for contributions to and critical reading of the manuscript.

Conflict of Interest

GTM and DPZ are employees of Ironwood Pharmaceuticals, and MF, PS, and JPS are employees of Bayer AG Pharmaceuticals.


  1. Agusti A, Hernandez-Rabaza V, Balzano T, Taoro-Gonzalez L, Ibanez-Grau A, Cabrera-Pastor A, Fustero S, Llansola M, Montoliu C, Felipo V (2017) Sildenafil reduces neuroinflammation in cerebellum, restores GABAergic tone, and improves motor in-coordination in rats with hepatic encephalopathy. CNS Neurosci Ther 23(5):386–394. Scholar
  2. Ahluwalia A, Foster P, Scotland RS, McLean PG, Mathur A, Perretti M, Moncada S, Hobbs AJ (2004) Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment. Proc Natl Acad Sci U S A 101(5):1386–1391. Scholar
  3. Alexander SP, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA, Collaborators CGTP (2015) The concise guide to PHARMACOLOGY 2015/16: enzymes. Br J Pharmacol 172(24):6024–6109. Scholar
  4. Almeida CB, Scheiermann C, Jang JE, Prophete C, Costa FF, Conran N, Frenette PS (2012) Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. Blood 120(14):2879–2888. Scholar
  5. Alruwaili N, Sun D, Wolin MS (2017) Modulation of heme biosynthesis by ferrochelatase inhibition controls soluble guanylate cyclase expression and superoxide production in bovine coronary arteries. FASEB J 31(1_Supp):1080–1015Google Scholar
  6. Armitage ME, Wingler K, Schmidt HH, La M (2009) Translating the oxidative stress hypothesis into the clinic: NOX versus NOS. J Mol Med 87(11):1071–1076. Scholar
  7. Armstrong PW, Roessig L, Patel MJ, Anstrom KJ, Butler J, Voors AA, Lam CSP, Ponikowski P, Temple T, Pieske B, Ezekowitz J, Hernandez AF, Koglin J, O’Connor CM (2017) A multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator: the VICTORIA trial. JACC Heart Fail 6(2):96–104. Scholar
  8. Balashova N, Chang FJ, Lamothe M, Sun Q, Beuve A (2005) Characterization of a novel type of endogenous activator of soluble guanylyl cyclase. J Biol Chem 280(3):2186–2196. Scholar
  9. Beyer C, Reich N, Schindler SC, Akhmetshina A, Dees C, Tomcik M, Hirth-Dietrich C, von Degenfeld G, Sandner P, Distler O, Schett G, Distler JH (2012) Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis. Ann Rheum Dis 71(6):1019–1026. Scholar
  10. Beyer C, Zenzmaier C, Palumbo-Zerr K, Mancuso R, Distler A, Dees C, Zerr P, Huang J, Maier C, Pachowsky ML, Friebe A, Sandner P, Distler O, Schett G, Berger P, Distler JH (2015) Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFbeta signalling. Ann Rheum Dis 74(7):1408–1416. Scholar
  11. Bittner AR, Sinz CJ, Chang J, Kim RM, Mirc JW, Parmee ER, Tan Q (2009) Soluble guanylate cyclase activators. WIPO, GenevaGoogle Scholar
  12. Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ (2003 Nov-Dec) Hellstrom WJ (2003) Endothelial dysfunction in erectile dysfunction: role of the endothelium in erectile physiology and disease. J Androl 24(6 Suppl):S17–S37Google Scholar
  13. Boerrigter G, Costello-Boerrigter LC, Cataliotti A, Lapp H, Stasch JP, Burnett JC Jr (2007) Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure. Hypertension 49(5):1128–1133Google Scholar
  14. Bollen E, Puzzo D, Rutten K, Privitera L, De Vry J, Vanmierlo T, Kenis G, Palmeri A, D’Hooge R, Balschun D, Steinbusch HM, Blokland A, Prickaerts J (2014) Improved long-term memory via enhancing cGMP-PKG signaling requires cAMP-PKA signaling. Neuropsychopharmacology 39(11):2497–2505. Scholar
  15. Bortolotti M, Mari C, Lopilato C, Porrazzo G, Miglioli M (2000) Effects of sildenafil on esophageal motility of patients with idiopathic achalasia. Gastroenterology 118(2):253–257Google Scholar
  16. Breitenstein S, Roessig L, Sandner P, Lewis KS (2017) Novel sGC stimulators and sGC activators for the treatment of heart failure. Handb Exp Pharmacol 243:225–247. Scholar
  17. Brunton TL (1867) On the use of nitrite of amyl in angina pectoris. Lancet 90(2290):97–98Google Scholar
  18. Bruzziches R, Francomano D, Gareri P, Lenzi A, Aversa A (2013) An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. Expert Opin Pharmacother 14(10):1333–1344. Scholar
  19. Buys ES, Ko YC, Alt C, Hayton SR, Jones A, Tainsh LT, Ren R, Giani A, Clerte M, Abernathy E, Tainsh RE, Oh DJ, Malhotra R, Arora P, de Waard N, Yu B, Turcotte R, Nathan D, Scherrer-Crosbie M, Loomis SJ, Kang JH, Lin CP, Gong H, Rhee DJ, Brouckaert P, Wiggs JL, Gregory MS, Pasquale LR, Bloch KD, Ksander BR (2013) Soluble guanylate cyclase alpha1-deficient mice: a novel murine model for primary open angle glaucoma. PLoS One 8(3):e60156. Scholar
  20. Buys ES, Sips P, Vermeersch P, Raher MJ, Rogge E, Ichinose F, Dewerchin M, Bloch KD, Janssens S, Brouckaert P (2008) Gender-specific hypertension and responsiveness to nitric oxide in sGCalpha1 knockout mice. Cardiovasc Res 79(1):179–186. Scholar
  21. Buys ES, Zimmer DP, Chickering J, Graul R, Chien YT, Profy A, Hadcock JR, Masferrer JL, Milne GT (2018) Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential. Nitric Oxide 78:72–80Google Scholar
  22. Cartledge JJ, Eardley I, Morrison JF (2001) Nitric oxide-mediated corpus cavernosal smooth muscle relaxation is impaired in ageing and diabetes. BJU Int 87(4):394–401Google Scholar
  23. Christina Alves P, Peixoto CA, Nunes AK, Garcia-Osta A, Ana Karolina Santana N, Ana G-O (2015) Phosphodiesterase-5 inhibitors: action on the signaling pathways of neuroinflammation, neurodegeneration, and cognition. Mediators Inflamm 2015:940207. Scholar
  24. Cokic VP, Smith RD, Beleslin-Cokic BB, Njoroge JM, Miller JL, Gladwin MT, Schechter AN (2003) Hydroxyurea induces fetal hemoglobin by the nitric oxide-dependent activation of soluble guanylyl cyclase. J Clin Invest 111(2):231–239. Scholar
  25. Cortese-Krott MM, Mergia E, Kramer CM, Lückstädt W, Yang J, Wolff G, Panknin C, Bracht T, Sitek B, Pernow J, Stasch JP, Feelisch M, Koesling D, Kelm M (2018) Identification of a soluble guanylate cyclase in RBCs: preserved activity in patients with coronary artery disease. Redox Biol 14:328–337. Scholar
  26. Derbyshire ER, Marletta MA (2012) Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 81:533–559. Scholar
  27. Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, Stasch JP, Gnoth MJ, Seeger W, Grimminger F, Schermuly RT (2006) Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling. Circulation 113(2):286–295. Scholar
  28. Eherer AJ, Schwetz I, Hammer HF, Petnehazy T, Scheidl SJ, Weber K, Krejs GJ (2002) Effect of sildenafil on oesophageal motor function in healthy subjects and patients with oesophageal motor disorders. Gut 50(6):758–764Google Scholar
  29. Erdmann J, Stark K, Esslinger UB, Rumpf PM, Koesling D, de Wit C, Kaiser FJ, Braunholz D, Medack A, Fischer M, Zimmermann ME, Tennstedt S, Graf E, Eck S, Aherrahrou Z, Nahrstaedt J, Willenborg C, Bruse P, Brænne I, Nöthen MM, Hofmann P, Braund PS, Mergia E, Reinhard W, Burgdorf C, Schreiber S, Balmforth AJ, Hall AS, Bertram L, Steinhagen-Thiessen E, Li SC, März W, Reilly M, Kathiresan S, McPherson R, Walter U, Ott J, Samani NJ, Strom TM, Meitinger T, Hengstenberg C, Schunkert H, CARDIoGRAM (2013) Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature 504(7480):432–436. Scholar
  30. Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HHHW, Stasch J-P (2006) NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 5(9):755–768. Scholar
  31. Evgenov OV, Zou L, Zhang M, Mino-Kenudson M, Mark EJ, Buys ES, Raher MJ, Li Y, Feng Y, Jones RC, Stasch J-P, Chao W (2011) Nitric oxide-independent stimulation of soluble guanylate cyclase attenuates pulmonary fibrosis. BMC Pharmacol 11(1):O9. Scholar
  32. Faraco G, Iadecola C (2013) Hypertension: a harbinger of stroke and dementia. Hypertension 62(5):810–817. Scholar
  33. Feil R, Lohmann SM, de Jonge H, Walter U, Hofmann F (2003) Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res 93(10):907–916Google Scholar
  34. Filippatos G, Maggioni AP, Lam CSP, Pieske-Kraigher E, Butler J, Spertus J, Ponikowski P, Shah SJ, Solomon SD, Scalise AV, Mueller K, Roessig L, Bamber L, Gheorghiade M, Pieske B (2017) Patient-reported outcomes in the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED ejection fraction (SOCRATES-PRESERVED) study. Eur J Heart Fail 19(6):782–791. Scholar
  35. Fischmeister R, Castro LR, Abi-Gerges A, Rochais F, Jurevicius J, Leroy J, Vandecasteele G (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases. Circ Res 99(8):816–828Google Scholar
  36. Flores-Costa R, Alcaraz-Quiles J, Titos E, López-Vicario C, Casulleras M, Duran-Güell M, Rius B, Diaz A, Hall K, Shea C, Sarno R, Masferrer JL, Claria J (2017) The soluble guanylate cyclase stimulator IW-1973 prevents inflammation and fibrosis in experimental non-alcoholic steatohepatitis. Br J Pharmacol 175(6):953–967. Scholar
  37. Follmann M, Griebenow N, Hahn MG, Hartung I, Mais F-J, Mittendorf J, Schaefer M, Schirok H, Stasch J-P, Stoll F, Straub A (2013) The chemistry and biology of soluble guanylate cyclase stimulators and activators. Angew Chem Int Ed 52:9442–9462Google Scholar
  38. Follmann M, Ackerstaff J, Redlich G, Wunder F, Lang D, Kern A, Fey P, Griebenow N, Kroh W, Becker-Pelster EM, Kretschmer A, Geiss V, Li V, Straub A, Mittendorf J, Jautelat R, Schirok H, Schlemmer KH, Lustig K, Gerisch M, Knorr A, Tinel H, Mondritzki T, Trübel H, Sandner P, Stasch JP (2017) Discovery of the soluble guanylate cyclase stimulator vericiguat (BAY 1021189) for the treatment of chronic heart failure. J Med Chem 60(12):5146–5161Google Scholar
  39. Frey R, Becker C, Saleh S, Unger S, van der Mey D, Mück W (2017) Clinical pharmacokinetic and pharmacodynamic profile of riociguat. Clin Pharmacokinet 57(6):647–661. Scholar
  40. 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 U S A 104(18):7699–7704. Scholar
  41. Friebe A, Sandner P, Schmidtko A (2017) Meeting report of the 8th International Conference on cGMP “cGMP: generators, effectors and therapeutic implications” at Bamberg, Germany from June 23rd to 25th 2017. Naunyn Schmiedebergs Arch Pharmacol 390(12):1177–1188. Scholar
  42. Garbán H, Vernet D, Freedman A, Rajfer J, González-Cadavid N (1995) Effect of aging on nitric oxide-mediated penile erection in rats. Am J Physiol 268(1. Pt 2):H467–H475Google Scholar
  43. Ge P, Navarro ID, Kessler MM, Bernier SG, Perl NR, Sarno R, Masferrer J, Hannig G, Stamer WD (2016) The soluble guanylate cyclase stimulator iwp-953 increases conventional outflow facility in mouse eyes. Invest Ophthalmol Vis Sci 57(3):1317–1326. Scholar
  44. Geschka S, Kretschmer A, Sharkovska Y, Evgenov OV, Lawrenz B, Hucke A, Hocher B, Stasch J (2011) Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats. PLoS One 6(7):e21853. Scholar
  45. Gheorghiade M, Greene SJ, Butler J, Filippatos G, Lam CS, Maggioni AP, Ponikowski P, Shah SJ, Solomon SD, Kraigher-Krainer E, Samano ET, Müller K, Roessig L, Pieske B, SOCRATES-REDUCED Investigators and Coordinators (2015) Effect of Vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction: the SOCRATES-REDUCED randomized trial. JAMA 314(21):2251–2262. Scholar
  46. Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C, Group C-S (2013a) Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 369(4):319–329. Scholar
  47. Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ (2013b) Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 369(4):330–340. Scholar
  48. Ghofrani HA, Grimminger F, Grünig E, Huang Y, Jansa P, Jing ZC, Kilpatrick D, Langleben D, Rosenkranz S, Menezes F, Fritsch A, Nikkho S, Humbert M (2016) Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med 4(5):361–371. Scholar
  49. Ghosh A, Stuehr DJ (2017) Regulation of sGC via hsp90, cellular heme, sGC agonists, and NO: new pathways and clinical perspectives. Antioxid Redox Signal 26(4):182–190. Scholar
  50. Gladwin MT (2006) Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome. J Clin Invest 116(9):2330–2332. Scholar
  51. Groneberg D, Voussen B, Friebe A (2016) Integrative control of gastrointestinal motility by nitric oxide. Curr Med Chem 23(24):2715–2735Google Scholar
  52. Gurbuz N, Mammadov E, Usta MF (2008) Hypogonadism and erectile dysfunction: an overview. Asian J Androl 10(1):36–43Google Scholar
  53. Hall K, Jacobson S, Zhang P, Liu G, Sarno R, Catanzano V, Bernier S, Currie M, Masferrer J (2017) Inhibition of fibrosis and inflammation by a soluble guanylate cyclase stimulator in models of liver disease. Paper presented at The Liver Meeting, Washington, DCGoogle Scholar
  54. Hall K, Bernier S, Jacobson S, Liu G, Sarno R, Catanzano V, Sheppeck J, Hadcock J, Currie M, Masferrer J (2018) Stimulation of soluble guanylate cyclase inhibited fibrosis and inflammation in human liver microtissues and in an animal model of liver disease. J Hepatol 68:S397. Scholar
  55. Hanrahan JP, Wakefield JD, Wilson PJ, Mihova M, Chickering JG, Ruff D, Hall M, Milne TM, Currie MG, Profy AT (2018) A randomized, placebo‐controlled, multiple‐ascending‐dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the soluble guanylate cyclase stimulator praliciguat in healthy subjects. Clin Pharmacol Drug Dev. [Epub ahead of print]
  56. Hanrahan JP, Wakefield JD, Wilson PJ, Miller P, Chickering J, Morrow L, Hall ML, Currie M, Milne GT, Profy AT (2018a) Fourteen-day study of praliciguat, a soluble guanylate cyclase stimulator, in patients with diabetes and hypertension. Diabetes 67(Supplement 1):74-OR. Scholar
  57. Hanrahan JP, Wakefield JD, Wilson PJ, Zimmer DP, Mihova M, Chickering J, Ruff D, Hall ML, Currie M, Milne GT, Profy AT (2018b) Rapid dose escalation study of praliciguat, a soluble guanylate cyclase stimulator, in patients with diabetes and hypertension. Diabetes 67(Supplement 1):1207-P. Scholar
  58. Herve D, Philippi A, Belbouab R, Zerah M, Chabrier S, Collardeau-Frachon S, Bergametti F, Essongue A, Berrou E, Krivosic V, Sainte-Rose C, Houdart E, Adam F, Billiemaz K, Lebret M, Roman S, Passemard S, Boulday G, Delaforge A, Guey S, Dray X, Chabriat H, Brouckaert P, Bryckaert M, Tournier-Lasserve E (2014) Loss of alpha1beta1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia. Am J Hum Genet 94(3):385–394. Scholar
  59. Hewitson TD, Martic M, Darby IA, Kelynack KJ, Bisucci T, Tait MG, Becker GJ (2004) Intracellular cyclic nucleotide analogues inhibit in vitro mitogenesis and activation of fibroblasts derived from obstructed rat kidneys. Nephron Exp Nephrol 96(2):e59–e66. Scholar
  60. Hoeper MM (2015) Pharmacological therapy for patients with chronic thromboembolic pulmonary hypertension. Eur Respir Rev 24(136):272–282Google Scholar
  61. Hoeper MM, Klinger JR, Benza RL, Simonneau G, Langleben D, Naeije R, Corris PA (2017a) Rationale and study design of RESPITE: an open-label, phase 3b study of riociguat in patients with pulmonary arterial hypertension who demonstrate an insufficient response to treatment with phosphodiesterase-5 inhibitors. Respir Med 122(Suppl 1):S18–S22. Scholar
  62. Hoeper MM, Simonneau G, Corris PA, Ghofrani HA, Klinger JR, Langleben D, Naeije R, Jansa P, Rosenkranz S, Scelsi L, Grünig E, Vizza CD, Chang M, Colorado P, Meier C, Busse D, Benza RL (2017b) RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J 50(3):1602425. Scholar
  63. Hoffmann LS, Etzrodt J, Willkomm L, Sanyal A, Scheja L, Fischer AW, Stasch JP, Bloch W, Friebe A, Heeren J, Pfeifer A (2015) Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue. Nat Commun 6:7235. Scholar
  64. Hoffmann LS, Schmidt PM, Keim Y, Hoffmann C, Schmidt HH, Stasch JP (2011) Fluorescence dequenching makes haem-free soluble guanylate cyclase detectable in living cells. PLoS One 6(8):e23596. Scholar
  65. Hoffmann LS, Schmidt PM, Keim Y, Schaefer S, Schmidt HH, Stasch JP (2009) Distinct molecular requirements for activation or stabilization of soluble guanylyl cyclase upon haem oxidation-induced degradation. Br J Pharmacol 157(5):781–795. Scholar
  66. Hoshino M, Omura N, Yano F, Tsuboi K, Kashiwagi H, Yanaga K (2013) Immunohistochemical study of the muscularis externa of the esophagus in achalasia patients. Dis Esophagus 26(1):14–21. Scholar
  67. Humbert M, Ghofrani HA (2016) The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax 71(1):73–83. Scholar
  68. Ibarra C, Nedvetsky PI, Gerlach M, Riederer P, Schmidt HH (2001) Regional and age-dependent expression of the nitric oxide receptor, soluble guanylyl cyclase, in the human brain. Brain Res 907(1–2):54–60Google Scholar
  69. Ingram VM (1956) A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature 178(4537):792–794Google Scholar
  70. International Consortium for Blood Pressure Genome-Wide Association S (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478(7367):103–109. Scholar
  71. 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(11):e44481. Scholar
  72. Kemp-Harper B, Feil R (2008) Meeting report: cGMP matters. Sci Signal 1(9):pe12. Scholar
  73. Kessler T, Wobst J, Wolf B, Eckhold J, Vilne B, Hollstein R, von Ameln S, Dang TA, Sager HB, Moritz Rumpf P, Aherrahrou R, Kastrati A, Björkegren JLM, Erdmann J, Lusis AJ, Civelek M, Kaiser FJ, Schunkert H (2017) Functional characterization of the GUCY1A3 coronary artery disease risk locus. Circulation 136(5):476–489. Scholar
  74. Klinger JR, Kadowitz PJ (2017) The nitric oxide pathway in pulmonary vascular disease. Am J Cardiol 120(8S):S71–S79. Scholar
  75. Knorr A, Hirth-Dietrich C, Alonso-Alija C, Harter M, Hahn M, Keim Y, Wunder F, Stasch JP (2008) Nitric oxide-independent activation of soluble guanylate cyclase by BAY 60-2770 in experimental liver fibrosis. Arzneimittelforschung 58(2):71–80. Scholar
  76. Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM (1994) YC-1, a novel activator of platelet guanylate cyclase. Blood 84(12):4226–4233Google Scholar
  77. Kollau A, Opelt M, Wölkart G, Gorren ACF, Russwurm M, Koesling D, Mayer B, Schrammel A (2018) Irreversible activation and stabilization of soluble guanylate cyclase by the protoporphyrin IX mimetic cinaciguat. Mol Pharmacol 93(2):73–78. Scholar
  78. Kone BC (1997) Nitric oxide in renal health and disease. Am J Kidney Dis 30(3):311–333Google Scholar
  79. Kotikoski H, Vapaatalo H, Oksala O (2003) Nitric oxide and cyclic GMP enhance aqueous humor outflow facility in rabbits. Curr Eye Res 26(2):119–123Google Scholar
  80. Krishnan SM, Kraehling JR, Eitner F, Bénardeau A, Sandner P (2018) The Impact of the nitric oxide (NO)/soluble guanylyl cyclase (sGC) signaling cascade on kidney health and disease: a preclinical perspective. Int J Mol Sci 19(6):1712. Scholar
  81. Kuhn M (2016) Molecular physiology of membrane guanylyl cyclase receptors. Physiol Rev 96(2):751–804. Scholar
  82. Lambers C, Roth M, Hofbauer E, Petkov V, Block LH (2014) Anti-remodeling potencies of the soluble guanylate cyclase activator BAY 41-2272 in human lung fibroblasts. Eur Respir J 44(Suppl 58):3423Google Scholar
  83. Lang M, Kojonazarov B, Tian X, Kalymbetov A, Weissmann N, Grimminger F, Kretschmer A, Stasch JP, Seeger W, Ghofrani HA, Schermuly RT, Baktybek K, Xia T, Anuar K, Norbert W, Friedrich G, Axel K, Johannes-Peter S, Werner S, Hossein Ardeschir G, Ralph Theo S (2012) The soluble guanylate cyclase stimulator Riociguat ameliorates pulmonary hypertension induced by hypoxia and SU5416 in rats. PLoS One 7(8):e43433. Scholar
  84. Leineweber K, Moosmang S, Paulson D (2017) Genetics of NO deficiency. Am J Cardiol 120(8S):S80–S88. Scholar
  85. Lewis KS, Butler J, Bauersachs J, Sandner P (2017) The three-decade long journey in heart failure drug development. Handb Exp Pharmacol 243:1–14. Scholar
  86. Liu G, Shea C, Ranganath S, Im GY, Sheppeck JE, Masferrer JL (2016) The sGC stimulator IWP-121 inhibits renal inflammation and fibrosis in human RTPC and Dahl-ss rat model. Paper presented at the Keystone symposia fibrosis: from basic mechanisms to targeted therapies, Keystone, CO, FebGoogle Scholar
  87. Lucas KA, Pitari GM, Kazerounian S, Ruiz-Stewart I, Park J, Schulz S, Chepenik KP, Waldman SA (2000) Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 52(3):375–414Google Scholar
  88. Lundberg JO, Gladwin MT, Weitzberg E (2015) Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov 14(9):623–641. Scholar
  89. Masferrer JL, Shea C, Lonie E, Liu G, Profy A, Milne GT, Currie MG (2016) Novel sGC stimulator IW-1701 prevents the progression of diabetic nephropathy when administered in combination with Enalapril in the ZSF1 rat model. Paper presented at the American Society of Nephrology Kidney Week, Chicago, IL, Nov 15–20Google Scholar
  90. Masuyama H, Tsuruda T, Kato J, Imamura T, Asada Y, Stasch JP, Kitamura K, Eto T (2006) Soluble guanylate cyclase stimulation on cardiovascular remodeling in angiotensin II-induced hypertensive rats. Hypertension 48(5):972–978. Scholar
  91. Masuyama H, Tsuruda T, Sekita Y, Hatakeyama K, Imamura T, Kato J, Asada Y, Stasch JP, Kitamura K (2009) Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart. Hypertens Res 32(7):597–603. Scholar
  92. Mátyás C, Németh BT, Oláh A, Hidi L, Birtalan E, Kellermayer D, Ruppert M, Korkmaz-Icöz S, Kökény G, Horváth EM, Szabó G, Merkely B, Radovits T (2015) The soluble guanylate cyclase activator cinaciguat prevents cardiac dysfunction in a rat model of type-1 diabetes mellitus. Cardiovasc Diabetol 14:145. Scholar
  93. Mergia E, Russwurm M, Zoidl G, Koesling D (2003) Major occurrence of the new alpha2beta1 isoform of NO-sensitive guanylyl cyclase in brain. Cell Signal 15(2):189–195Google Scholar
  94. Methner C, Buonincontri G, Hu CH, Vujic A, Kretschmer A, Sawiak S, Carpenter A, Stasch JP, Krieg T (2013) Riociguat reduces infarct size and post-infarct heart failure in mouse hearts: insights from MRI/PET imaging. PLoS One 8(12):e83910. Scholar
  95. Meurer S, Pioch S, Pabst T, Opitz N, Schmidt PM, Beckhaus T, Wagner K, Matt S, Gegenbauer K, Geschka S, Karas M, Stasch JP, Schmidt HH, Müller-Esterl W (2009) Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteasomal degradation. Circ Res 105(1):33–41. Scholar
  96. 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(9):1015–1025Google Scholar
  97. Mittleman RS, Wilson P, Sykes K, Mihova M, Chickering JG, Ruff D, Hall M, Milne TG, Currie MG, Chien Y (2017) Multiple-ascending-dose study of the soluble guanylate cyclase stimulator, IW-1701, in healthy subjects. Blood 130(Suppl 1):3533. Accessed 07 Dec 2018Google Scholar
  98. Mittendorf J, Weigand S, Alonso-Alija C, Bischoff E, Feurer A, Gerisch M, Kern A, Knorr A, Lang D, Muenter K, Radtke M, Schirok H, Schlemmer KH, Stahl E, Straub A, Wunder F, Stasch JP (2009) Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 4(5):853–865. Scholar
  99. Mulhall J, Teloken P, Brock G, Kim E (2006) Obesity, dyslipidemias and erectile dysfunction: a report of a subcommittee of the sexual medicine society of North America. J Sex Med 3(5):778–786. Scholar
  100. Munzel T, Genth-Zotz S, Hink U (2007) Targeting heme-oxidized soluble guanylate cyclase: solution for all cardiorenal problems in heart failure? Hypertension 49(5):974–976Google Scholar
  101. Murrell W (1879) Nitro-glycerin as a remedy for angina pectoris. Lancet 113(2890):80–81 ffGoogle Scholar
  102. Musicki B, Burnett AL (2007) Endothelial dysfunction in diabetic erectile dysfunction. Int J Impot Res 19(2):129–138Google Scholar
  103. Nahavandi M, Tavakkoli F, Wyche MQ, Perlin E, Winter WP, Castro O (2002) Nitric oxide and cyclic GMP levels in sickle cell patients receiving hydroxyurea. Br J Haematol 119(3):855–857Google Scholar
  104. Nakai T, Perl NR, Barden TC, Carvalho A, Fretzen A, Germano P, Im GY, Jin H, Kim C, Lee TW, Long K, Moore J, Rohde JM, Sarno R, Segal C, Solberg EO, Tobin J, Zimmer DP, Currie MG (2016) Discovery of IWP-051, a novel orally bioavailable sGC stimulator with once-daily dosing potential in humans. ACS Med Chem Lett 7(5):465–469. Scholar
  105. Nathan S, Behr J, Collard HR, Cottin V, Hoeper MM, Martinez F, Corte T, Keogh A, Leuchte H, Mogulkoc N, Ulrich S, Wuyts W, Malcolm S, Shah S, Yao M, Wells A (2017) RISE-IIP: Riociguat for the treatment of pulmonary hypertension associated with idiopathic interstitial pneumonia. Eur Respir J 50:OA1985. Scholar
  106. Oudiz R, Shapiro S, Torres F, Feldman J, Frost A, Allard M, Blair C, Gillies H (2011) ATHENA-1: hemodynamic improvements following the addition of ambrisentan to background PDE5i therapy in patients with pulmonary arterial hypertension. Chest 140:905A (4_MeetingAbstracts)Google Scholar
  107. Pan J, Zhang X, Yuan H, Xu Q, Zhang H, Zhou Y, Huang ZX, Tan X (2016) The molecular mechanism of heme loss from oxidized soluble guanylate cyclase induced by conformational change. Biochim Biophys Acta 1864(5):488–500. Scholar
  108. Patel D, Lakhkar A, Wolin MS (2017) Redox mechanisms influencing cGMP signaling in pulmonary vascular physiology and pathophysiology. Adv Exp Med Biol 967:227–240. Scholar
  109. Patel DA, Kim HP, Zifodya JS, Vaezi MF (2015) Idiopathic (primary) achalasia: a review. Orphanet J Rare Dis 10:89. Scholar
  110. Paulus WJ, Tschope C (2013) A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 62(4):263–271. Scholar
  111. Pieske B, Butler J, Filippatos G, Lam C, Maggioni AP, Ponikowski P, Shah S, Solomon S, Kraigher-Krainer E, Samano ET, Scalise AV, Müller K, Roessig L, Gheorghiade M, SOCRATES Investigators and Coordinators (2014) Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES). Eur J Heart Fail 16(9):1026–1038. Scholar
  112. Pieske B, Maggioni AP, Lam CSP, Pieske-Kraigher E, Filippatos G, Butler J, Ponikowski P, Shah SJ, Solomon SD, Scalise AV, Mueller K, Roessig L, Gheorghiade M (2017) Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArTfailurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study. Eur Heart J 38(15):1119–1127. Scholar
  113. Pimenta E, Calhoun DA (2016) Drug development for hypertension: do we need another antihypertensive agent for resistant hypertension? Curr Hypertens Rep 18(4):25. Scholar
  114. Potoka KP, Wood KC, Baust JJ, Bueno M, Hahn S, Vanderpool RR, Bachman T, Mallampalli GM, Hwedieh DO, Schrott V, Bullock GC, Becker-Pelster EM, Stampfuss J, Mather I, Stasch JP, Truebel H, Sandner P, Mora AL, Straub AC, Gladwin MT (2018) Nitric oxide-independent activation of soluble guanylate cyclase improves vascular function and reverses cardiac remodeling in sickle cell disease. Am J Respir Cell Mol Biol 58(5):636–647Google Scholar
  115. Prabhakar SS (2004) Role of nitric oxide in diabetic nephropathy. Semin Nephrol 24(4):333–344Google Scholar
  116. Pradhan K, Sydykov A, Tian X, Mamazhakypov A, Neupane B, Luitel H, Weissmann N, Seeger W, Grimminger F, Kretschmer A, Stasch JP, Ghofrani HA, Schermuly RT (2016) Soluble guanylate cyclase stimulator riociguat and phosphodiesterase 5 inhibitor sildenafil ameliorate pulmonary hypertension due to left heart disease in mice. Int J Cardiol 216:85–91. Scholar
  117. Prasanna G, Ferrara L, Adams C, Ehara T, Li B, Yang L, Xiang C, Ng CTH, Kim S, Towler C, Topley T, McAllister C, Ghosh M, Newton R, Stacy R, Rice DS, Mogi MA (2018) novel selective soluble guanylate cyclase activator, MGV354, lowers intraocular pressure in preclinical models, following topical ocular dosing. Invest Ophthalmol Vis Sci 59(5):1704–1716. Scholar
  118. Profy AT, Shea C, Lonie E, Liu G, Milne GT, Currie MG, Masferrer J (2017) IW-1973, a soluble guanylate cyclase stimulator, inhibits progression of diabetic nephropathy in the ZSF1 rat model. Paper presented at the American Diabetes Association 77th scientific sessions, San Diego, CA, June 9–13Google Scholar
  119. Raffaella M, Moretti R, Leger PL, Besson VC, Csaba Z, Pansiot J, Di Criscio L, Gentili A, Titomanlio L, Bonnin P, Baud O, Charriaut-Marlangue C, Pierre-Louis L, Valérie CB, Zsolt C, Julien P, Di Lorena C, Andrea G, Luigi T, Philippe B, Olivier B, Christiane C-M (2016) Sildenafil, a cyclic GMP phosphodiesterase inhibitor, induces microglial modulation after focal ischemia in the neonatal mouse brain. J Neuroinflammation 13(1):95. Scholar
  120. Rahaman MM, Nguyen AT, Miller MP, Hahn SA, Sparacino-Watkins C, Jobbagy S, Carew NT, Cantu-Medellin N, Wood KC, Baty CJ, Schopfer FJ, Kelley EE, Gladwin MT, Martin E, Straub AC (2017) Cytochrome b5 reductase 3 modulates soluble guanylate cyclase redox state and cGMP signaling. Circ Res 121(2):137–148. Scholar
  121. Ritchie RH, Drummond GR, Sobey CG, De Silva TM, Kemp-Harper BK (2017) The opposing roles of NO and oxidative stress in cardiovascular disease. Pharmacol Res 116:57–69. Scholar
  122. Rubin LJ, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh A, Langleben D, Fritsch A, Menezes F, Davie N, Ghofrani HA (2015) Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J 45(5):1303–1313. Scholar
  123. Sandner P, Berger P, Zenzmaier C (2017) The potential of sGC modulators for the treatment of age-related fibrosis: a mini-review. Gerontology 63(3):216–227. Scholar
  124. Sandner P, Stasch JP (2017) Anti-fibrotic effects of soluble guanylate cyclase stimulators and activators: a review of the preclinical evidence. Respir Med 122(Suppl 1):S1–S9. Scholar
  125. Schinner E, Wetzl V, Schramm A, Kees F, Sandner P, Stasch JP, Hofmann F, Schlossmann J (2017) Inhibition of the TGFbeta signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis. FEBS Open Bio 7(4):550–561. Scholar
  126. Schmidt HH, Schmidt PM, Stasch JP (2009) NO- and haem-independent soluble guanylate cyclase activators. Handb Exp Pharmacol 191:309–339. Scholar
  127. Schmidt P, Schramm M, Schröder H, Stasch JP (2003) Receptor binding assay for nitric oxide- and heme-independent activators of soluble guanylate cyclase. Anal Biochem 314(1):162–165Google Scholar
  128. Schmidt PM, Schramm M, Schröder H, Wunder F, Stasch JP (2004) Identification of residues crucially involved in the binding of the heme moiety of soluble guanylate cyclase. J Biol Chem 279(4):3025–3032Google Scholar
  129. Schulz E, Jansen T, Wenzel P, Daiber A, Munzel T (2008) Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. Antioxid Redox Signal 10(6):1115–1126. Scholar
  130. Schwabl P, Brusilovskaya K, Supper P, Bauer D, Königshofer P, Riedl F, Hayden H, Fuchs CD, Stift J, Oberhuber G, Aschauer S, Bonderman D, Gnad T, Pfeifer A, Uschner FE, Trebicka J, Rohr-Udilova N, Podesser BK, Peck-Radosavljevic M, Trauner M, Reiberger T (2018) The soluble guanylate cyclase stimulator riociguat reduces fibrogenesis and portal pressure in cirrhotic rats. Sci Rep 8(1):9372. Scholar
  131. Schwam EM, Nicholas T, Chew R, Billing CB, Davidson W, Ambrose D, Altstiel LD (2014) A multicenter, double-blind, placebo-controlled trial of the PDE9A inhibitor, PF-04447943, in Alzheimer’s disease. Curr Alzheimer Res 11(5):413–421Google Scholar
  132. Schwartzkopf CD, Hadcock J, Jones JE, Currie M, Milne GT, Masferrer J (2018) Praliciguat, a clinical-stage sGC stimulator, improved glucose tolerance and insulin sensitivity and lowered triglycerides in a mouse diet-induced obesity model. Diabetes 67(Supplement 1):1886-P. Scholar
  133. Selwood DL, Brummell DG, Budworth J, Burtin GE, Campbell RO, Chana SS, Charles IG, Fernandez PA, Glen RC, Goggin MC, Hobbs AJ, Kling MR, Liu Q, Madge DJ, Meillerais S, Powell KL, Reynolds K, Spacey GD, Stables JN, Tatlock MA, Wheeler KA, Wishart G, Woo CK (2001) Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase. J Med Chem 44:78–93Google Scholar
  134. Shabsigh R (2004) Therapy of ED: PDE-5 inhibitors. Endocrine 23(2–3):135–141Google Scholar
  135. Shapiro S, Gillies H, Allard M, Blair C, Oudiz RJ (2012) ATHENA-1: long term clinical improvements following the addition of ambrisentan to background PDE5i therapy in patients with pulmonary arterial hypertension. J Heart Lung Transplant 31(4):S28eS29Google Scholar
  136. Sharina IG, Martin E (2017) The role of reactive oxygen and nitrogen species in the expression and splicing of nitric oxide receptor. Antioxid Redox Signal 26(3):122–136. Scholar
  137. Simonneau G, D’Armini AM, Ghofrani HA, Grimminger F, Jansa P, Kim NH, Mayer E, Pulido T, Wang C, Colorado P, Fritsch A, Meier C, Nikkho S, Hoeper MM (2016) Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med 4(5):372–380. Scholar
  138. Sivarao DV, Mashimo HL, Thatte HS, Goyal RK (2001) Lower esophageal sphincter is achalasic in nNOS(-/-) and hypotensive in W/W(v) mutant mice. Gastroenterology 121(1):34–42Google Scholar
  139. Stacy R, Huttner K, Watts J, Peace J, Wirta D, Walters T, Sall K, Seaman J, Ni X, Prasanna G, Mogi M, Adams C, Yan JH, Wald M, He Y, Newton R, Kolega R, Grosskreutz C (2018) A Randomized, controlled phase I/II study to evaluate the safety and efficacy of MGV354 for ocular hypertension or glaucoma. Am J Ophthalmol 192:113–123. Epub 2018 May 24Google Scholar
  140. Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Gerzer R, Minuth T, Perzborn E, Pleiss U, Schröder H, Schroeder W, Stahl E, Steinke W, Straub A, Schramm M (2001) NO-independent regulatory site on soluble guanylate cyclase. Nature 410(6825):212–215Google Scholar
  141. Stasch JP, Evgenov OV (2013) Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol 218:279–313. Scholar
  142. Stasch J-P, Hobbs AJ (2009) NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol 191:277–308. Scholar
  143. Stasch JP, Pacher P, Evgenov OV (2011) Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 123(20):2263–2273. Scholar
  144. Stasch JP, Schlossmann J, Hocher B (2015) Renal effects of soluble guanylate cyclase stimulators and activators: a review of the preclinical evidence. Curr Opin Pharmacol 21:95–104. Scholar
  145. Stasch JP, Schmidt P, Alonso-Alija C, Apeler H, Dembowsky K, Haerter M, Heil M, Minuth T, Perzborn E, Pleiss U, Schramm M, Schroeder W, Schröder H, Stahl E, Steinke W, Wunder F (2002) NO- and haem-independent activation of soluble guanylyl cyclase: molecular basis and cardiovascular implications of a new pharmacological principle. Br J Pharmacol 136(5):773–783Google Scholar
  146. Stasch JP, Schmidt PM, Nedvetsky PI, Nedvetskaya TY, Hs AK, Meurer S, Deile M, Taye A, Knorr A, Lapp H, Muller H, Turgay Y, Rothkegel C, Tersteegen A, Kemp-Harper B, Muller-Esterl W, Schmidt HH (2006) Targeting the heme-oxidized nitric oxide receptor for selective vasodilatation of diseased blood vessels. J Clin Invest 116:2552–2561Google Scholar
  147. Tchernychev BT, Feil S, Germano P, Warren W, Lonie E, Feil R, Milne GT, Hadcock J, Chien Y-T, Currie MG, Graul R (2017) The clinical-stage sGC stimulator IW-1701 prevents increase of plasma biomarkers of intravascular inflammation and suppresses leukocyte-endothelial interactions in TNFalpha-treated mice. Paper presented at the American Society of Hematology – 59th Annual Meeting, Atlanta, GAGoogle Scholar
  148. Thoonen R, Cauwels A, Decaluwe K, Geschka S, Tainsh RE, Delanghe J, Hochepied T, De Cauwer L, Rogge E, Voet S, Sips P, Karas RH, Bloch KD, Vuylsteke M, Stasch JP, Van de Voorde J, Buys ES, Brouckaert P (2015) Cardiovascular and pharmacological implications of haem-deficient NO-unresponsive soluble guanylate cyclase knock-in mice. Nat Commun 6:8482. Scholar
  149. Tobin JV, Zimmer DP, Shea C, Germano P, Bernier SG, Liu G, Long K, Miyashiro J, Ranganath S, Jacobson S, Tang K, Im GJ, Sheppeck J, Moore JD, Sykes K, Wakefield J, Sarno R, Banijamali AR, Profy AT, Milne GT, Currie MG, Masferrer JL (2018) Pharmacological characterization of IW-1973, a novel soluble guanylate cyclase stimulator with extensive tissue distribution, anti-hypertensive, anti-inflammatory, and anti-fibrotic effects in preclinical models of disease. J Pharmacol Exp Ther 365:664–675. Scholar
  150. van der Staay FJ, Rutten K, Bärfacker L, Devry J, Erb C, Heckroth H, Karthaus D, Tersteegen A, van Kampen M, Blokland A, Prickaerts J, Reymann KG, Schröder UH, Hendrix M (2008) The novel selective PDE9 inhibitor BAY 73-6691 improves learning and memory in rodents. Neuropharmacology 55(5):908–918. Scholar
  151. Venema RC, Venema VJ, Ju H, Harris MB, Snead C, Jilling T, Dimitropoulou C, Maragoudakis ME, Catravas JD (2003) Novel complexes of guanylate cyclase with heat shock protein 90 and nitric oxide synthase. Am J Physiol Heart Circ Physiol 285(2):H669–H678Google Scholar
  152. Vettel C, Lammle S, Ewens S, Cervirgen C, Emons J, Ongherth A, Dewenter M, Lindner D, Westermann D, Nikolaev VO, Lutz S, Zimmermann WH, El-Armouche A (2014) PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways. Am J Physiol Heart Circ Physiol 306(8):H1246–H1252. Scholar
  153. Wales JA, Chen CY, Breci L, Weichsel A, Bernier SG, Sheppeck JE 2nd, Solinga R, Nakai T, Renhowe PA, Jung J, Montfort WR (2018) Discovery of stimulator binding to a conserved pocket in the heme domain of soluble guanylyl cyclase. J Biol Chem 293(5):1850–1864. Scholar
  154. Wallace S, Guo DC, Regalado E, Mellor-Crummey L, Bamshad M, Nickerson DA, Dauser R, Hanchard N, Marom R, Martin E, Berka V, Sharina I, Ganesan V, Saunders D, Morris SA, Milewicz DM (2016) Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension. Clin Genet 90(4):351–360. Scholar
  155. Walseth TF, Graff G, Krick TP, Goldberg ND (1981) The fate of 18O in guanosine monophosphate during enzymic transformations leading to guanosine 3′,5′-monophosphate generation. J Biol Chem 256:2176–2179Google Scholar
  156. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr (2017) 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Hypertension 138(17):e426–e483. Scholar
  157. Wilck N, Markó L, Balogh A, Kräker K, Herse F, Bartolomaeus H, Szijártó IA, Reichhart N, Strauß O, Heuser A, Brockschnieder D, Kretschmer A, Lesche R, Stasch JP, Sandner P, Luft FC, Müller DN, Dechend R, Haase N (2018) Nitric oxide sensitive guanylyl cyclase stimulation improves experimental heart failure in rats with preserved ejection fraction. JCI Insight 3(4):96006Google Scholar
  158. Winter MB, Herzik MA Jr, Kuriyan J, Marletta MA (2011) Tunnels modulate ligand flux in a heme nitric oxide/oxygen binding (H-NOX) domain. Proc Natl Acad Sci U S A 108(43):E881–E889. Scholar
  159. Xiao J, Jin C, Liu Z, Guo S, Zhang X, Zhou X, Wu X (2015) The design, synthesis, and biological evaluation of novel YC-1 derivatives as potent anti-hepatic fibrosis agents. Org Biomol Chem 13(26):7257–7264. Scholar
  160. Zimmer DP, Silva IA, Chien Y-T, Milne GT, Currie M (2017) The soluble guanylate cyclase stimulator IW-1701 enhances nitric oxide-mediated relaxation of human lower esophageal sphincter ex vivo. Gastroenterology 152(5):S699. Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Peter Sandner
    • 1
    • 2
    Email author
  • Daniel P. Zimmer
    • 3
  • G. Todd Milne
    • 3
  • Markus Follmann
    • 1
  • Adrian Hobbs
    • 4
  • Johannes-Peter Stasch
    • 1
    • 5
  1. 1.Bayer AG, Pharmaceuticals R&D, Pharma Research CenterWuppertalGermany
  2. 2.Department of PharmacologyHannover Medical SchoolHannoverGermany
  3. 3.Ironwood PharmaceuticalsCambridgeUSA
  4. 4.Barts and the London School of Medicine and Dentistry QMULLondonUK
  5. 5.Institute of PharmacyUniversity Halle-WittenbergHalleGermany

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