Soluble Guanylate Cyclase Stimulators and Activators.
Cyclic guanosine monophosphate
Nitric oxide
Soluble guanylyl cyclase
cGMP
sGC
sGC activator
sGC stimulator
Journal
Handbook of experimental pharmacology
ISSN: 0171-2004
Titre abrégé: Handb Exp Pharmacol
Pays: Germany
ID NLM: 7902231
Informations de publication
Date de publication:
2021
2021
Historique:
pubmed:
29
1
2019
medline:
26
2
2021
entrez:
29
1
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30689085
doi: 10.1007/164_2018_197
doi:
Substances chimiques
Nitric Oxide
31C4KY9ESH
Guanylate Cyclase
EC 4.6.1.2
Soluble Guanylyl Cyclase
EC 4.6.1.2
Cyclic GMP
H2D2X058MU
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
355-394Commentaires et corrections
Type : ErratumIn
Références
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. https://doi.org/10.1111/cns.12688
doi: 10.1111/cns.12688
pubmed: 28296282
pmcid: 6492705
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. https://doi.org/10.1073/pnas.0304264101
doi: 10.1073/pnas.0304264101
pubmed: 14742866
pmcid: 337062
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. https://doi.org/10.1111/bph.13354
doi: 10.1111/bph.13354
pubmed: 26650445
pmcid: 4718211
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. https://doi.org/10.1182/blood-2012-02-409524
doi: 10.1182/blood-2012-02-409524
pubmed: 22833547
pmcid: 3466969
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):1080–1015
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. https://doi.org/10.1007/s00109-009-0544-2
doi: 10.1007/s00109-009-0544-2
pubmed: 19834654
pmcid: 2772954
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. https://doi.org/10.1016/j.jchf.2017.08.013
doi: 10.1016/j.jchf.2017.08.013
pubmed: 29032136
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. https://doi.org/10.1074/jbc.M411545200
doi: 10.1074/jbc.M411545200
pubmed: 15509556
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. https://doi.org/10.1136/annrheumdis-2011-200862
doi: 10.1136/annrheumdis-2011-200862
pubmed: 22294631
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. https://doi.org/10.1136/annrheumdis-2013-204508
doi: 10.1136/annrheumdis-2013-204508
pubmed: 24567525
Bittner AR, Sinz CJ, Chang J, Kim RM, Mirc JW, Parmee ER, Tan Q (2009) Soluble guanylate cyclase activators. WIPO, Geneva
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–S37
pubmed: 14581492
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):1128–1133
pubmed: 17325237
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. https://doi.org/10.1038/npp.2014.106
doi: 10.1038/npp.2014.106
pubmed: 24813825
pmcid: 4207334
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):253–257
pubmed: 10648452
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. https://doi.org/10.1007/164_2016_100
doi: 10.1007/164_2016_100
pubmed: 27900610
Brunton TL (1867) On the use of nitrite of amyl in angina pectoris. Lancet 90(2290):97–98
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. https://doi.org/10.1517/14656566.2013.799665
doi: 10.1517/14656566.2013.799665
pubmed: 23675780
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. https://doi.org/10.1371/journal.pone.0060156
doi: 10.1371/journal.pone.0060156
pubmed: 23527308
pmcid: 3603933
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. https://doi.org/10.1093/cvr/cvn068
doi: 10.1093/cvr/cvn068
pubmed: 18339647
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 78:72–80
pubmed: 29859918
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):394–401
pubmed: 11251538
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. https://doi.org/10.1155/2015/940207
doi: 10.1155/2015/940207
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. https://doi.org/10.1172/JCI16672
doi: 10.1172/JCI16672
pubmed: 12531879
pmcid: 151872
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. https://doi.org/10.1016/j.redox.2017.08.020
doi: 10.1016/j.redox.2017.08.020
pubmed: 29024896
Derbyshire ER, Marletta MA (2012) Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 81:533–559. https://doi.org/10.1146/annurev-biochem-050410-100030
doi: 10.1146/annurev-biochem-050410-100030
pubmed: 22404633
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. https://doi.org/10.1161/CIRCULATIONAHA.105.581405
doi: 10.1161/CIRCULATIONAHA.105.581405
pubmed: 16391154
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):758–764
pubmed: 12010875
pmcid: 1773249
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. https://doi.org/10.1038/nature12722
doi: 10.1038/nature12722
pubmed: 24213632
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. https://doi.org/10.1038/nrd2038
doi: 10.1038/nrd2038
pubmed: 16955067
pmcid: 2225477
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. https://doi.org/10.1186/1471-2210-11-s1-o9
doi: 10.1186/1471-2210-11-s1-o9
pmcid: 3363200
Faraco G, Iadecola C (2013) Hypertension: a harbinger of stroke and dementia. Hypertension 62(5):810–817. https://doi.org/10.1161/HYPERTENSIONAHA.113.01063
doi: 10.1161/HYPERTENSIONAHA.113.01063
pubmed: 23980072
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):907–916
pubmed: 14615494
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. https://doi.org/10.1002/ejhf.800
doi: 10.1002/ejhf.800
pubmed: 28586537
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):816–828
pubmed: 17038651
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. https://doi.org/10.1111/bph.14137
doi: 10.1111/bph.14137
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 52:9442–9462
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):5146–5161
pubmed: 28557445
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. https://doi.org/10.1007/s40262-017-0604-7
doi: 10.1007/s40262-017-0604-7
pmcid: 5974002
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. https://doi.org/10.1073/pnas.0609778104
doi: 10.1073/pnas.0609778104
pubmed: 17452643
pmcid: 1863512
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. https://doi.org/10.1007/s00210-017-1429-5
doi: 10.1007/s00210-017-1429-5
pubmed: 29018913
pmcid: 5783999
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–H475
pubmed: 7530924
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. https://doi.org/10.1167/iovs.15-18958
doi: 10.1167/iovs.15-18958
pubmed: 26998718
pmcid: 4811179
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. https://doi.org/10.1371/journal.pone.0021853
doi: 10.1371/journal.pone.0021853
pubmed: 21789188
pmcid: 3138745
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. https://doi.org/10.1001/jama.2015.15734
doi: 10.1001/jama.2015.15734
pubmed: 26547357
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. https://doi.org/10.1056/NEJMoa1209657
doi: 10.1056/NEJMoa1209657
pubmed: 23883377
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. https://doi.org/10.1056/NEJMoa1209655
doi: 10.1056/NEJMoa1209655
pubmed: 23883378
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. https://doi.org/10.1016/S2213-2600(16)30019-4
doi: 10.1016/S2213-2600(16)30019-4
pubmed: 27067479
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. https://doi.org/10.1089/ars.2016.6690
doi: 10.1089/ars.2016.6690
pubmed: 26983679
pmcid: 5278824
Gladwin MT (2006) Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome. J Clin Invest 116(9):2330–2332. https://doi.org/10.1172/JCI29807
doi: 10.1172/JCI29807
pubmed: 16955136
pmcid: 1555666
Groneberg D, Voussen B, Friebe A (2016) Integrative control of gastrointestinal motility by nitric oxide. Curr Med Chem 23(24):2715–2735
pubmed: 27528058
Gurbuz N, Mammadov E, Usta MF (2008) Hypogonadism and erectile dysfunction: an overview. Asian J Androl 10(1):36–43
pubmed: 18087642
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, DC
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. https://doi.org/10.1016/S0168-8278(18)31030-4
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. https://doi.org/10.1002/cpdd.627 . [Epub ahead of print]
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. https://doi.org/10.2337/db18-74-OR
doi: 10.2337/db18-74-OR
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. https://doi.org/10.2337/db18-1207-P
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. https://doi.org/10.1016/j.ajhg.2014.01.018
doi: 10.1016/j.ajhg.2014.01.018
pubmed: 24581742
pmcid: 3951937
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. https://doi.org/10.1159/000076405
doi: 10.1159/000076405
pubmed: 14988593
Hoeper MM (2015) Pharmacological therapy for patients with chronic thromboembolic pulmonary hypertension. Eur Respir Rev 24(136):272–282
pubmed: 26028639
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. https://doi.org/10.1016/j.rmed.2016.11.001
doi: 10.1016/j.rmed.2016.11.001
pubmed: 27887774
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. https://doi.org/10.1183/13993003.02425-2016
doi: 10.1183/13993003.02425-2016
pubmed: 28889107
pmcid: 5898946
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. https://doi.org/10.1038/ncomms8235
doi: 10.1038/ncomms8235
pubmed: 26011238
pmcid: 4455111
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. https://doi.org/10.1371/journal.pone.0023596
doi: 10.1371/journal.pone.0023596
pubmed: 21858179
pmcid: 3157391
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. https://doi.org/10.1111/j.1476-5381.2009.00263.x
doi: 10.1111/j.1476-5381.2009.00263.x
pubmed: 19466990
pmcid: 2721263
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. https://doi.org/10.1111/j.1442-2050.2011.01318.x
doi: 10.1111/j.1442-2050.2011.01318.x
pubmed: 22309323
Humbert M, Ghofrani HA (2016) The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax 71(1):73–83. https://doi.org/10.1136/thoraxjnl-2015-207170
doi: 10.1136/thoraxjnl-2015-207170
pubmed: 26219978
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):54–60
pubmed: 11430885
Ingram VM (1956) A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature 178(4537):792–794
pubmed: 13369537
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. https://doi.org/10.1038/nature10405
doi: 10.1038/nature10405
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. https://doi.org/10.1371/journal.pone.0044481
doi: 10.1371/journal.pone.0044481
pubmed: 23144773
pmcid: 3492396
Kemp-Harper B, Feil R (2008) Meeting report: cGMP matters. Sci Signal 1(9):pe12. https://doi.org/10.1126/stke.19pe12
doi: 10.1126/stke.19pe12
pubmed: 18319447
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. https://doi.org/10.1161/CIRCULATIONAHA.116.024152
doi: 10.1161/CIRCULATIONAHA.116.024152
pubmed: 28487391
pmcid: 5560301
Klinger JR, Kadowitz PJ (2017) The nitric oxide pathway in pulmonary vascular disease. Am J Cardiol 120(8S):S71–S79. https://doi.org/10.1016/j.amjcard.2017.06.012
doi: 10.1016/j.amjcard.2017.06.012
pubmed: 29025573
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. https://doi.org/10.1055/s-0031-1296471
doi: 10.1055/s-0031-1296471
pubmed: 18412020
Ko FN, Wu CC, Kuo SC, Lee FY, Teng CM (1994) YC-1, a novel activator of platelet guanylate cyclase. Blood 84(12):4226–4233
pubmed: 7527671
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. https://doi.org/10.1124/mol.117.109918
doi: 10.1124/mol.117.109918
pubmed: 29138269
Kone BC (1997) Nitric oxide in renal health and disease. Am J Kidney Dis 30(3):311–333
pubmed: 9292559
Kotikoski H, Vapaatalo H, Oksala O (2003) Nitric oxide and cyclic GMP enhance aqueous humor outflow facility in rabbits. Curr Eye Res 26(2):119–123
pubmed: 12815531
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. https://doi.org/10.3390/ijms19061712
pmcid: 6032334
Kuhn M (2016) Molecular physiology of membrane guanylyl cyclase receptors. Physiol Rev 96(2):751–804. https://doi.org/10.1152/physrev.00022.2015
doi: 10.1152/physrev.00022.2015
pubmed: 27030537
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):3423
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. https://doi.org/10.1371/journal.pone.0043433
doi: 10.1371/journal.pone.0043433
pubmed: 22912874
pmcid: 3422306
Leineweber K, Moosmang S, Paulson D (2017) Genetics of NO deficiency. Am J Cardiol 120(8S):S80–S88. https://doi.org/10.1016/j.amjcard.2017.06.013
doi: 10.1016/j.amjcard.2017.06.013
pubmed: 29025574
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. https://doi.org/10.1007/164_2016_101
doi: 10.1007/164_2016_101
pubmed: 27995390
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, Feb
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):375–414
pubmed: 10977868
Lundberg JO, Gladwin MT, Weitzberg E (2015) Strategies to increase nitric oxide signalling in cardiovascular disease. Nat Rev Drug Discov 14(9):623–641. https://doi.org/10.1038/nrd4623
doi: 10.1038/nrd4623
pubmed: 26265312
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 15–20
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. https://doi.org/10.1161/01.HYP.0000241087.12492.47
doi: 10.1161/01.HYP.0000241087.12492.47
pubmed: 16982964
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. https://doi.org/10.1038/hr.2009.64
doi: 10.1038/hr.2009.64
pubmed: 19424280
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. https://doi.org/10.1186/s12933-015-0309-x
doi: 10.1186/s12933-015-0309-x
pubmed: 26520063
pmcid: 4628236
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):189–195
pubmed: 12464390
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. https://doi.org/10.1371/journal.pone.0083910
doi: 10.1371/journal.pone.0083910
pubmed: 24391843
pmcid: 3877128
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. https://doi.org/10.1161/CIRCRESAHA
doi: 10.1161/CIRCRESAHA
pubmed: 19478201
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):1015–1025
pubmed: 12495780
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. http://www.bloodjournal.org/content/130/Suppl_1/3533 . Accessed 07 Dec 2018
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. https://doi.org/10.1002/cmdc.200900014
doi: 10.1002/cmdc.200900014
pubmed: 19263460
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. https://doi.org/10.1111/j.1743-6109.2006.00286.x
pubmed: 16942522
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):974–976
pubmed: 17325236
Murrell W (1879) Nitro-glycerin as a remedy for angina pectoris. Lancet 113(2890):80–81 ff
Musicki B, Burnett AL (2007) Endothelial dysfunction in diabetic erectile dysfunction. Int J Impot Res 19(2):129–138
pubmed: 16775612
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):855–857
pubmed: 12437671
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. https://doi.org/10.1021/acsmedchemlett.5b00479
doi: 10.1021/acsmedchemlett.5b00479
pubmed: 27190594
pmcid: 4867485
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. https://doi.org/10.1183/1393003.congress-2017.OA1985
doi: 10.1183/1393003.congress-2017.OA1985
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)
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. https://doi.org/10.1016/j.bbapap.2016.02.012
doi: 10.1016/j.bbapap.2016.02.012
pubmed: 26876536
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. https://doi.org/10.1007/978-3-319-63245-2_13
doi: 10.1007/978-3-319-63245-2_13
pubmed: 29047089
pmcid: 5766272
Patel DA, Kim HP, Zifodya JS, Vaezi MF (2015) Idiopathic (primary) achalasia: a review. Orphanet J Rare Dis 10:89. https://doi.org/10.1186/s13023-015-0302-1
doi: 10.1186/s13023-015-0302-1
pubmed: 26198208
pmcid: 4509143
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. https://doi.org/10.1016/j.jacc.2013.02.092
doi: 10.1016/j.jacc.2013.02.092
pubmed: 23684677
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. https://doi.org/10.1002/ejhf.135
doi: 10.1002/ejhf.135
pubmed: 25056511
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. https://doi.org/10.1002/ejhf.135
doi: 10.1002/ejhf.135
pubmed: 28369340
pmcid: 5400074
Pimenta E, Calhoun DA (2016) Drug development for hypertension: do we need another antihypertensive agent for resistant hypertension? Curr Hypertens Rep 18(4):25. https://doi.org/10.1007/s11906-016-0634-9
doi: 10.1007/s11906-016-0634-9
pubmed: 26949263
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):636–647
pubmed: 29268036
pmcid: 5946331
Prabhakar SS (2004) Role of nitric oxide in diabetic nephropathy. Semin Nephrol 24(4):333–344
pubmed: 15252773
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. https://doi.org/10.1016/j.ijcard.2016.04.098
doi: 10.1016/j.ijcard.2016.04.098
pubmed: 27140341
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. https://doi.org/10.1167/iovs.18-23772
pubmed: 29610853
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 9–13
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. https://doi.org/10.1186/s12974-016-0560-4
doi: 10.1186/s12974-016-0560-4
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. https://doi.org/10.1161/CIRCRESAHA.117.310705
doi: 10.1161/CIRCRESAHA.117.310705
pubmed: 28584062
pmcid: 5527687
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. https://doi.org/10.1016/j.phrs.2016.12.017
doi: 10.1016/j.phrs.2016.12.017
pubmed: 27988384
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. https://doi.org/10.1183/09031936.00090614
doi: 10.1183/09031936.00090614
pubmed: 25614164
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. https://doi.org/10.1159/000450946
pubmed: 27784018
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. https://doi.org/10.1016/j.rmed.2016.08.022
pubmed: 28341058
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. https://doi.org/10.1002/2211-5463.12202
doi: 10.1002/2211-5463.12202
pubmed: 28396839
pmcid: 5377407
Schmidt HH, Schmidt PM, Stasch JP (2009) NO- and haem-independent soluble guanylate cyclase activators. Handb Exp Pharmacol 191:309–339. https://doi.org/10.1007/978-3-540-68964-5_14
doi: 10.1007/978-3-540-68964-5_14
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):162–165
pubmed: 12633618
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):3025–3032
pubmed: 14570894
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. https://doi.org/10.1089/ars.2007.1989
doi: 10.1089/ars.2007.1989
pubmed: 18321209
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. https://doi.org/10.1038/s41598-018-27656-y
pubmed: 29921982
pmcid: 6008436
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):413–421
pubmed: 24801218
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. https://doi.org/10.2337/db18-1886-P
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 44:78–93
pubmed: 11141091
Shabsigh R (2004) Therapy of ED: PDE-5 inhibitors. Endocrine 23(2–3):135–141
pubmed: 15146092
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):S28eS29
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. https://doi.org/10.1089/ars.2016.6687
doi: 10.1089/ars.2016.6687
pubmed: 26972233
pmcid: 7061304
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. https://doi.org/10.1016/S2213-2600(16)30022-4
doi: 10.1016/S2213-2600(16)30022-4
pubmed: 27067478
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):34–42
pubmed: 11438492
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. https://doi.org/10.1016/j.ajo.2018.05.015. Epub 2018 May 24
pubmed: 29802818
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):212–215
pubmed: 11242081
Stasch JP, Evgenov OV (2013) Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol 218:279–313. https://doi.org/10.1007/978-3-642-38664-0_12
doi: 10.1007/978-3-642-38664-0_12
pubmed: 24092345
Stasch J-P, Hobbs AJ (2009) NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol 191:277–308. https://doi.org/10.1007/978-3-540-68964-5_13
doi: 10.1007/978-3-540-68964-5_13
Stasch JP, Pacher P, Evgenov OV (2011) Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 123(20):2263–2273. https://doi.org/10.1161/CIRCULATIONAHA.110.981738
doi: 10.1161/CIRCULATIONAHA.110.981738
pubmed: 21606405
pmcid: 3103045
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. https://doi.org/10.1016/j.coph.2014.12.014
doi: 10.1016/j.coph.2014.12.014
pubmed: 25645316
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):773–783
pubmed: 12086987
pmcid: 1573403
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 116:2552–2561
pubmed: 16955146
pmcid: 1555649
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, GA
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. https://doi.org/10.1038/ncomms9482
doi: 10.1038/ncomms9482
pubmed: 26442659
pmcid: 4699393
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. https://doi.org/10.1124/jpet.117.247429
pubmed: 29643251
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. https://doi.org/10.1016/j.neuropharm.2008.07.005
doi: 10.1016/j.neuropharm.2008.07.005
pubmed: 18674549
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–H678
pubmed: 12676772
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. https://doi.org/10.1152/ajpheart.00852.2013
doi: 10.1152/ajpheart.00852.2013
pubmed: 24531807
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. https://doi.org/10.1074/jbc.RA117.000457
pubmed: 29222330
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. https://doi.org/10.1111/cge.12739
doi: 10.1111/cge.12739
pubmed: 26777256
pmcid: 4949143
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 256:2176–2179
pubmed: 6109725
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. https://doi.org/10.1161/HYP.0000000000000066
doi: 10.1161/HYP.0000000000000066
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):96006
pubmed: 29467337
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. https://doi.org/10.1073/pnas.1114038108
pubmed: 21997213
pmcid: 3203760
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. https://doi.org/10.1039/c5ob00710k
doi: 10.1039/c5ob00710k
pubmed: 26055070
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. https://doi.org/10.1016/S0016-5085(17)32443-5
doi: 10.1016/S0016-5085(17)32443-5