Skip to main content
SpringerLink
Log in

NO- and Haem-Independent Soluble Guanylate Cyclase Activators

  • Chapter
cGMP: Generators, Effectors and Therapeutic Implications

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 191))

Abstract

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

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Abraham NG, Quan S, Mieyal PA, Yang L, Burke-Wolin T, Mingone CJ, Goodman AI, Nasjletti A, Wolin MS (2002) Modulation of cGMP by human HO-1 retrovirus gene transfer in pulmonary microvessel endothelial cells. Am J Physiol Lung Cell Mol Physiol 283:L1117–L1124

    PubMed  CAS  Google Scholar 

  • Antonova G, Lichtenbeld H, Xia T, Chatterjee A, Dimitropoulou C, Catravas JD (2007) Func tional significance of hsp90 complexes with NOS and sGC in endothelial cells. Clin Hemorheol Microcirc 37:19–35

    PubMed  CAS  Google Scholar 

  • 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 280:2186–2196

    PubMed  CAS  Google Scholar 

  • Benz K, Orth SR, Simonaviciene A, Linz W, Schindler U, Rütten H, Amann K (2007) Blood pressure-independent effect of long-term treatment with the soluble heme-independent guany-lyl cyclase activator HMR1766 on progression in a model of noninflammatory chronic renal damage. Kidney Blood Press Res 30:224–233

    PubMed  CAS  Google Scholar 

  • Bloch KD, Ichinose F, Roberts JD Jr, Zapol WM (2007) Inhaled NO as a therapeutic agent. Car-diovasc Res 75:339–348

    Article  CAS  Google Scholar 

  • Boerrigter G, Burnett JC Jr (2004) Recent advances in natriuretic peptides in congestive heart failure. Expert Opin Investig Drugs 13:643–652

    PubMed  CAS  Google Scholar 

  • Boerrigter G, Costello-Boerrigter LC, Cataliotti A, Lapp H, Stasch JP, Burnett JC Jr (2007a) Tar geting heme-oxidized soluble guanylate cyclase in experimental heart failure. Hypertension 49:1128–1133

    CAS  Google Scholar 

  • Boerrigter G, Costello-Boerrigter LC, Lapp H, Stasch JP, Burnett JC (2007b) Beneficial actions of co-targeting particulate and soluble guanylate cyclase dependent cGMP pools in experimental heart failure. Circulation 116 (Suppl):II-550

    Google Scholar 

  • Burley DS, Ferdinandy P, Baxter GF (2007) Cyclic GMP and protein kinase-G in myocardial ischaemia-reperfusion: opportunities and obstacles for survival signaling. Br J Pharmacol 152:855–869

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Chirkov YY, Horowitz JD (2007) Impaired tissue responsiveness to organic nitrates and nitric oxide: A new therapeutic frontier? Pharmacol Ther 116:287–305

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Costa ADT, Garlid KD, West IC, Lincoln TM, Downey JM, Cohen MV, Critz SD (2005) Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res 97:329– 336

    PubMed  CAS  Google Scholar 

  • Derbyshire ER, Marletta MA (2007) Butyl isocyanide as a probe of the activation mechanism of soluble guanylate cyclase. Investigating the role of non-heme nitric oxide. J Biol Chem 282:35741–35748

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Evgenov OV, Kohane DS, Bloch KD, Stasch JP, Volpato GP, Bellas E, Evgenov NV, Buys ES, Gnoth MJ, Graveline AR, Liu R, Hess DR, Langer R, Zapol EM (2007) Pulmonary vasodila-tion induced by inhalation of soluble guanylate cyclase agonists encapsulated into dry-powder microparticles. Am J Respir Crit Care Med 176:1138–1145

    PubMed  CAS  Google Scholar 

  • Evgenov OV, Egorina EM, Stasch JP, Sovershaev MA (2008) Inhibition of expression and pro-coagulant activity of tissue factor by soluble guanylate cyclase agonists in monocytes and en-dothelial cells. Nitric Oxide. 19 (Suppl.): S61

    Google Scholar 

  • Farber HW, Loscalzo J (2004) Pulmonary arterial hypertension. N Engl J Med 351:1655–1665

    PubMed  CAS  Google Scholar 

  • Feil R, Kemp-Harper B (2006) cGMP signalling: From bench to bedside. Conference on cGMP generators, effectors and therapeutic implications. EMBO Rep 7:149–153

    PubMed  CAS  Google Scholar 

  • Foerster J, Harteneck C, Malkewitz J, Schultz G, Koesling D (1996) A functional heme-binding site of soluble guanylyl cyclase requires intact N-termini of alpha 1 and beta 1 subunits. Eur J Biochem 240:380–386

    PubMed  CAS  Google Scholar 

  • Francois M, Kojda G (2004) Effect of hypercholesterolemia and of oxidative stress on the nitric oxide-cGMP pathway. Neurochem Int 45:955–961

    PubMed  CAS  Google Scholar 

  • Frenzel M, Methner C, Felix SB, Krieg T (2008) The guanylyl cyclase activator BAY 58–2667 protects isolated rat hearts against ischemia-reperfusion injury. Clin Res Cardiol 97 (Suppl 1):P453

    Google Scholar 

  • Frey R, Mück W, Unger S, Artmeier-Brandt U, Weimann G, Wensing G (2008) Pharmacokinet-ics, Pharmacodynamics, Tolerability and Safety of the Soluble Guanylate Cyclase Activator Cinaciguat (BAY 58–2667) in Healthy Male Volunteers. J Clin Pharmacol. 2008 Sep 8. [Epub ahead of print]

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Friedman SL (2004) Stellate cells: A moving target in hepatic fibrogenesis. Hepatology 40: 1041–1003

    PubMed  CAS  Google Scholar 

  • Garthwaite J, Southam E, Boulton CL, Nielsen EB, Schmidt K, Mayer B (1995) Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one. Mol Pharmacol 48:184–188

    PubMed  CAS  Google Scholar 

  • Gessler T, Schmehl T, Olschewski H, Grimminger F, Seeger W (2002) Aerosolized vasodilators in pulmonary hypertension. J Aerosol Med 15:117–122

    PubMed  CAS  Google Scholar 

  • Ghofrani HA, Osterloh IH, Grimminger F (2006) Sildenafil: From angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev Drug Discov 5:689–702

    PubMed  CAS  Google Scholar 

  • Gladwin MT (2006) Deconstructing endothelial dysfunction: Soluble guanylyl cyclase oxidation and the NO resistance syndrome. J Clin Invest 116:2330–2332

    PubMed  CAS  Google Scholar 

  • Hahn MG, Alonso-Alija C, Stoll F, Heil M, Mittendorf J, Schlemmer KH, Wunder F, Stasch JP (2007) Design and synthesis of the first NO- and haem-independent sGC activator BAY 58– 2667 for the treatment of acute decompensated heart failure. BMC Pharmacol 7:P25

    Google Scholar 

  • Hare JM, Stamler JS (2005) NO/Redox disequilibrium in the failing heart and cardiovascular sys tem. J Clin Invest 115:509–517

    PubMed  CAS  Google Scholar 

  • Hobbs AJ (1997) Soluble guanylate cyclase: The forgotten sibling. Trends Pharmacol Sci 18: 484–491

    PubMed  CAS  Google Scholar 

  • Hobbs AJ (2000) Soluble guanylate cyclase. Emerg Therap Targets 4:735–749

    CAS  Google Scholar 

  • Hobbs AJ (2002) Soluble guanylate cyclase: An old therapeutic target re-visited. Br J Pharmacol 136:637–640

    PubMed  CAS  Google Scholar 

  • Hoenicka M, Becker EM, Apeler H, Sirichoke T, Schroder H, Gerzer R, Stasch JP (1999) Purified soluble guanylyl cyclase expressed in a baculovirus/Sf9 system: Stimulation by YC-1, nitric oxide, and carbon monoxide. J Mol Med 77:14–23

    PubMed  CAS  Google Scholar 

  • Hoffmann M, Thuss U (2007) Cardiovascular effects of the soluble guanylyl cyclase activator BAY 58–2667 in anesthetized dogs. BMC Pharmacol 7(Suppl 1):P28

    Google Scholar 

  • Hoffmann LS, Keim Y, Schmidt PM, Schäfer S, Schmidt HHHW, Stasch JP (2008) Distinct molec ular requirements to activate and stabilize soluble guanylate cyclase upon heme oxidation-induced degradation. Mol Pharmacol (under review)

    Google Scholar 

  • Hohenstein B, Daniel C, Wagner A, Stasch JP, Hugo C (2005) Stimulation of soluble guanylyl cyclase inhibits mesangial cell proliferation and matrix accumulation in experimental glomeru-lonephritis. Am J Physiol Renal Physiol 288:F685–F693

    PubMed  CAS  Google Scholar 

  • Ignarro LJ, Wood KS, Wolin MS (1982) Activation of purified soluble guanylate cyclase by proto-porphyrin IX. Proc Natl Acad Sci USA 79:2870–2873

    PubMed  CAS  Google Scholar 

  • Ignarro LJ, Wood KS, Wolin MS (1984) Regulation of purified soluble guanylate cyclase by por-phyrins and metalloporphyrins: A unifying concept. Adv Cyclic Nucl Protein Phosph Res 17:267–274

    CAS  Google Scholar 

  • Illiano SC, Riva L, Bouloy M, Beauverger P, O'Connor SE (2006) Effect of HMR1766, a soluble guanylate cyclase activator, on differentiation of cardiac fibroblasts and extracellular matrix synthesis induced by TGFbeta. Circulation 114:II-281

    Google Scholar 

  • Jones ES, Kemp-Harper BA, Stasch JP, Schmidt HHHW, Widdop RE (2008) Beneficial cardiovas cular effects of chronic stimulation/activation of sGC in aged spontaneously hypertensive rats. J Hypertens 26 (Suppl. 1):S362–S363

    Google Scholar 

  • Kalk P, Godes M, Relle K, Rothkegel C, Hucke A, Stasch JP, Hocher B (2006) NO-independent ac tivation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy. Br J Pharmacol 148:853–859

    PubMed  CAS  Google Scholar 

  • Kawada N, Kuroki T, Uoya M, Inue M, Kobayashi K (1996) Smooth muscle alpha actin expression in rat hepatic stellate cell is regulated by nitric oxide and cGMP production. Biochem Biophys Res Commun 229:238–242

    PubMed  CAS  Google Scholar 

  • Kemp-Harper B, Feil R. Meeting report: cGMP matters. Sci Signal. 2008 Mar 4; 1(9):pe12.

    PubMed  Google Scholar 

  • Kirsch M, Kemp-Harper B, Weissmann N, Grimminger F, Schmidt HHHW (2008) Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up-regulation of NO-cGMP sig naling. FASEB J 22:30–40

    PubMed  CAS  Google Scholar 

  • Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, Seguchi O, Myoishi M, Minamino T, Ohara T, Nagai Y, Nanto S, Watanabe K, Fukuzawa S, Hirayama A, Nakamura N, Kimura K, Fujii K, Ishihara M, Saito Y, Tomoike H, Kitamura S; J-WIND investigators (2007) Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet 370:1483–1493

    PubMed  CAS  Google Scholar 

  • Knorr A, Hirth-Dietrich C, Alonso-Alija C, Härter 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. Arzneim.-Forsch./Drug Res 58:71–80

    CAS  Google Scholar 

  • Krieg T, Liu Y, Rütz T, Dost T, Yang XM, Stasch JP, Felix SB, Cohen MV, Downey JM (2009) Cardioprotective effects of the NO-independent guanylyl cyclase activator BAY 58–2667.

    Google Scholar 

  • Kuno A, Solenkova NV, Solodushko V, Dost T, Liu Y, Yang XM, Cohen MV, Downey JM (2008) Infarct Limitation by a Protein Kinase G Activator at Reperfusion in Rabbit Hearts Is Depen dent on Sensitizing the Heart to A2b agonists by Protein Kinase C. Am J Physiol Heart Circ Physiol 295:H1288–1295

    PubMed  CAS  Google Scholar 

  • Lapp H, Mitrovic V, Franz N, Heuer H, Buerke M, Wolfertz J, Mück W, Unger S, Wensing G, Frey R (2007) BAY 58–2667, a soluble guanylate cyclase activator, improves cardiopulmonary

    Google Scholar 

  • Lee CY, Burnett JC Jr (2007) Natriuretic peptides and therapeutic applications. Heart Fail Rev 12:131–142

    PubMed  CAS  Google Scholar 

  • Lincoln TM (2004) Cyclic GMP and phosphodiesterase 5 inhibitor therapies: What's on the hori zon? Mol Pharmacol 66:11–13

    PubMed  CAS  Google Scholar 

  • Makino R, Matsuda H, Obayashi E, Shiro Y, Iizuka T, Hori H (1999) EPR characterization of axial bond in metal center of native and cobalt-substituted guanylate cyclase. J Biol Chem 274: 7714–7723

    PubMed  CAS  Google Scholar 

  • Martin E, Lee YC, Murad F (2001) YC-1 activation of human soluble guanylyl cyclase has both heme-dependent and heme-independent components. Proc Natl Acad Sci USA 98: 12938–12942

    PubMed  CAS  Google Scholar 

  • Melichar VO, Behr-Roussel D, Zabel U, Uttenthal LO, Rodrigo J, Rupin A, Verbeuren TJ, Kumar HSA, Schmidt HHHW (2004) Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis. Proc Natl Acad Sci USA 101:16671–16676

    PubMed  CAS  Google Scholar 

  • Mergia E, Friebe A, Dangel O, Russwurm M, Koesling D (2006) Spare guanylyl cyclase NO receptors ensure high NO sensitivity in the vascular system. J Clin Invest 116:1731–1737

    PubMed  CAS  Google Scholar 

  • Meurer S, Pioch S, Pabst T, Opitz N, Schmidt PM, Beckhaus T, Wagner K, Matt S, Gebauer K, Karas M, Stasch JP, Schmidt HHHW, Müller-Esterl W (2008) Heme-oxidized soluble guanylyl cyclase targeted to proteosomal degradation is rescued by NO-independent activator BAY 58– 2667. Circ Res (under review)

    Google Scholar 

  • Mingone CJ, Gupte SA, Chow JL, Ahmad M, Abraham NG, Wolin MS (2006) Protoporphyrin IX generation from delta-aminolevulinic acid elicits pulmonary artery relaxation and soluble guanylate cyclase activation. Am J Physiol Lung Cell Mol Physiol 291:L337–L344

    PubMed  CAS  Google Scholar 

  • Mingone CJ, Ahmad M, Gupte SA, Chow JL, Wolin MS (2008) Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide. Am J Physiol Heart Circ Physiol 294:H1244–H1250

    PubMed  CAS  Google Scholar 

  • Miura T, Miki T (2008) Limitation of myocardial infarct size in the clinical setting: current sta tus and challenges in translating animal experiments into clinical therapy. Basic Res Cardiol 103:501–513

    PubMed  Google Scholar 

  • Moncada S and Higgs EA (2006) Nitric oxide and the vascular endothelium. Handb Exp Pharmacol 176:213–254

    PubMed  Google Scholar 

  • Münzel T, Genth-Zotz S, Hink U (2007) Targeting heme-oxidized soluble guanylate cyclase: Solution for all cardiorenal problems in heart failure? Hypertension 49:974–976

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Murthy KS (2008) Inhibitory phosphorylation of soluble guanylyl cyclase by muscarinic m2 re ceptors via Gβγ-dependent activation of c-Src kinase. J Pharmacol Exp Ther 325:183–189

    PubMed  CAS  Google Scholar 

  • Nedvetsky PI, Meurer S, Opitz N, Nedvetskaya TY, Muller H, Schmidt HHHW (2008) Heat shock protein 90 regulates stabilization rather than activation of soluble guanylate cyclase. FEBS Lett 582:327–331

    PubMed  CAS  Google Scholar 

  • Nielsch U, Schäfer S, Wild H, Busch A (2008) One target-multiple indications: A call for an integrated common mechanisms strategy. Drug Discov Today 12:1025–1031

    Google Scholar 

  • Oberwittler H, Hirschfeld-Warneken A, Wesch R, Willerich H, Teichert L, Lehr KH, Ding R, Haefeli WE, Mikus G (2007) Significant pharmacokinetic and pharmacodynamic interaction of warfarin with the NO-independent sGC activator HMR1766. J Clin Pharmacol 47:70–77

    PubMed  CAS  Google Scholar 

  • Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87nd peroxynitrite in health and disease Physiol Rev 87:315–424

    PubMed  CAS  Google Scholar 

  • Papapetropoulos A, Zhou Z, Gerassimou C, Yetik G, Venema RC, Roussos C, Sessa WC, Catravas JD (2005) Interaction between the 90-kDa heat shock protein and soluble guanylyl cyclase: Physiological significance and mapping of the domains mediating binding. Mol Phar macol 68:1133–1141

    CAS  Google Scholar 

  • Patel NM, Lederer DJ, Borczuk AC, Kawut SM (2007) Pulmonary hypertension in idiopathic pulmonary fibrosis. Chest 132:998–1006

    PubMed  Google Scholar 

  • Paton JS, Byron PR (2007) Inhaling medicines: Delivering drugs to the body through the lungs. Nat Rev Drug Discov 6:67–74

    Google Scholar 

  • Pellicena P, Karow DS, Boon EM, Marletta MA, Kuriyan J (2004) Crystal structure of an oxygen-binding heme domain related to soluble guanylate cyclases. Proc Natl Acad Sci USA 101:12854–12859

    PubMed  CAS  Google Scholar 

  • Perkins WJ (2006) Regulation of soluble guanylyl cyclase: Looking beyond NO. Am J Physiol Lung Cell Mol Physiol 29:L337–L344

    Google Scholar 

  • Perri RE, Langer DA, Chatterjee S, Gibbons SJ, Gadgil J, Cao S, Farrugia G, Shah VH (2006) Defects in cGMP-PKG pathway contribute to impaired NO-dependent responses in hepatic stellate cells upon activation. Am J Physiol Gastrointest Liver Physiol 290:G535–G542

    PubMed  CAS  Google Scholar 

  • Peters H, Wang Y, Loof T, Martini S, Kron S, Krämer S, Neumayer HH (2004) Expression and ac tivity of soluble guanylate cyclase in injury and repair of anti-thy1 glomerulonephritis. Kidney Int 66:2224–2236

    PubMed  CAS  Google Scholar 

  • Rajendran S, Chirkov YY (2008) Platelet hyperaggregability: impaired responsiveness to nitric oxide (“platelet NO resistance”) as a therapeutic target. Cardiovasc Drugs Ther. 22:193–203.

    PubMed  CAS  Google Scholar 

  • Reynaert H, Thompson MG, Thomas T, Geerts A (2002) Hepatic stellate cells: Role in microcir-culation and pathophysiology of portal hypertension. Gut 50:571–581

    PubMed  CAS  Google Scholar 

  • Ritz E (2007) Endothelial cell dysfunction—can one outsmart oxidative stress by direct interaction with the pathological oxidized or heme-free soluble guanylate cyclase? J Am Soc Nephrol 18:663–666

    Google Scholar 

  • Rothkegel C, Schmidt PM, Stoll F, Schröder H, Schmidt HH, Stasch JP (2006) Identification of residues crucially involved in soluble guanylate cyclase activation. FEBS Lett 580:4205–4213

    PubMed  CAS  Google Scholar 

  • Rothkegel C, Schmidt PM, Atkins DJ, Hoffmann LS, Schmidt HHHW, Schröder H, Stasch JP (2007) Dimerization region of soluble guanylate cyclase characterized by bimolecular fluores cence complementation in vivo. Mol Pharmacol 72:1181–1190

    PubMed  CAS  Google Scholar 

  • Roy B, Garthwaite J (2006) Nitric oxide activation of guanylyl cyclase in cells revisited. Proc Natl Acad Sci USA 103:12185–12190

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Ruetten H, Zabel U, Linz W, Schmidt HHHW (1999) Downregulation of soluble guanylyl cyclase in young and aging spontaneously hypertensive rats. Circ Res 85:534–541

    PubMed  CAS  Google Scholar 

  • Russwurm M, Koesling D (2004) NO activation of guanylyl cyclase. EMBO J 23:4443–4450

    PubMed  CAS  Google Scholar 

  • Salloum FN, Takenoshita Y, Ockaili RA, Daoud VP, Chou E, Yoshida K, Kukreja RC (2007) Sildenafil and vardenafil but not nitroglycerin limit myocardial infarction through opening of mitochondrial KATPchannels when administered at reperfusion following ischemia in rabbits. J Mol Cell Cardiol 42:453–458

    PubMed  CAS  Google Scholar 

  • Salloum FN, Abbate A, Das A, Houser JE, Mudrick CA, Qureshi IZ, Hoke NN, Roy SK, Brown WR, Prabhakar S, Kukreja RC (2008) Sildenafil (Viagra) attenuates ischemic cardiomyopathy and improves left ventricular function in mice. Am J Physiol Heart Circ Physiol. 294:H1398– 1406.

    PubMed  CAS  Google Scholar 

  • Sayed N, Baskaran P, Ma X, van den Akker F, Beuve A (2007) Desensitization of soluble guanylyl cyclase, the NO receptor, by S-nitrosylation. Proc Natl Acad Sci USA 104:12312–12317

    PubMed  CAS  Google Scholar 

  • Schäfer A, Bauersachs J (2007) Therapeutic targets of ataciguat. Drugs Fut 32:731–738

    Article  CAS  Google Scholar 

  • Schäfer A, Flierl U, Kobsar A, Eigenthaler M, Ertl G, Bauersachs J (2006) Soluble guanylyl cyclase activation with HMR1766 attenuates platelet activation in diabetic rats. Arterioscler Thromb Vasc Biol 26:2813–2818

    PubMed  Google Scholar 

  • Schermuly RT, Stasch JP, Pullamsetti SS, Middendorff R, Müller D, Schlüter KD, Dingendorf A, Hackemack S, Kolosionek E, Kaulen C, Dumitrascu R, Weissmann N, Mittendorf J, Klepetko W, Seeger W, Ghofrani HA, Grimminger F (2008) Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 32:881–891.

    PubMed  CAS  Google Scholar 

  • Schindler U, Klein M, Linz W, Rütten H, Schäfer S, Strobel H, Schäfer A, Bauersachs J, Wassmann S, Van Eickels M (2005) Role of activators of ferric sGC in cardiovascular disease. BMC Pharmacol 5(Suppl 1):S19

    Google Scholar 

  • Schindler U, Strobel H, Schonafinger K, Linz W, Lohn M, Martorana PA, Rutten H, Schindler PW, Busch AE, Sohn M, Topfer A, Pistorius A, Jannek C, Mulsch A (2006) Biochemistry and pharmacology of novel anthranilic acid derivatives activating heme-oxidized soluble guanylyl cyclase. Mol Pharmacol 69:1260–1268

    PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Schmidt P, Schramm M, Schröder H, Stasch JP (2003b) Preparation of heme-free soluble guanylate cyclase. Protein Expr Purif 31:42–46

    CAS  Google Scholar 

  • Schmidt PM, Schramm M, Schroder 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 279:3025–3032

    PubMed  CAS  Google Scholar 

  • Schmidt PM, Rothkegel C, Wunder F, Schroder H, Stasch JP (2005) Residues stabilizing the heme moiety of the nitric oxide sensor soluble guanylate cyclase. Eur J Pharmacol 513:67–74

    PubMed  CAS  Google Scholar 

  • Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Gerzer R, Minuth T, Perzborn E, Pleiβ U, Schröder H, Schroeder W, Stahl E, Steinke W, Straub A, Schramm M (2001) NO-independent regulatory site on soluble guanylate cyclase. Nature 410:212–215

    PubMed  CAS  Google Scholar 

  • 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, Schroder H, Stahl E, Steinke W, Wunder F (2002a) NO- and haem-independent activation of soluble guanylyl cyclase: Molecular basis and cardiovascular implications of a new pharmacological principle. Br J Pharmacol 136:773–783

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  • Stasch JP, Schmidt PM, Nedvetsky PI, Nedvetskaya TY, Kumar A, Meurer S, Deile M, Taye A, Knorr A, Lapp H, Müller H, Turgay Y, Rothkegel C, Tersteegen A, Kemp-Harper B, Müller-Esterl W, Schmidt HHHW (2006) Targeting the heme-oxidized nitric oxide receptor for selec tive vasodilatation of diseased blood vessels. J Clin Invest 116:2552–2561

    PubMed  CAS  Google Scholar 

  • Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS (2003) Intravenous sildenafil and inhaled nitric oxide: A randomised trial in infants after cardiac surgery. Intensive Care Med 1996–2003

    Google Scholar 

  • Tulis DA (2007) Salutary properties of YC-1 in the cardiovascular and hematological systems. Curr Med Chem Cardiovasc Hematol Agents 2:343–359

    Google Scholar 

  • Van de Casteele M, Omasta A, Janssens S, Roskams T, Desmet V, Nevens F, Fevery J (2002) In vivo gen transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetized CCl4 cirrhotic rats. Gut 51:440–445

    PubMed  Google Scholar 

  • 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:H669–H678

    PubMed  CAS  Google Scholar 

  • Wang Y, Krämer S, Loof T, Martini S, Kron S, Kawachi H, Shimizu F, Neumayer HH, Peters H (2005) Stimulation of soluble guanylate cyclase slows progression in anti-thy1-induced chronic glomerulosclerosis. Kidney Int 68:47–61

    PubMed  CAS  Google Scholar 

  • Wang Y, Krämer S, Loof T, Martini S, Kron S, Kawachi H, Shimizu F, Neumayer HH, Peters H (2006) Enhancing cGMP in experimental progressive renal fibrosis: Soluble guanylate cyclase stimulation vs. phosphodiesterase inhibition. Am J Physiol Renal Physiol 290:F167–F176

    PubMed  CAS  Google Scholar 

  • Wang-Rosenke Y, Neumayer HH, Peters H (2008) NO signaling through cGMP in renal tissue fibrosis and beyond: Key pathway and novel therapeutic target. Curr Med Chem 15:1396–1406

    PubMed  CAS  Google Scholar 

  • Weber M, Lauer N, Mulsch A, Kojda G (2001) The effect of peroxynitrite on the catalytic activity of soluble guanylyl cyclase. Free Radic Biol Med 31:1360–1367

    PubMed  CAS  Google Scholar 

  • Wedel B, Humbert P, Harteneck C, Foerster J, Malkewitz J, Bohme E, Schultz G, Koesling D (1994) Mutation of His-105 in the beta 1 subunit yields a nitric oxide-insensitive form of soluble guanylyl cyclase. Proc Natl Acad Sci USA 91:2592–2596

    PubMed  CAS  Google Scholar 

  • Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MW, Bloch KD, Zapol WM (2000) Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension. Anesthesiology 92:1702–1712

    PubMed  CAS  Google Scholar 

  • Wunder F, Stasch JP, Hutter J, Alonso-Alija C, Huser J, Lohrmann E (2005) A cell-based cGMP assay useful for ultra-high-throughput screening and identification of modulators of the nitric oxide/cGMP pathway. Anal Biochem 339:104–112

    PubMed  CAS  Google Scholar 

  • Xia T, Dimitropoulou C, Zeng J, Antonova GN, Snead C, Venema RC, Fulton D, Qian S, Patterson C, Papapetropoulos A, Catravas JD (2007) Chaperone-dependent E3 ligase CHIP ubiquitinates and mediates proteasomal degradation of soluble guanylyl cyclase. Am J Physiol Heart Circ Physiol 293:H3080–H3087

    PubMed  CAS  Google Scholar 

  • Yang XM, Philipp S, Downey JM, Cohen MV (2006) Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts. Basic Res Cardiol 101:311–18

    PubMed  CAS  Google Scholar 

  • Yellon DM, Downey JM (2003) Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev 83:1113–1151

    PubMed  CAS  Google Scholar 

  • Zabel U, Kleinschnitz C, Oh P, Smolenski A, Nedvetsky P, Kugler P, Walter U, Schnitzer JE,Schmidt HHHW (2002) Calcium-dependent membrane association sensitises soluble guanylyl cyclase to NO. Nat Cell Biol 4:307–311

    PubMed  CAS  Google Scholar 

  • Zhao Y, Schelvis JP, Babcock GT, Marletta MA (1998) Identification of histidine 105 in the beta1 subunit of soluble guanylate cyclase as the heme proximal ligand. Biochemistry 37:4502–4509

    PubMed  CAS  Google Scholar 

  • Zhao Y, Brandish PE, Ballou DP, Marletta MA (1999) A molecular basis for nitric oxide sensing by soluble guanylate cyclase. Proc Natl Acad Sci USA 96:14753–14758

    PubMed  CAS  Google Scholar 

  • Zhao Y, Brandish PE, DiValentin M, Schelvis JP, Babcock GT, Marletta MA (2000) Inhibition of soluble guanylate cyclase by ODQ. Biochemistry 39:10848–10854

    PubMed  CAS  Google Scholar 

  • Zhou Z, Pyriochou A, Kotanidou A, Dalkas G, Eickels MV, Spyroulias G, Roussos C, Papapetropoulos A (2008) Soluble guanylyl cyclase (sGC) activation by HMR-1766 (ataciguat) in cells exposed to oxidative stress. Am J Physiol Heart Circ Physiol. H1763–1771.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Centre for Vascular Health, Monash University, Clayton, VIC, 3800, Australia

    Harald H. H. W. Schmidt

  2. CSIRO Molecular & Health Technologies, 343 Royal Parade, Parkville, VIC, 3052, Australia

    Peter M. Schmidt

  3. Bayer Schering Pharma AG, Cardiology Research, Pharma Research Center, Wuppertal, 42096, Germany

    Johannes-Peter Stasch

Authors
  1. Harald H. H. W. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter M. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Johannes-Peter Stasch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johannes-Peter Stasch .

Editor information

Editors and Affiliations

  1. Dept. Pharmacology, Monash University, Wellington Road, Clayton, VIC, 3800, Australia

    Harald H. H. W. Schmidt

  2. Inst. Pharmakologie und Toxikologie, TU München, Biedersteiner Str. 29, München, 80802, Germany

    Franz Hofmann

  3. Bayer Schering Pharma AG Cardiology Research, Pharma Research Center, Wuppertal, 42096, Germany

    Johannes-Peter Stasch

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer

About this chapter

Cite this chapter

Schmidt, H.H.H.W., Schmidt, P.M., Stasch, JP. (2009). NO- and Haem-Independent Soluble Guanylate Cyclase Activators. In: Schmidt, H.H.H.W., Hofmann, F., Stasch, JP. (eds) cGMP: Generators, Effectors and Therapeutic Implications. Handbook of Experimental Pharmacology, vol 191. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-68964-5_14

Download citation

Publish with us

Policies and ethics

Search

Navigation