Current Heart Failure Reports

, Volume 8, Issue 1, pp 38–44 | Cite as

Soluble Guanylate Cyclase Modulators in Heart Failure

  • Veselin MitrovicEmail author
  • Ana Jovanovic
  • Stefan Lehinant


This review summarizes the role of soluble guanylate cyclase (sGC)-cyclic guanosine 3′, 5′-monophosphate pathways in heart failure and several new drugs that modify guanylate cyclase. The sGC activators and stimulators as modulators of sGC are promising drugs in the therapy for decompensated heart failure and pulmonary hypertension. Cinaciguat is a nitric oxide (NO)–independent direct activator of sGC, which also may be effective under oxidative stress conditions resulting in oxidized or heme-free sGC refractory to organic nitrates. Riociguat is an NO-independent direct stimulator of sGC with beneficial effects in patients with decompensated heart failure and pulmonary hypertension. The sGC modulators play an important role in patients with heart failure and pulmonary hypertension.


Heart failure Guanylate cyclase Cyclic guanosine monophosphate sCG stimulator Cinaciguat sGC activator Riociguat 



No potential conflicts of interest relevant to this article were reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance

  1. 1.
    Stuart S, MacIntyre K, Hole DJ, et al.: More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail 2001; 3(3): 315-322)Google Scholar
  2. 2.
    Grigioni F, Potena L, Galiè N, et al.: Prognostic implications of serial assessments of pulmonary hypertension in severe chronic heart failure. J Heart Lung Transplant. 2006; 25: 1241-1246.PubMedCrossRefGoogle Scholar
  3. 3.
    Evgenov OV, Pacher P, Schmidt PM, et al.: NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat.Rev.Drug Discov.2006.Sep.;5(9.):755.-68. 2006, 5:755-768Google Scholar
  4. 4.
    Schermuly RT, Stasch JP, Pullamsetti SS, et al.: Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008; 32: 881-891.PubMedCrossRefGoogle Scholar
  5. 5.
    •• Stasch JP, Hobbs AJ: NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol. 2009; (191): 277-308. This is an excellent overview of background of effects of NO-independent sGC stimulators.Google Scholar
  6. 6.
    Ghofrani HA, Hoeper MM, Hoeffken G, et al.: Riociguat Dose Titration in Patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH) or Pulmonary Arterial Hypertension (PAH). Conference abstract. 2009 American Thoracic Society International Conference, San Diego, USA, 16-20 May 2009.Google Scholar
  7. 7.
    Mitrovic V, Swidnicki B, Ghofrani A, et al.: Acute hemodynamic response to single oral doses of BAY 60-4552, a soluble guanylate cyclase stimulator, in patients with biventricular heart failure. Conference abstract. 4th International Conference on cGMP, Regensburg, Germany, 19-21 Jun 2009.Google Scholar
  8. 8.
    Feil R, Kemp-Harper B: cGMP signalling: from bench to bedside. Conference on cGMP generators, effectors and therapeutic implications. EMBO Rep.2006.Feb.;7.(2):149.-53. 2006, 7:149-153Google Scholar
  9. 9.
    Lucas KA, Pitari GM, Kazerounian S, et al.: Guanylyl cyclases and signaling by cyclic GMP. Pharmacol.Rev.2000.Sep.;52.(3):375.-414. 2000, 52:375-414Google Scholar
  10. 10.
    1•• Mitrovic V, Hernandez AF, Meyer M, et al.: Role of guanylate cyclase modulators in decompensated heart failure. Heart Fail.Rev.2009.Dec.;14(4):309.-19. 2009, 14:309-319. This is a first-time overview of effects of pGC and sGC modulators in patients with heart failure. Natriuretic peptides (nesiritide and ularitide) lead to an increase of cGMP through stimulation of pGC; however. sGC stimulators and activators lead to an increase of intracellular cGMP through modulation of soluble guanylate cyclase.Google Scholar
  11. 11.
    Joseph L, Jr. Izzo, American Council on High Blood Pressure, and Henry R.Black: Hypertension Primer: The Essentials of High Blood Pressure 2003:Chapter A3, 8-13Google Scholar
  12. 12.
    Burnett JC Jr.: Novel therapeutic directions for the natriuretic peptides in cardiovascular diseases: what's on the horizon. J.Cardiol.2006.Nov.;48.(5):235.-41. 2006, 48:235-241Google Scholar
  13. 13.
    Lee CY, Burnett, JC Jr.: Natriuretic peptides and therapeutic applications. Heart Fail.Rev.2007.Jun.;12.(2):131.-42. 2007, 12:131-142Google Scholar
  14. 14.
    Clerico A, Iervasi G, Pilo A.: Turnover studies on cardiac natriuretic peptides: methodological, pathophysiological and therapeutical considerations. Curr.Drug Metab.2000.Jul.;1(1):85.-105. 2000, 1:85-105Google Scholar
  15. 15.
    Volpe M, Tritto C, De Luca N, et al.: Failure of atrial natriuretic factor to increase with saline load in patients with dilated cardiomyopathy and mild heart failure. J.Clin.Invest. 1991, 88:1481-1489PubMedCrossRefGoogle Scholar
  16. 16.
    • Pacher P, Beckman JS, Liaudet L: Nitric oxide and peroxynitrite in health and disease. Physiol Rev.2007.Jan.;87.(1):315.-424. 2007, 87:315-424. This paper describes the role of oxidative stress in cardiovascular disease.Google Scholar
  17. 17.
    Atlas SA, Maack T: Effects of atrial natriuretic factor on the kidney and the renin-angiotensin-aldosterone system. Endocrinol.Metab Clin.North Am. 1987, 16:107-143PubMedGoogle Scholar
  18. 18.
    van der Zander K, Houben AJ, Hofstra L, et al.: Hemodynamic and renal effects of low-dose brain natriuretic peptide infusion in humans: a randomized, placebo-controlled crossover study. Am.J.Physiol Heart Circ.Physiol.2003.Sep.;285.(3):H1206.-12.Epub.2003.May.8. 2003, 285:H1206-H1212Google Scholar
  19. 19.
    Mills RM, LeJemtel TH, Horton DP, et al.: Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. Natrecor Study Group. J.Am.Coll.Cardiol. 1999, 34:155-162Google Scholar
  20. 20.
    Sackner-Bernstein JD, Skopicki HA, Aaronson KD: Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation.2005.Mar.29.;111.(12.):1487.-91.Epub.2005.Mar.21. 2005, 111:1487-1491Google Scholar
  21. 21.
    Luss H, Mitrovic V, Seferovic PM, Simeunovic D, et al. Renal effects of ularitide in patients with decompensated heart failure. Am.Heart J.2008.Jun.;155.(6.):1012.e1.-8. 2008, 155:1012-1018Google Scholar
  22. 22.
    Mitrovic V, Seferovic PM, Simeunovic D, et al.: Haemodynamic and clinical effects of ularitide in decompensated heart failure. Eur.Heart J.2006.Dec.;27.(23):2823.-32.Epub.2006.Oct.30. 2006, 27:2823-2832Google Scholar
  23. 23.
    Su J, Scholz PM, Weiss HR: Differential effects of cGMP produced by soluble and particulate guanylyl cyclase on mouse ventricular myocytes. Exp.Biol.Med.(Maywood.).2005.Apr;230.(4):242.-50. 2005, 230:242-250Google Scholar
  24. 24.
    Knowles RG, and Moncada S: Nitric oxide synthases in mammals. Biochem.J. 1994, 298 (Pt 2):249-258PubMedGoogle Scholar
  25. 25.
    Torfgard KE, Ahlner J: Mechanisms of action of nitrates. Cardiovasc.Drugs Ther. 1994, 8:701-717PubMedCrossRefGoogle Scholar
  26. 26.
    Packer M, Lee WH, Kessler PD, et al.: Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N.Engl.J.Med. 1987, 317:799-804Google Scholar
  27. 27.
    Foerster J, Harteneck C, Malkewitz J, et al.: A functional heme-binding site of soluble guanylyl cyclase requires intact N-termini of alpha 1 and beta 1 subunits. Eur.J.Biochem. 1996, 240:380-386PubMedCrossRefGoogle Scholar
  28. 28.
    Ignarro LJ, Adams JB, Horwitz PM, et al.: Activation of soluble guanylate cyclase by NO-hemoproteins involves NO-heme exchange. Comparison of heme-containing and heme-deficient enzyme forms. J.Biol.Chem. 1986, 261:4997-5002PubMedGoogle Scholar
  29. 29.
    • Boerrigter G, Costello-Boerrigter LC, Cataliotti A, et al.: Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure. Hypertension 2007. 49:1128–1133. The authors show that sGC activators act by an oxidized form of sGC, in contrast to sGC stimulators, which exert their effect through a reduced variant of sGC.Google Scholar
  30. 30.
    Boerrigter G, Costello-Boerrigter LC, Cataliotti A, et al.: Targeting heme-oxidized soluble guanylate cyclase with BAY 58-2667 in experimental heart failure. BMC Pharmacology 2007. 7:P9CrossRefGoogle Scholar
  31. 31.
    •• Frey R, Muck W, Unger S, et al.: Pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase activator cinaciguat (BAY 58-2667) in healthy male volunteers. J Clin Pharmacol 2008.48:1400-1410. This is a first-time description of efficacy and safety of the sGC activator cinaciguat in healthy male volunteers.PubMedCrossRefGoogle Scholar
  32. 32.
    Lapp H, Mitrovic V, Franz N, et al.: BAY 58–2667, a soluble guanylate cyclase activator, improves cardiopulmonary haemodynamics in acute decompensated heart failure and has a favourable safety profile. BMC Pharmacology. 2007: 7:S9CrossRefGoogle Scholar
  33. 33.
    Mitrovic V, Lapp H, Franz N, et al.: The soluble guanylate cyclase activator cinaciguat (BAY 58-2667) has a favourable safety profile and improves cardiopulmonary haemodynamics in acute decompensated heart failure. Poster presented at Heart Failure 2008, 14–17 June, Milan, Italy.Google Scholar
  34. 34.
    •• Lapp H, Mitrovic V, Franz N, et al.: Cinaciguat (BAY 58 2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. Circulation. Published online May 18, 2009. This is a first-time description of the hemodynamic effects of the sGC activator cinaciguat in patients with decompensated heart failure as a new promising model for therapy.Google Scholar
  35. 35.
    Erdmann E, Semigran MJ, Nieminen MS, et al.: Cinaciguat, a soluble Guanylate Cyclase Activator, unloads the heart in acute decompensated heart failure. Cinaciguat phase IIb abstract for ACC 2010.Google Scholar
  36. 36.
    Kemp-Harper B, Feil R. Meeting report: cGMP matters. Sci Signal. 2008 Mar 4;1(9):pe12.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Veselin Mitrovic
    • 1
    Email author
  • Ana Jovanovic
    • 1
  • Stefan Lehinant
    • 1
  1. 1.Kerckhoff-Klinik gGmbHBad NauheimGermany

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