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Published in:

01-03-2013

Soluble guanylate cyclase: a potential therapeutic target for heart failure

Authors: Mihai Gheorghiade, Catherine N. Marti, Hani N. Sabbah, Lothar Roessig, Stephen J. Greene, Michael Böhm, John C. Burnett, Umberto Campia, John G. F. Cleland, Sean P. Collins, Gregg C. Fonarow, Phillip D. Levy, Marco Metra, Bertram Pitt, Piotr Ponikowski, Naoki Sato, Adriaan A. Voors, Johannes-Peter Stasch, Javed Butler

Published in: Heart Failure Reviews | Issue 2/2013

Abstract

The number of annual hospitalizations for heart failure (HF) and the mortality rates among patients hospitalized for HF remains unacceptably high. The search continues for safe and effective agents that improve outcomes when added to standard therapy. The nitric oxide (NO)—soluble guanylate cyclase (sGC)—cyclic guanosine monophosphate (cGMP) pathway serves an important physiologic role in both vascular and non-vascular tissues, including regulation of myocardial and renal function, and is disrupted in the setting of HF, leading to decreased protection against myocardial injury, ventricular remodeling, and the cardio-renal syndrome. The impaired NO–sGC–cGMP pathway signaling in HF is secondary to reduced NO bioavailability and an alteration in the redox state of sGC, making it unresponsive to NO. Accordingly, increasing directly the activity of sGC is an attractive pharmacologic strategy. With the development of two novel classes of drugs, sGC stimulators and sGC activators, the hypothesis that restoration of NO–sGC–cGMP signaling is beneficial in HF patients can now be tested. Characterization of these agents in pre-clinical and clinical studies has begun with investigations suggesting both hemodynamic effects and organ-protective properties independent of hemodynamic changes. The latter could prove valuable in long-term low-dose therapy in HF patients. This review will explain the role of the NO–sGC–cGMP pathway in HF pathophysiology and outcomes, data obtained with sGC stimulators and sGC activators in pre-clinical and clinical studies, and a plan for the further clinical development to study these agents as HF therapy.

Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J (2010) Heart disease and stroke statistics–2010 update: a report from the American Heart Association. Circulation 121(7):e46–e215. doi:10.1161/CIRCULATIONAHA.109.192667 PubMedCrossRef

Gheorghiade M, Abraham WT, Albert NM, Greenberg BH, O’Connor CM, She L, Stough WG, Yancy CW, Young JB, Fonarow GC (2006) Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 296(18):2217–2226. doi:10.1001/jama.296.18.2217 PubMedCrossRef

Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C (2007) Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 297(12):1319–1331. doi:10.1001/jama.297.12.1319 PubMedCrossRef

Wilcox JE, Fonarow GC, Yancy CW, Albert NM, Curtis AB, Heywood JT, Inge PJ, McBride ML, Mehra MR, O’Connor CM, Reynolds D, Walsh MN, Gheorghiade M (2012) Factors associated with improvement in ejection fraction in clinical practice among patients with heart failure: findings from IMPROVE HF. Am Heart J 163(1):49–56.e2. doi:10.1016/j.ahj.2011.10.001

Gheorghiade M, Adams KF, Cleland JG, Cotter G, Felker GM, Filippatos GS, Fonarow GC, Greenberg BH, Hernandez AF, Khan S, Komajda M, Konstam MA, Liu PP, Maggioni AP, Massie BM, McMurray JJ, Mehra M, Metra M, O’Connell J, O’Connor CM, Pang PS, Pina IL, Sabbah HN, Teerlink JR, Udelson JE, Yancy CW, Zannad F, Stockbridge N (2009) Phase III clinical trial end points in acute heart failure syndromes: a virtual roundtable with the Acute Heart Failure Syndromes International Working Group. Am Heart J 157(6):957–970. doi:10.1016/j.ahj.2009.04.010 PubMedCrossRef

Gheorghiade M, Zannad F, Sopko G, Klein L, Pina IL, Konstam MA, Massie BM, Roland E, Targum S, Collins SP, Filippatos G, Tavazzi L (2005) Acute heart failure syndromes: current state and framework for future research. Circulation 112(25):3958–3968. doi:10.1161/CIRCULATIONAHA.105.590091 PubMedCrossRef

Gheorghiade M, Peterson ED (2011) Improving postdischarge outcomes in patients hospitalized for acute heart failure syndromes. JAMA 305(23):2456–2457. doi:10.1001/jama.2011.836 PubMedCrossRef

Bock JS, Gottlieb SS (2010) Cardiorenal syndrome: new perspectives. Circulation 121(23):2592–2600. doi:10.1161/CIRCULATIONAHA.109.886473 PubMedCrossRef

Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewski S, Reed JC, Anversa P (1997) Apoptosis in the failing human heart. New England J Med 336(16):1131–1141. doi:10.1056/NEJM199704173361603 CrossRef

10.

Whelan RS, Kaplinskiy V, Kitsis RN (2010) Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu Rev Physiol 72:19–44. doi:10.1146/annurev.physiol.010908.163111 PubMedCrossRef

11.

Paulus WJ, Bronzwaer JG (2004) Nitric oxide’s role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol 287(1):H8–13PubMedCrossRef

12.

Mohan P, Brutsaert DL, Paulus WJ, Sys SU (1996) Myocardial contractile response to nitric oxide and cGMP. Circulation 93(6):1223–1229PubMedCrossRef

13.

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):179–186PubMedCrossRef

14.

Paulus WJ, Vantrimpont PJ, Shah AM (1994) Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Assessment by bicoronary sodium nitroprusside infusion. Circulation 89(5):2070–2078PubMedCrossRef

15.

Varin R, Mulder P, Tamion F, Richard V, Henry JP, Lallemand F, Lerebours G, Thuillez C (2000) Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure : role of nitric oxide, prostanoids, oxidant stress, and bradykinin. Circulation 102(3):351–356PubMedCrossRef

16.

Kojda G, Kottenberg K, Nix P, Schluter KD, Piper HM, Noack E (1996) Low increase in cGMP induced by organic nitrates and nitrovasodilators improves contractile response of rat ventricular myocytes. Circ Res 78(1):91–101PubMedCrossRef

17.

Ito N, Bartunek J, Spitzer KW, Lorell BH (1997) Effects of the nitric oxide donor sodium nitroprusside on intracellular pH and contraction in hypertrophied myocytes. Circulation 95(9):2303–2311PubMedCrossRef

18.

Shah AM, Spurgeon HA, Sollott SJ, Talo A, Lakatta EG (1994) 8-bromo-cGMP reduces the myofilament response to Ca2⁺ in intact cardiac myocytes. Circ Res 74(5):970–978PubMedCrossRef

19.

Munzel T, Gori T, Bruno RM, Taddei S (2010) Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J 31:2741–2748PubMedCrossRef

20.

Ontkean M, Gay R, Greenberg B (1991) Diminished endothelium-derived relaxing factor activity in an experimental model of chronic heart failure. Circ Res 69(4):1088–1096PubMedCrossRef

21.

Vanhoutte PM, Shimokawa H, Tang EH, Feletou M (2009) Endothelial dysfunction and vascular disease. Acta Physiol (Oxf) 196(2):193–222CrossRef

22.

Schmidt HH, Hofmann F, Stasch JP (2009) Handbook of experimental pharmacology. 191 cGMP generators, effectors and therapeutic implications. Preface. Handb Exp Pharmacol 191:v–vi

23.

Ben Driss A, Devaux C, Henrion D, Duriez M, Thuillez C, Levy BI, Michel JB (2000) Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure. Circulation 101(23):2764–2770PubMedCrossRef

24.

Moraes DL, Colucci WS, Givertz MM (2000) Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation 102(14):1718–1723PubMedCrossRef

25.

Blair JE, Manuchehry A, Chana A, Rossi J, Schrier RW, Burnett JC, Gheorghiade M (2007) Prognostic markers in heart failure–congestion, neurohormones, and the cardiorenal syndrome. Acute Card Care 9(4):207–213. doi:10.1080/17482940701606913 PubMedCrossRef

26.

Treasure CB, Vita JA, Cox DA, Fish RD, Gordon JB, Mudge GH, Colucci WS, Sutton MG, Selwyn AP, Alexander RW et al (1990) Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 81(3):772–779PubMedCrossRef

27.

Zeiher AM, Krause T, Schachinger V, Minners J, Moser E (1995) Impaired endothelium-dependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation 91(9):2345–2352PubMedCrossRef

28.

Mitchell GF, Tardif JC, Arnold JM, Marchiori G, O’Brien TX, Dunlap ME, Pfeffer MA (2001) Pulsatile hemodynamics in congestive heart failure. Hypertension 38(6):1433–1439PubMedCrossRef

29.

Ramsey MW, Goodfellow J, Jones CJ, Luddington LA, Lewis MJ, Henderson AH (1995) Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation 92(11):3212–3219PubMedCrossRef

30.

Buus NH, Bottcher M, Hermansen F, Sander M, Nielsen TT, Mulvany MJ (2001) Influence of nitric oxide synthase and adrenergic inhibition on adenosine-induced myocardial hyperemia. Circulation 104(19):2305–2310PubMedCrossRef

31.

Massion PB, Feron O, Dessy C, Balligand JL (2003) Nitric oxide and cardiac function: ten years after, and continuing. Circ Res 93(5):388–398. doi:10.1161/01.RES.0000088351.58510.21 PubMedCrossRef

32.

Scherrer-Crosbie M, Ullrich R, Bloch KD, Nakajima H, Nasseri B, Aretz HT, Lindsey ML, Vancon AC, Huang PL, Lee RT, Zapol WM, Picard MH (2001) Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 104(11):1286–1291PubMedCrossRef

33.

Agnoletti L, Curello S, Bachetti T, Malacarne F, Gaia G, Comini L, Volterrani M, Bonetti P, Parrinello G, Cadei M, Grigolato PG, Ferrari R (1999) Serum from patients with severe heart failure downregulates eNOS and is proapoptotic: role of tumor necrosis factor-alpha. Circulation 100(19):1983–1991PubMedCrossRef

34.

Seta Y, Shan K, Bozkurt B, Oral H, Mann DL (1996) Basic mechanisms in heart failure: the cytokine hypothesis. J Card Fail 2(3):243–249PubMedCrossRef

35.

Maxwell AJ, Schauble E, Bernstein D, Cooke JP (1998) Limb blood flow during exercise is dependent on nitric oxide. Circulation 98(4):369–374PubMedCrossRef

36.

Prasad A, Higano ST, Al Suwaidi J, Holmes DR Jr, Mathew V, Pumper G, Lennon RJ, Lerman A (2003) Abnormal coronary microvascular endothelial function in humans with asymptomatic left ventricular dysfunction. Am Heart J 146(3):549–554. doi:10.1016/S0002-8703(03)00364-8 PubMedCrossRef

37.

Bachetti T (2000) Endothelial dysfunction in chronic heart failure: some new basic mechanisms. Ital Heart J 1(10):656–661PubMed

38.

Bank AJ, Lee PC, Kubo SH (2000) Endothelial dysfunction in patients with heart failure: relationship to disease severity. J Card Fail 6(1):29–36PubMedCrossRef

39.

Katz SD, Hryniewicz K, Hriljac I, Balidemaj K, Dimayuga C, Hudaihed A, Yasskiy A (2005) Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation 111(3):310–314. doi:10.1161/01.CIR.0000153349.77489.CF PubMedCrossRef

40.

Mathier MA, Rose GA, Fifer MA, Miyamoto MI, Dinsmore RE, Castano HH, Dec GW, Palacios IF, Semigran MJ (1998) Coronary endothelial dysfunction in patients with acute-onset idiopathic dilated cardiomyopathy. J Am Coll Cardiol 32(1):216–224PubMedCrossRef

41.

Fischer D, Rossa S, Landmesser U, Spiekermann S, Engberding N, Hornig B, Drexler H (2005) Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death. Eur Heart J 26(1):65–69. doi:10.1093/eurheartj/ehi001 PubMedCrossRef

42.

Poelzl G, Frick M, Huegel H, Lackner B, Alber HF, Mair J, Herold M, Schwarzacher S, Pachinger O, Weidinger F (2005) Chronic heart failure is associated with vascular remodeling of the brachial artery. Eur J Heart Fail 7(1):43–48. doi:10.1016/j.ejheart.2004.04.008 PubMedCrossRef

43.

Meyer B, Mortl D, Strecker K, Hulsmann M, Kulemann V, Neunteufl T, Pacher R, Berger R (2005) Flow-mediated vasodilation predicts outcome in patients with chronic heart failure: comparison with B-type natriuretic peptide. J Am Coll Cardiol 46(6):1011–1018. doi:10.1016/j.jacc.2005.04.060 PubMedCrossRef

44.

Roberts CK, Barnard RJ, Sindhu RK, Jurczak M, Ehdaie A, Vaziri ND (2005) A high-fat, refined-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant imbalance and depresses NOS protein expression. J Appl Physiol 98(1):203–210. doi:10.1152/japplphysiol.00463.2004 PubMedCrossRef

45.

Murakami T, Mizuno S, Ohsato K, Moriuchi I, Arai Y, Nio Y, Kaku B, Takahashi Y, Ohnaka M (1999) Effects of troglitazone on frequency of coronary vasospastic-induced angina pectoris in patients with diabetes mellitus. Am J Cardiol 84(1):92–94, A98

46.

Schachinger V, Britten MB, Zeiher AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101(16):1899–1906PubMedCrossRef

47.

Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A (2000) Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 101(9):948–954PubMedCrossRef

48.

Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA (2002) Prognostic value of coronary vascular endothelial dysfunction. Circulation 106(6):653–658PubMedCrossRef

49.

Brevetti G, Silvestro A, Schiano V, Chiariello M (2003) Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation 108(17):2093–2098PubMedCrossRef

50.

Chan SY, Mancini GB, Kuramoto L, Schulzer M, Frohlich J, Ignaszewski A (2003) The prognostic importance of endothelial dysfunction and carotid atheroma burden in patients with coronary artery disease. J Am Coll Cardiol 42(6):1037–1043PubMedCrossRef

51.

Hambrecht R, Fiehn E, Weigl C, Gielen S, Hamann C, Kaiser R, Yu J, Adams V, Niebauer J, Schuler G (1998) Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 98(24):2709–2715PubMedCrossRef

52.

Jones SP, Greer JJ, van Haperen R, Duncker DJ, de Crom R, Lefer DJ (2003) Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice. Proc Natl Acad Sci USA 100(8):4891–4896. doi:10.1073/pnas.0837428100 PubMedCrossRef

53.

Pacher P, Schulz R, Liaudet L, Szabo C (2005) Nitrosative stress and pharmacological modulation of heart failure. Trends Pharmacol Sci 26(6):302–310PubMedCrossRef

54.

Schmidt HH, Hofmann F, Stasch JP (2009) Preface. In: Hofmann F (ed) cGMP: generators, effectors and therapeutic implications, vol 191. Handb Exp Pharmacol. Springer, Berlin, pp v–vi

55.

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(9):755–768PubMedCrossRef

56.

Hobbs AJ, Stasch JP (2010) Soluble guanylate cyclase: allosteric activation and redox regulation. In: Ignarro LJ (ed) Nitric oxide: biology and pathobiology. (2nd edn). Academic Press, pp 301–326

57.

58.

Gladwin MT (2006) Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome. J Clin Invest 116(9):2330–2332. doi:10.1172/JCI29807 PubMedCrossRef

59.

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. doi:10.1161/HYPERTENSIONAHA.106.085456 PubMedCrossRef

60.

Ahrens I, Habersberger J, Baumlin N, Qian H, Smith BK, Stasch JP, Bode C, Schmidt HH, Peter K (2011) Measuring oxidative burden and predicting pharmacological response in coronary artery disease patients with a novel direct activator of haem-free/oxidised sGC. Atherosclerosis 218(2):431–434. doi:10.1016/j.atherosclerosis.2011.06.042 PubMedCrossRef

61.

Stasch JP, Schmidt PM, Nedvetsky PI, Nedvetskaya TY, Arun kumar HS, 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(9):2552–2561. doi:10.1172/JCI28371 PubMedCrossRef

62.

Stasch JP, Pacher P, Evgenov OV (2011) Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 123(20):2263–2273. doi:10.1161/CIRCULATIONAHA.110.981738 PubMedCrossRef

63.

Lapp H, Mitrovic V, Franz N, Heuer H, Buerke M, Wolfertz J, Mueck W, Unger S, Wensing G, Frey R (2009) Cinaciguat (BAY 58-2667) improves cardiopulmonary hemodynamics in patients with acute decompensated heart failure. Circulation 119(21):2781–2788. doi:10.1161/CIRCULATIONAHA.108.800292 PubMedCrossRef

64.

Gheorghiade M, Erdmann E, Ferrari R, Filippatos G, Levy P, Maggioni A, Mebazaa A, Nowack C (2011) Treatment of acute decompensated heart failure with the soluble guanylate cyclase activator cinaciguat: The COMPOSE program – three randomized, controlled, phase IIb studies. J Card Fail 17(11):971. doi:10.1016/j.cardfail.2011.10.004 CrossRef

65.

Martin F, Baskaran P, Ma X, Dunten PW, Schaefer M, Stasch JP, Beuve A, van den Akker F (2010) Structure of cinaciguat (BAY 58-2667) bound to nostoc H-NOX domain reveals insights into heme-mimetic activation of the soluble guanylyl cyclase. J Biol Chem 285(29):22651–22657PubMedCrossRef

66.

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

67.

Thoonen R, Buys E, Cauwels A, Rogge E, Nimmegeers S, Van den Hemel M, Hochepied T, Van de Voorde J, Stasch JP, Brouckaert P (2009) NO-insensitive sGCbeta1 H105F knockin mice: if NO has no place to go. BMC Pharmacol 9 (Suppl. 1):S41 (abstr)

68.

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):853–865PubMedCrossRef

69.

Straub A, Stasch JP, Alonso-Alija C, Benet-Buchholz J, Ducke B, Feurer A, Furstner C (2001) NO-independent stimulators of soluble guanylate cyclase. Bioorg Med Chem Lett 11(6):781–784PubMedCrossRef

70.

Stasch JP, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Minuth T, Perzborn E, Schramm M, Straub A (2002) Pharmacological actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vitro studies. Br J Pharmacol 135(2):333–343PubMedCrossRef

71.

Stasch JP, Dembowsky K, Perzborn E, Stahl E, Schramm M (2002) Cardiovascular actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vivo studies. Br J Pharmacol 135(2):344–355. doi:10.1038/sj.bjp.0704483 PubMedCrossRef

72.

Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A, Gerzer R, Minuth T, Perzborn E, Pleiss U, Schroder H, Schroeder W, Stahl E, Steinke W, Straub A, Schramm M (2001) NO-independent regulatory site on soluble guanylate cyclase. Nature 410(6825):212–215PubMedCrossRef

73.

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(4):1260–1268PubMedCrossRef

74.

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

75.

Jones ES, Kemp-Harper B, Stasch JP, Schmidt H, Widdop RE (2009) Cardioprotective effects in aged spontaneously hypertensive rats due to chronic stimulation/activation of sGC without hypotension. BMC Pharmacol 9(Suppl 1):P29 (abstr)

76.

Sharkovska Y, Kalk P, Lawrenz B, Godes M, Hoffmann LS, Wellkisch K, Geschka S, Relle K, Hocher B, Stasch JP (2010) Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models. J Hypertens 28(8):1666–1675PubMedCrossRef

77.

Boerrigter G, Costello-Boerrigter LC, Cataliotti A, Tsuruda T, Harty GJ, Lapp H, Stasch JP, Burnett JC Jr (2003) Cardiorenal and humoral properties of a novel direct soluble guanylate cyclase stimulator BAY 41-2272 in experimental congestive heart failure. Circulation 107(5):686–689PubMedCrossRef

78.

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):972–978PubMedCrossRef

79.

Schafer A, Fraccarollo D, Werner L, Bauersachs J (2010) Guanylyl cyclase activator ataciguat improves vascular function and reduces platelet activation in heart failure. Pharmacol Res Official J Italian Pharmacol Soc 62(5):432–438. doi:10.1016/j.phrs.2010.06.008 CrossRef

80.

Benz K, Orth SR, Simonaviciene A, Linz W, Schindler U, Rutten H, Amann K (2007) Blood pressure-independent effect of long-term treatment with the soluble heme-independent guanylyl cyclase activator HMR1766 on progression in a model of noninflammatory chronic renal damage. Kidney Blood Press Res 30(4):224–233PubMedCrossRef

81.

Melichar VO, Behr-Roussel D, Zabel U, Uttenthal LO, Rodrigo J, Rupin A, Verbeuren TJ, Kumar HSA, Schmidt HH (2004) Reduced cGMP signaling associated with neointimal proliferation and vascular dysfunction in late-stage atherosclerosis. Proc Natl Acad Sci USA 101(47):16671–16676PubMedCrossRef

82.

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 USA 101(5):1386–1391PubMedCrossRef

83.

Sovershaev MA, Egorina EM, Hansen JB, Østerud B, Stasch JP, Evgenov OV (2009) Soluble guanylate cyclase agonists inhibit expression and procoagulant activity of tissue factor. Arterioscl Thromb Vasc Biol 29(10):1578–1586PubMedCrossRef

84.

Peters H, Wang Y, Loof T, Martini S, Kron S, Kramer S, Neumayer HH (2004) Expression and activity of soluble guanylate cyclase in injury and repair of anti-thy1 glomerulonephritis. Kidney Int 66(6):2224–2236. doi:10.1111/j.1523-1755.2004.66012.x PubMedCrossRef

85.

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 glomerulonephritis. Am J Physiol Renal Physiol 288(4):F685–693. doi:10.1152/ajprenal.00280.2004 PubMedCrossRef

86.

Wang Y, Kramer 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(1):47–61. doi:10.1111/j.1523-1755.2005.00380.x PubMedCrossRef

87.

Wang Y, Kramer 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(1):F167–F176. doi:10.1152/ajprenal.00197.2005

88.

Alter M, Ott I, von Websky K, Tsuprykov O, Sharkovska Y, Krause-Relle K, Raila J, Henze A, Kretschmer A, Stasch J-P, Hocher B (2011) Additional stimulation of sGC on top of standard treatment with ARB`s may offer a new therapeutic approach for the treatment of diabetic nephropathy resistant to ARB treatment alone. BMC Pharmacol 11(Suppl 1):P1CrossRef

89.

Kalk P, Godes M, Relle K, Rothkegel C, Hucke A, Stasch JP, Hocher B (2006) NO-independent activation of soluble guanylate cyclase prevents disease progression in rats with 5/6 nephrectomy. Br J Pharmacol 148(6):853–859. doi:10.1038/sj.bjp.0706792 PubMedCrossRef

90.

Hoffman L (2009) http://digital.bibliothek.uni-halle.de/hs/content/titleinfo/711081. Accessed: November 10, 2011

91.

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

92.

Vaidya VS, Waikar SS, Ferguson MA, Collings FB, Sunderland K, Gioules C, Bradwin G, Matsouaka R, Betensky RA, Curhan GC, Bonventre JV (2008) Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci 1(3):200–208PubMedCrossRef

93.

Doi K, Noiri E, Sugaya T (2010) Urinary L-type fatty acid-binding protein as a new renal biomarker in critical care. Curr Opin Crit Care. doi:10.1097/MCC.0b013e32833e2fa4 PubMed

Title: Soluble guanylate cyclase: a potential therapeutic target for heart failure
Authors: Mihai Gheorghiade
Catherine N. Marti
Hani N. Sabbah
Lothar Roessig
Stephen J. Greene
Michael Böhm
John C. Burnett
Umberto Campia
John G. F. Cleland
Sean P. Collins
Gregg C. Fonarow
Phillip D. Levy
Marco Metra
Bertram Pitt
Piotr Ponikowski
Naoki Sato
Adriaan A. Voors
Johannes-Peter Stasch
Javed Butler
Publication date: 01-03-2013
Publisher: Springer US
Published in: Heart Failure Reviews / Issue 2/2013
Print ISSN: 1382-4147
Electronic ISSN: 1573-7322
DOI: https://doi.org/10.1007/s10741-012-9323-1

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Soluble guanylate cyclase: a potential therapeutic target for heart failure

Abstract

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Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

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Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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Other articles of this Issue 2/2013

Heart failure among South Asians: a narrative review of risk, nature, outcomes and management

From discrete dilated cardiomyopathy to successful cardiac transplantation in congenital disorders of glycosylation due to dolichol kinase deficiency (DK1-CDG)

Incretins as a novel therapeutic strategy in patients with diabetes and heart failure

Current management and future directions for the treatment of patients hospitalized for heart failure with low blood pressure

Obesity cardiomyopathy and systolic function: Obesity is not independently associated with dilated cardiomyopathy

Diabetic cardiomyopathy: pathophysiology and clinical features

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Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

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