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• W2100382012 abstract "HomeHypertensionVol. 49, No. 5Targeting Heme-Oxidized Soluble Guanylate Cyclase Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTargeting Heme-Oxidized Soluble Guanylate CyclaseSolution for All Cardiorenal Problems in Heart Failure? Thomas Münzel, Sabine Genth-Zotz and Ulrich Hink Thomas MünzelThomas Münzel From the Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität Mainz, Mainz, Germany. Search for more papers by this author , Sabine Genth-ZotzSabine Genth-Zotz From the Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität Mainz, Mainz, Germany. Search for more papers by this author and Ulrich HinkUlrich Hink From the Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität Mainz, Mainz, Germany. Search for more papers by this author Originally published26 Feb 2007https://doi.org/10.1161/HYPERTENSIONAHA.106.085456Hypertension. 2007;49:974–976Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: February 26, 2007: Previous Version 1 Increased peripheral vascular resistance is a hallmark of advanced chronic congestive heart failure (CHF) and contributes to the phenomenon of increased afterload that complicates that condition. Multiple factors have been proposed to contribute to this phenomenon, such as increased sodium water content of the vasculature, increased activation of neurohormonal vasoconstrictor forces, and intrinsic abnormalities of the vasculature. During the past decade, it has also been shown that CHF is associated with a severe degree of endothelial dysfunction in experimental animals, as well as in humans. Given that the endothelium, as well as endothelium-dependent vasodilation, plays a crucial role in the control of systemic hemodynamics, this phenomenon is probably an important reason for increased vascular resistance and afterload in heart failure. Because the NO–cGMP–cGMP-dependent kinase-1 relaxation pathway is predominantly responsible for the regulation of vascular tone (Figure), numerous studies have examined abnormalities of this pathway in heart failure. Experimental and clinical studies revealed that NO production is decreased because of decreased expression of endothelial NO synthase and diminished endothelial NO synthase–mediated NO production. A further related mechanism related to this is increased production of vascular superoxide anions, which may react with NO in a diffusion-limited reaction to form the highly reactive intermediate peroxynitrite (Figure). Increased superoxide production, however, is clearly not limited to the endothelium, because more recent experimental studies revealed increased oxidative stress throughout the vasculature, including the media and adventitia.1 Oxidative stress within the media reacts with NO formed as it diffuses from the endothelium and also inhibits NO signaling, thereby causing a state of vascular NO resistance. Theoretically, the decrease in vascular NO bioavailability may be used as an argument to initiate therapy in CHF with nitroglycerin, which improves systemic hemodynamics and renal function when given acutely. There is, however, a marked degree of “nitrate resistance” in the setting of CHF,2 and its therapeutic usefulness is also limited because of the development of nitrate tolerance3 and the induction of oxidative stress and endothelial dysfunction,4 all of which can decrease sensitivity of the NO target enzyme, soluble guanylyl cyclase (sGC). It is important to note that sGC is a heterodimeric enzyme containing a prosthetic heme group and that oxidation of this ferrous heme to its ferric form (from Fe2+ to Fe3+) completely prevents NO-mediated activation of sGC5 (Figure). This seems to be an important mechanism underlying altered vascular function caused by oxidant stress and nitrate tolerance. Download figureDownload PowerPointEndothelial-derived NO or NO released from nitrovasodilators such as glyceryl trinitrate (GTN) activates reduced sGC (sGC-Fe2+) leading to increased cellular cGMP levels. cGMP, in turn, activates the cGMP-dependent kinase (cGK), which, in turn, causes, for example, vasorelaxation by decreasing intracellular Ca2+ concentrations. In the presence of CHF, cardiovascular risk factors, chronic treatment with organic nitrates, or in the setting of ischemia/reperfusion, activation of vascular superoxide-producing enzymes, such as the reduced nicotinamide-adenine dinucleotide phosphate oxidase (NADPH oxidase), will lead to increased formation of reactive oxygen species, such as superoxide (O2·−) and peroxynitrite (ONOO−) and to endothelial NO synthase (eNOS) uncoupling, which, in turn, will decrease vascular NO bioavailability but will also cause an oxidation of the sGC, thereby shifting the intracellular molar ratio of the sGC from Fe2+ (ferrous heme) more toward Fe3+ (ferric heme), which, in turn, will lead to an sGC NO-resistant state. In contrast to Bay 41-2272, which activates sGC synergistically with NO, substances like Bay 58-2667 are able to activate the oxidized and heme-free sGC, thereby producing potent vasodilation of diseased vessels.To avoid these disadvantages of oxidant stress and nitrate therapy, direct heme-independent sGC activators have been developed (for review see Reference 6). These compounds are NO-independent sGC activators (Figure) with unique biochemical and pharmacological properties. They are capable of causing vasodilatation even when the prosthetic heme iron of sGC is oxidized and, in fact, seems to selectively activate the enzyme when it is in the oxidized state.6In this issue of Hypertension, Boerrigter et al7 demonstrate that 1 such compound, Bay 58-2667, dose-dependently reduces mean arterial pressure, lowers central venous filling pressures, increases cardiac output, and enhances renal blood flow in an animal model of heart failure because of rapid ventricular pacing. Glomerular filtration rate and sodium and water excretion were improved. Consistent with cardiac unloading, this agent also lowered plasma levels of ANP and BNP. Interestingly, although this agent caused vasodilation and reduced mean arterial pressure, it did not cause an increase in either plasma renin activity or aldosterone. These data indicate that direct activation of oxidized sGC with drugs such as Bay 58-2667 could represent a novel therapeutic strategy for the treatment of CHF and perhaps other cardiovascular diseases.Our current therapeutic options might also address some of the issues related to sGC oxidation and nitrate tolerance. The Vasodilator in Heart Failure Trial I and II trials showed that a combination of isosorbide dinitrate and the arteriolar dilator hydralazine was very effective in improving both exercise tolerance and prognosis in patients with severe CHF.8 Importantly, the recently published A-HeFFT trial reported huge reductions in mortality in black Americans treated with the combination of these 2 compounds.9 There are likely several mechanisms that are important: (1) the combination of hydralazine and isosorbide dinitrate provides both preload (isosorbide dinitrate) and afterload (hydralazine) reduction that favorably influences hemodynamics in CHF; and (2) more recent studies show that hydralazine can scavenge reactive oxygen species, such as superoxide and peroxynitrite,10 and could, therefore, potentially prevent oxidation of the heme iron of sGC. Finally, hydralazine inhibits the reduced nicotinamide-adenine dinucleotide phosphate oxidases (NADPH oxidase) and other major sources of reactive oxygen species, which are activated in response to nitroglycerin treatment.11 Thus, the combinations of isosorbide dinitrate and hydralazine or similar agents could prevent sGC oxidation and preserve vascular responsiveness. Likewise, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists can reduce tissue oxidant stress by inhibiting signaling events leading to activation of several reactive oxygen species generating enzymes. These agents might also prevent sGC oxidation and preserve responsiveness to organic nitrates. Head-to-head comparisons between these agents and drugs like Bay 58-2667 will be very helpful.Compared with nitrate therapy, sGC activators such as Bay 58-2667 seem to have several advantages. Most importantly, these agents preferentially and very effectively activate sGC when it is in the oxidized state. This actually promotes vasodilatation in vessels where endogenous NO fails to function. To date, there is no evidence that they promote oxidative stress, as do organic nitrates. They do not need be bioactivated like organic nitrates, and, thus, impairments to organic nitrate activation caused by oxidant stress would not alter their effectiveness. They do not induce endothelial dysfunction and do not seem to promote reflex neurohumoral vasoconstriction. Taken together, these direct sGC activators would seem to avoid many of the untoward effects of long-term nitrate therapy.11Despite these encouraging results, many questions are left. As a matter of semantics, it is confusing to apply the term endothelial dysfunction to dysfunctional sCG, because the latter is likely most important in the vascular smooth muscle. It would be ideal to determine the intracellular ratio of sGC in the ferrous versus ferric state in vessels from animals with CHF. This would allow a more specific application of these agents. Moreover, understanding this biochemical property would help us determine whether the preferential effect of these drugs is really dependent on this ratio.Although Boerrigter et al7 did not observe an increase in plasma renin or aldosterone levels, this does not reflect all of the neurohumoral responses to heart failure or vasodilator therapy. The effect of this drug on catecholamine or vasopressin levels or fluid shifts from the extravascular to intravascular spaces needs further investigation. Another potential compensatory mechanism is activation of phosphodiesterases, which could degrade cGMP distal to sGC activation, preventing the effects of these drugs during chronic therapy. Despite these concerns, the results of this study are encouraging and support the substantial therapeutic potential of these new vasodilators. These agents could revolutionize the treatment of not only CHF but also other conditions, such as coronary artery disease, systemic hypertension, and pulmonary hypertension.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.DisclosuresNone.FootnotesCorrespondence to Thomas Münzel, II Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. E-mail [email protected] References 1 Mollnau H, Oelze M, August M, Wendt M, Daiber A, Schulz E, Baldus S, Kleschyov AL, Materne A, Wenzel P, Hink U, Nickenig G, Fleming I, Munzel T. Mechanisms of increased vascular superoxide production in an experimental model of idiopathic dilated cardiomyopathy. Arterioscler Thromb Vasc Biol. 2005; 25: 2554–2559.LinkGoogle Scholar2 Elkayam U, Mehra A, Shotan A, Ostrzega E. Nitrate resistance and tolerance: potential limitations in the treatment of congestive heart failure. Am J Cardiol. 1992; 70: 98B–104B.CrossrefMedlineGoogle Scholar3 Munzel T, Daiber A, Mulsch A. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005; 97: 618–628.LinkGoogle Scholar4 Munzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest. 1995; 95: 187–194.CrossrefMedlineGoogle Scholar5 Schrammel A, Behrends S, Schmidt K, Koesling D, Mayer B. Characterization of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one as a heme-site inhibitor of nitric oxide-sensitive guanylyl cyclase. Mol Pharmacol. 1996; 50: 1–5.MedlineGoogle Scholar6 Evgenov OV, Pacher P, Schmidt PM, Hasko G, Schmidt HH, Stasch JP. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov. 2006; 5: 755–768.CrossrefMedlineGoogle Scholar7 Boerrigter G, Costello-Boerrigter LC, Cataliotti A, Lapp H, Stasch J-P, Burnett JC Jr. Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure. Hypertension. 2007; 49: 1128–1133.LinkGoogle Scholar8 Ziesche S, Cobb FR, Cohn JN, Johnson G, Tristani F. Hydralazine and isosorbide dinitrate combination improves exercise tolerance in heart failure. Results from V-HeFT I and V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation. 1993; 87: VI56–VI64.MedlineGoogle Scholar9 Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004; 351: 2049–2057.CrossrefMedlineGoogle Scholar10 Daiber A, Oelze M, Coldewey M, Kaiser K, Huth C, Schildknecht S, Bachschmid M, Nazirisadeh Y, Ullrich V, Mulsch A, Munzel T, Tsilimingas N. Hydralazine is a powerful inhibitor of peroxynitrite formation as a possible explanation for its beneficial effects on prognosis in patients with congestive heart failure. Biochem Biophys Res Commun. 2005; 338: 1865–1874.CrossrefMedlineGoogle Scholar11 Munzel T, Kurz S, Rajagopalan S, Thoenes M, Berrington WR, Thompson JA, Freeman BA, Harrison DG. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug. J Clin Invest. 1996; 98: 1465–1470.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Becker-Pelster E, Hahn M, Delbeck M, Dietz L, Hüser J, Kopf J, Kraemer T, Marquardt T, Mondritzki T, Nagelschmitz J, Nikkho S, Pires P, Tinel H, Weimann G, Wunder F, Sandner P, Schuhmacher J, Stasch J and Truebel H (2022) Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC, Respiratory Research, 10.1186/s12931-022-02189-1, 23:1 Sandner P, Follmann M, Becker‐Pelster E, Hahn M, Meier C, Freitas C, Roessig L and Stasch J (2021) Soluble GC stimulators and activators: Past, present and future, British Journal of Pharmacology, 10.1111/bph.15698 Wennysia I, Zhao L, Schomber T, Braun D, Golz S, Summer H, Benardeau A, Lai E, Lichtenberger F, Schubert R, Persson P, Xu M and Patzak A (2021) Role of soluble guanylyl cyclase in renal afferent and efferent arterioles, American Journal of Physiology-Renal Physiology, 10.1152/ajprenal.00272.2020, 320:2, (F193-F202), Online publication date: 1-Feb-2021. Singh P, Vijayakumar S, Kalogeroupoulos A and Butler J (2018) Multiple Avenues of Modulating the Nitric Oxide Pathway in Heart Failure Clinical Trials, Current Heart Failure Reports, 10.1007/s11897-018-0383-y, 15:2, (44-52), Online publication date: 1-Apr-2018. Sandner P, Zimmer D, Milne G, Follmann M, Hobbs A and Stasch J (2018) Soluble Guanylate Cyclase Stimulators and Activators Reactive Oxygen Species, 10.1007/164_2018_197, (355-394), . Loganathan S, Korkmaz-Icöz S, Radovits T, Li S, Mikles B, Barnucz E, Hirschberg K, Karck M and Szabo G (2016) Rolle der löslichen Guanylatzyklase im Modell der Herztransplantation in der RatteEffects of soluble guanylate cyclase activation on heart transplantation in a rat model, Zeitschrift für Herz-,Thorax- und Gefäßchirurgie, 10.1007/s00398-016-0093-2, 30:4, (271-277), Online publication date: 1-Aug-2016. Wang D, Jones A, Wang W, Wang M and Korthuis R (2016) Soluble guanylate cyclase activation during ischemic injury in mice protects against postischemic inflammation at the mitochondrial level, American Journal of Physiology-Gastrointestinal and Liver Physiology, 10.1152/ajpgi.00323.2015, 310:9, (G747-G756), Online publication date: 1-May-2016. Franssen C and González Miqueo A (2016) The role of titin and extracellular matrix remodelling in heart failure with preserved ejection fraction, Netherlands Heart Journal, 10.1007/s12471-016-0812-z, 24:4, (259-267), Online publication date: 1-Apr-2016. Loganathan S, Korkmaz-Icöz S, Radovits T, Li S, Mikles B, Barnucz E, Hirschberg K, Karck M and Szabó G (2015) Effects of soluble guanylate cyclase activation on heart transplantation in a rat model, The Journal of Heart and Lung Transplantation, 10.1016/j.healun.2015.05.006, 34:10, (1346-1353), Online publication date: 1-Oct-2015. Greene S, Gheorghiade M, Borlaug B, Pieske B, Vaduganathan M, Burnett J, Roessig L, Stasch J, Solomon S, Paulus W and Butler J (2013) The cGMP Signaling Pathway as a Therapeutic Target in Heart Failure With Preserved Ejection Fraction, Journal of the American Heart Association, 2:6, Online publication date: 18-Nov-2013.Kong Q and Blanton R (2013) Protein Kinase G I and Heart Failure, Circulation: Heart Failure, 6:6, (1268-1283), Online publication date: 1-Nov-2013. Wang W, Jones A, Wang M, Durante W and Korthuis R (2013) Preconditioning with soluble guanylate cyclase activation prevents postischemic inflammation and reduces nitrate tolerance in heme oxygenase-1 knockout mice, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00810.2012, 305:4, (H521-H532), Online publication date: 15-Aug-2013. Gheorghiade M, Marti C, Sabbah H, Roessig L, Greene S, Böhm M, Burnett J, Campia U, Cleland J, Collins S, Fonarow G, Levy P, Metra M, Pitt B, Ponikowski P, Sato N, Voors A, Stasch J and Butler J (2012) Soluble guanylate cyclase: a potential therapeutic target for heart failure, Heart Failure Reviews, 10.1007/s10741-012-9323-1, 18:2, (123-134), Online publication date: 1-Mar-2013. Korkmaz S, Loganathan S, Mikles B, Radovits T, Barnucz E, Hirschberg K, Li S, Hegedüs P, Páli S, Weymann A, Karck M and Szabó G (2012) Nitric Oxide- and Heme-Independent Activation of Soluble Guanylate Cyclase Attenuates Peroxynitrite-Induced Endothelial Dysfunction in Rat Aorta, Journal of Cardiovascular Pharmacology and Therapeutics, 10.1177/1074248412455696, 18:1, (70-77), Online publication date: 1-Jan-2013. Münzel T and Gori T (2012) Oxidative Stress, Endothelial Dysfunction, and Its Impact on Smooth Muscle Signaling Muscle, 10.1016/B978-0-12-381510-1.00091-0, (1219-1229), . Jones A, Durante W and Korthuis R (2010) Heme Oxygenase-1 Deficiency Leads to Alteration of Soluble Guanylate Cyclase Redox Regulation, Journal of Pharmacology and Experimental Therapeutics, 10.1124/jpet.110.169755, 335:1, (85-91), Online publication date: 1-Oct-2010. Schäfer A, Galuppo P, Fraccarollo D, Vogt C, Widder J, Pfrang J, Tas P, Barbosa-Sicard E, Ruetten H, Ertl G, Fleming I and Bauersachs J (2010) Increased Cytochrome P4502E1 Expression and Altered Hydroxyeicosatetraenoic Acid Formation Mediate Diabetic Vascular Dysfunction, Diabetes, 10.2337/db09-1668, 59:8, (2001-2009), Online publication date: 1-Aug-2010. Osto E and Cosentino F (2010) The Role of Oxidative Stress in Endothelial Dysfunction and Vascular Inflammation Nitric Oxide, 10.1016/B978-0-12-373866-0.00022-8, (705-754), . Korkmaz S, Radovits T, Barnucz E, Neugebauer P, Arif R, Hirschberg K, Loganathan S, Seidel B, Karck M and Szabó G (2009) Dose-dependent effects of a selective phosphodiesterase-5-inhibitor on endothelial dysfunction induced by peroxynitrite in rat aorta, European Journal of Pharmacology, 10.1016/j.ejphar.2009.05.020, 615:1-3, (155-162), Online publication date: 1-Aug-2009. Hoffmann L, Schmidt P, Keim Y, Schaefer S, Schmidt H and Stasch J (2009) Distinct molecular requirements for activation or stabilization of soluble guanylyl cyclase upon haem oxidation-induced degradation, British Journal of Pharmacology, 10.1111/j.1476-5381.2009.00263.x, 157:5, (781-795), Online publication date: 1-Jul-2009. Boerrigter G, Lapp H and Burnett J (2009) Modulation of cGMP in Heart Failure: A New Therapeutic Paradigm cGMP: Generators, Effectors and Therapeutic Implications, 10.1007/978-3-540-68964-5_21, (485-506), . Schmidt H, Schmidt P and Stasch J NO- and Haem-Independent Soluble Guanylate Cyclase Activators cGMP: Generators, Effectors and Therapeutic Implications, 10.1007/978-3-540-68964-5_14, (309-339) Stasch J and Hobbs A NO-Independent, Haem-Dependent Soluble Guanylate Cyclase Stimulators cGMP: Generators, Effectors and Therapeutic Implications, 10.1007/978-3-540-68964-5_13, (277-308) Frey R, Mück W, Unger S, Artmeier-Brandt U, Weimann G and Wensing G (2013) Pharmacokinetics, Pharmacodynamics, Tolerability, and Safety of the Soluble Guanylate Cyclase Activator Cinaciguat (BAY 58-2667) in Healthy Male Volunteers, The Journal of Clinical Pharmacology, 10.1177/0091270008322906, 48:12, (1400-1410), Online publication date: 1-Dec-2008. Harinstein M, Flaherty J, Fonarow G and Gheorghiade M (2008) Directions for Research in the Post-Myocardial Infarction Patient with Left Ventricular Dysfunction, The American Journal of Cardiology, 10.1016/j.amjcard.2008.06.012, 102:5, (57G-61G), Online publication date: 1-Sep-2008. Münzel T, Sinning C, Post F, Warnholtz A and Schulz E (2009) Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction, Annals of Medicine, 10.1080/07853890701854702, 40:3, (180-196), Online publication date: 1-Jan-2008. May 2007Vol 49, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.106.085456PMID: 17325236 Originally publishedFebruary 26, 2007 PDF download Advertisement SubjectsCardiorenal SyndromePharmacology" @default.
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