Nitric oxide–sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

Wilck, Nicola; Markó, Lajos; Balogh, András; Kräker, Kristin; Herse, Florian; Bartolomaeus, Hendrik; Szijártó, István András; Gollasch, Maik; Reichhart, Nadine; Strauß, Olaf; Heuser, Arnd; Brockschnieder, Damian; Kretschmer, Axel; Lesche, Ralf; Sohler, Florian; Stasch, Johannes‐Peter; Sandner, Peter; Luft, Friedrich C.; Müller, Dominik N.; Dechend, Ralf; Haase, Nadine

doi:10.1172/jci.insight.96006

Cited by 30 publications

(26 citation statements)

References 54 publications

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“…Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and also less susceptibility to ventricular arrhythmias. Thus, sGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients (Wilck et al 2018). Moreover, in mouse studies, it has been shown that treatment with NO and sGC stimulators reduced P-selectin expression and leukocyte recruitment (Ahluwalia et al 2004;Tchernychev et al 2017), indicating potential to reduce microvascular inflammation.…”

Section: 1mentioning

confidence: 62%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

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128

149

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When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.

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Section: 1mentioning

confidence: 62%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

Self Cite

128

149

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“…Cardiac fibrosis is also involved in the modulation of diastolic function and is an important contributor to diastolic impairment in HFpEF as it increases LV and peripheral vascular stiffness (Borbely et al, 2005;van Heerebeek et al, 2008;Zile et al, 2015), an impairment due to the migration of leukocytes and macrophages in humans (Kai et al, 2005) and experimental HF models (Luft et al, 1999;Fischer et al, 2008;Haase et al, 2014). BAY 58-2667 has been shown to reduce monocyte/macrophage infiltration into cardiac tissue and to reverse inflammatory gene expression patterns in failing rat hearts (Wilck et al, 2018), in addition to its role in reducing interstitial fibrosis and blood pressure (Masuyama et al, 2006); these combined actions likely result in improved diastolic function.…”

Section: Discussionmentioning

confidence: 99%

“…Studies of sGC stimulators and activators in experimental models of hypertension have provided valuable insights into their therapeutic potential. These drugs induced vasodilation, attenuated cardiac fibrosis and hypertrophy, normalized blood pressure, protected against cardiac and renal damage, and improved survival in rat models of hypertension (Mittendorf et al, 2009;Stasch and Hobbs, 2009;Wilck et al, 2018). Beneficial effects were also observed in patients with pulmonary arterial hypertension (Stasch et al, 2011).…”

Section: Introductionmentioning

confidence: 95%

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator

et al. 2020

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Aims: Our aim was to investigate the effect of nitric oxide (NO)-independent activation of soluble guanylyl cyclase (sGC) on cardiomyocyte function in a hypertensive animal model with diastolic dysfunction and in biopsies from human heart failure with preserved ejection fraction (HFpEF). Methods: Dahl salt-sensitive (DSS) rats and control rats were fed a high-salt diet for 10 weeks and then acutely treated in vivo with the sGC activator BAY 58-2667 (cinaciguat) for 30 min. Single skinned cardiomyocyte passive stiffness (F passive) was determined in rats and human myocardium biopsies before and after acute treatment. Titin phosphorylation, activation of the NO/sGC/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) cascade, as well as hypertrophic pathways including NO/sGC/cGMP/PKG, PKA, calcium-calmodulin kinase II (CaMKII), extracellular signalregulated kinase 2 (ERK2), and PKC were assessed. In addition, we explored the contribution of pro-inflammatory cytokines and oxidative stress levels to the modulation of cardiomyocyte function. Immunohistochemistry and electron microscopy were used to assess the translocation of sGC and connexin 43 proteins in the rat model before and after treatment. Results: High cardiomyocyte F passive was found in rats and human myocardial biopsies compared to control groups, which was attributed to hypophosphorylation of total

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“…40 In a recent paper using the sGC stimulator Bay 41-8543 in an experimental rat model of HEFPEF (Heart Failure with Preserved Ejection Fraction), Wilck and coworkers observed a normalization of diastolic dysfunction. 41 Of particular clinical interest, the phase 3 study of Vericiguat in HEFPEF still awaits conclusion. 42…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic Effects of a Soluble Guanylate Cyclase Stimulator, Riociguat, and an Activator, Cinaciguat, During NO-Modulation in Healthy Pigs

Næsheim

How

Myrmel

2020

J Cardiovasc Pharmacol Ther

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Cardiovascular diseases are often characterized by dysfunctional endothelium. To compensate for the related lack of nitric oxide (NO), a class of soluble guanylate cyclase (sGC) stimulators and activators have been developed with the purpose of acting downstream of NO in the NO-sGC-cGMP cascade. These drugs have been discovered using photoaffinity labeling of sGC and high-throughput screening of a vast number of chemical compounds. Therefore, an understanding of the integrated physiological effects of these drugs in vivo is necessary on the path to clinical application. We have characterized the integrated hemodynamic impact of the sGC stimulator riociguat and the activator cinaciguat in different NO-states in healthy juvenile pigs (n = 30). We assessed the vascular effects in both systemic and pulmonary circulation, the contractile effects in the right and left ventricles, and the effects on diastolic cardiac functions. Nitric oxide-tone in these pigs were set by using the NO-blocker l-NAME and by infusion of nitroglycerine. The studies show a more pronounced vasodilatory effect in the systemic than pulmonary circulation for both drugs. Riociguat acts integrated with NO in an additive manner, while cinaciguat, in principle, completely blocks the endogenous NO effect on vascular control. Neither compound demonstrated pronounced cardiac effects but had unloading effect on both systolic and diastolic function. Thus, riociguat can potentially act in various disease states as a mean to increase NO-tone if systemic vasodilation can be balanced. Cinaciguat is a complicated drug to apply clinically due to its almost complete lack of integration in the NO-tone and balance.

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Nitric oxide–sensitive guanylyl cyclase stimulation improves experimental heart failure with preserved ejection fraction

Cited by 30 publications

References 54 publications

Soluble Guanylate Cyclase Stimulators and Activators

Soluble Guanylate Cyclase Stimulators and Activators

Enhanced Cardiomyocyte Function in Hypertensive Rats With Diastolic Dysfunction and Human Heart Failure Patients After Acute Treatment With Soluble Guanylyl Cyclase (sGC) Activator

Hemodynamic Effects of a Soluble Guanylate Cyclase Stimulator, Riociguat, and an Activator, Cinaciguat, During NO-Modulation in Healthy Pigs

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