Soluble guanylate cyclase stimulator riociguat and phosphodiesterase 5 inhibitor sildenafil ameliorate pulmonary hypertension due to left heart disease in mice

Pradhan, Kabita; Sydykov, Akylbek; Tian, Xiaoling; Mamazhakypov, Argen; Neupane, Balram; Luitel, Himal; Weißmann, Norbert; Seeger, Werner; Grimminger, Friedrich; Kretschmer, Axel; Stasch, Johannes‐Peter; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo

doi:10.1016/j.ijcard.2016.04.098

Cited by 28 publications

(31 citation statements)

References 38 publications

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“…Our findings of increased LVEDP, RVSP, and RVH are consistent with previous studies showing evidence of PH-LHF in rodent models (2,8,31,33,37,49,56,61,80). In addition to documenting the development of PH in a murine model of HFrEF, this study demonstrated changes in the pulmonary vascular response to steady and pulsatile flow developing in this context through both in vivo and ex vivo assessments.…”

Section: Discussionsupporting

confidence: 91%

Pulmonary vascular mechanical consequences of ischemic heart failure and implications for right ventricular function

Philip

Murphy

Schreier

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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Left heart failure (LHF) is the most common cause of pulmonary hypertension, which confers an increase in morbidity and mortality in this context. Pulmonary vascular resistance has prognostic value in LHF, but otherwise the mechanical consequences of LHF for the pulmonary vasculature and right ventricle (RV) remain unknown. We sought to investigate mechanical mechanisms of pulmonary vascular and RV dysfunction in a rodent model of LHF to address the knowledge gaps in understanding disease pathophysiology. LHF was created using a left anterior descending artery ligation to cause myocardial infarction (MI) in mice. Sham animals underwent thoracotomy alone. Echocardiography demonstrated increased left ventricle (LV) volumes and decreased ejection fraction at 4 wk post-MI that did not normalize by 12 wk post-MI. Elevation of LV diastolic pressure and RV systolic pressure at 12 wk post-MI demonstrated pulmonary hypertension (PH) due to LHF. There was increased pulmonary arterial elastance and pulmonary vascular resistance associated with perivascular fibrosis without other remodeling. There was also RV contractile dysfunction with a 35% decrease in RV end-systolic elastance and 66% decrease in ventricular-vascular coupling. In this model of PH due to LHF with reduced ejection fraction, pulmonary fibrosis contributes to increased RV afterload, and loss of RV contractility contributes to RV dysfunction. These are key pathologic features of human PH secondary to LHF. In the future, novel therapeutic strategies aimed at preventing pulmonary vascular mechanical changes and RV dysfunction in the context of LHF can be tested using this model. NEW & NOTEWORTHY In this study, we investigate the mechanical consequences of left heart failure with reduced ejection fraction for the pulmonary vasculature and right ventricle. Using comprehensive functional analyses of the cardiopulmonary system in vivo and ex vivo, we demonstrate that pulmonary fibrosis contributes to increased RV afterload and loss of RV contractility contributes to RV dysfunction. Thus this model recapitulates key pathologic features of human pulmonary hypertension-left heart failure and offers a robust platform for future investigations.

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Section: Discussionsupporting

confidence: 91%

Pulmonary vascular mechanical consequences of ischemic heart failure and implications for right ventricular function

Philip

Murphy

Schreier

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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“…In the Su5416/ hypoxia model of pulmonary hypertension, riociguat decreased RV hypertrophy, increased cardiac output, and decreased total pulmonary resistance (Lang et al 2012). In addition, riociguat reduced PH, pulmonary vascular remodeling and improved right ventricular function in a mouse TAC model of Group 2 PH, but did not improve left ventricular function or hypertrophy (Pradhan et al 2016). Subsequently, there have been more than 30 preclinical publications demonstrating the effect of sGC stimulators including riociguat in cardiopulmonary diseases and pulmonary hypertension (Stasch and Evgenov 2013).…”

Section: 1mentioning

confidence: 99%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

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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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“…Left ventricular pressure overload was induced by TAC in FHL-1 −/− mice and their littermates as previously described [34]. Briefly, buprenorphine hydrochloride (Temgesic ® , 0.1 mg/kg bw, Essex Pharma GmbH) was administered s.c. as an analgesic prior to operation.…”

Section: Model Of Tacmentioning

confidence: 99%

FHL-1 is not involved in pressure overload-induced maladaptive right ventricular remodeling and dysfunction

et al. 2020

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Aims The cytoskeletal signaling protein four and-a-half LIM domains 1 (FHL-1) has recently been identified as a novel key player in pulmonary hypertension as well as in left heart diseases. In this regard, FHL-1 has been implicated in dysregulated hypertrophic signaling in pulmonary arterial smooth muscle cells leading to pulmonary hypertension. In mice, FHL-1-deficiency (FHL-1 −/− ) led to an attenuated hypertrophic signaling associated with a blunted hypertrophic response of the pressure-overloaded left ventricle (LV). However, the role of FHL-1 in right heart hypertrophy has not yet been addressed. Methods and resultsWe investigated FHL-1 expression in C57Bl/6 mice subjected to chronic biomechanical stress and found it to be enhanced in the right ventricle (RV). Next, we subjected FHL-1 −/− and corresponding wild-type mice to pressure overload of the RV by pulmonary arterial banding for various time points. However, in contrast to the previously published study in LV-pressure overload, which was confirmed here, RV hypertrophy and hypertrophic signaling was not diminished in FHL-1 −/− mice. In detail, right ventricular pressure overload led to hypertrophy, dilatation and fibrosis of the RV from both FHL-1 −/− and wild-type mice. RV remodeling was associated with impaired RV function as evidenced by reduced tricuspid annular plane systolic excursion. Additionally, PAB induced upregulation of natriuretic peptides and slight downregulation of phospholamban and ryanodine receptor 2 in the RV. However, there was no difference between genotypes in the degree of expression change. Conclusion FHL-1 pathway is not involved in the control of adverse remodeling in the pressure overloaded RV.

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Soluble guanylate cyclase stimulator riociguat and phosphodiesterase 5 inhibitor sildenafil ameliorate pulmonary hypertension due to left heart disease in mice

Cited by 28 publications

References 38 publications

Pulmonary vascular mechanical consequences of ischemic heart failure and implications for right ventricular function

Pulmonary vascular mechanical consequences of ischemic heart failure and implications for right ventricular function

Soluble Guanylate Cyclase Stimulators and Activators

FHL-1 is not involved in pressure overload-induced maladaptive right ventricular remodeling and dysfunction

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