Clinical trials of endothelin antagonists in heart failure: publication is good for the public health

Kelland, NF; Webb, David J.

doi:10.1136/hrt.2006.089250

Cited by 65 publications

(69 citation statements)

References 38 publications

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“…Therefore, clinical trials of endothelin blockade in heart failure patients were undertaken. However, the results of these studies were neutral in terms of mortality and symptoms (24), leading to an intense discussion on whether the use of receptor subtype-specific endothelin receptor blockers may be of advantage. Interestingly, the above cited study by Yang and coworkers showed that the combined ET A /ET B antagonist LU420627, but not the selective ET A antagonist LU135252, prolonged the survival of ET-1-overexpressing cardiomyopathic mice (4).…”

Section: Discussionmentioning

confidence: 99%

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

et al. 2007

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Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiacspecific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-A content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.

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Section: Discussionmentioning

confidence: 99%

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

et al. 2007

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“…Lately, ET-1 receptor blockers have been approved in the treatment of pulmonary hypertension (Sastry 2006), but clinical studies where both selective ETA-R and nonselective ETR antagonists were used in patients with different degrees of heart failure brought mixed results (Abrahams 2001;Kelland and Webb 2006). Therefore, additional knowledge about ET-1 receptor antagonist in regulation of oxidative stress and signaling pathways can provide a survival benefit.…”

Section: Resultsmentioning

confidence: 99%

The influence of ETA and ETB receptor blockers on LPS-induced oxidative stress and NF-κB signaling pathway in heart

Piechota-Polańczyk¹,

Kleniewska²,

Gorąca³

2012

gpb

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Abstract. The aim of this study was to assess whether an endothelin-A receptor (ETA-R) blocker, BQ123, or an endothelin-B (ETB-R) receptor blocker, BQ788, influences nuclear factor kappa beta (NF-κB) pathway, free radical generation, tumor necrosis factor-alpha (TNF-α) concentration, and glutathione redox system in hearts obtained from lipopolysaccharide (LPS)-induced endotoxic rats. The study was performed on rats divided into groups: 1) saline, 2) saline + LPS (15 mg/kg), 3) BQ123 (1 mg/kg b.w.) + LPS, 4) BQ123 (0.5 mg/kg b.w.) + LPS, 5) BQ788 (3 mg/kg b.w.) + LPS. The ETA-R and ETB-R antagonists were injected i.v. 30 min before LPS administration. In rats, BQ123 caused a significant decrease in TBARS (p < 0.05) but not in H 2 O 2 concentration. It also decreased tissue protein level and improved tissue redox status (p < 0.01). Only a dose of 1 mg/kg decreased TNF-α concentration (p < 0.05). BQ788 lowered TBARS, H 2 O 2 and protein concentration (p < 0.05; p < 0.02; p < 0.001, respectively), however, it did not affect TNF-α concentration. Neither ETA-R nor ETB-R blockers influenced LPS-induced increase in p65 subunit level and activation of NF-κB pathway. Our results demonstrated that ETA-R blockage is more effective in inhibiting free radical generation and improving heart antioxidant properties than ETB-R blockage under oxidative stress. NF-κB pathway is not incorporated in ETA-R and ETB-R influence on ROS production.

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“…Death and hospitalisation for HF were increased in subjects with echocardiographic evidence of PH [31]. Previous analysis of the ENABLE trial has raised the possibility that if only HF patients with increased pulmonary arterial pressures had been included, a clear benefit of treatment with ET antagonists may have emerged [32]. The current pre-clinical study carefully selected rats that developed moderate PH and found no benefit of bosentan on PH, RVH, lung remodeling and fibrosis, as well as on RV function and respiratory function.…”

Section: Effects Of Bosentan On Lung Structural Remodeling and Functionmentioning

confidence: 99%

Bosentan does not improve pulmonary hypertension and lung remodeling in heart failure

Jiang

Jc²,

Shi³

et al. 2010

Eur Respir J

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Pulmonary hypertension (PH) and right ventricular (RV) dysfunction associated with heart failure (HF) carry a poor prognosis. Although endothelin receptor antagonists (ERAs) demonstrated benefits in pulmonary arterial hypertension, their efficacy in PH associated with HF was not specifically evaluated.2 weeks after myocardial infarction (MI) rats received bosentan (100 or 200 mg?kg -1 ?day -1 ) or no treatment for 3 weeks. PH, RV hypertrophy and function as well as lung remodeling and function were evaluated. LV echocardiographic wall motion abnormality and function measured before treatment (2 weeks after MI) and after treatment (5 weeks after MI) were similar in MI control and MI treatment groups. HF induced PH and RV hypertrophy compared with sham: RV systolic pressure 39¡5 versus 23¡0.8 mmHg and RV/left ventricular+septum weight 52¡7 versus 24¡0.5% (all p,0.01). Bosentan did not significantly modify these parameters. In addition, bosentan did not improve depressed RV function measured by echocardiograph from the RV myocardial performance index and tricuspid annular plane systolic excursion. The respiratory pressurevolume relationship revealed that HF caused a restrictive lung syndrome with histological lung remodeling and fibrosis, also not improved by bosentan.Dual ERA therapy with bosentan does not reduce PH, RV hypertrophy and lung remodeling and dysfunction associated with ischaemic HF.

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Clinical trials of endothelin antagonists in heart failure: publication is good for the public health

Cited by 65 publications

References 38 publications

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy

The influence of ETA and ETB receptor blockers on LPS-induced oxidative stress and NF-κB signaling pathway in heart

Bosentan does not improve pulmonary hypertension and lung remodeling in heart failure

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