Endothelin-1 has haemodynamic effects at pathophysiological concentrations in patients with left ventricular dysfunction

Cowburn, Peter J.; Cleland, John G.F.; McArthur, John D.; MacLean, Margaret R.; Dargie, Henry J.; McMurray, John J.V.; Morton, J. J.

doi:10.1016/s0008-6363(98)00084-4

Cited by 20 publications

(13 citation statements)

References 37 publications

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“…Plasma ET-1 concentration is increased in humans with CHF 18 and in dogs and cats with naturally occurring CHF. [6][7][8] The cellular effects of endothelin include cell proliferation, constriction of vascular smooth muscle, hypertrophy of cardiac myocytes, and activation of cardiac fibroblasts, all of which are associated with pathologic remodeling of the heart.…”

Section: Figmentioning

confidence: 97%

Distinguishing Cardiac and Noncardiac Dyspnea in 48 Dogs Using Plasma Atrial Natriuretic Factor, B‐Type Natriuretic Factor, Endothelin, and Cardiac Troponin‐I

Prosek

Sisson

Oyama

et al. 2007

Veterinary Internal Medicne

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Background: It is challenging to differentiate congestive heart failure (CHF) from noncardiac cause of dyspnea. Hypothesis: Circulating concentrations of atrial natriuretic peptide (NT-proANP), B-type natriuretic peptide (BNP), endothelin-1 (ET-1), and cardiac troponin-I (cTnI) can be used to help distinguish between cardiac and noncardiac causes of dyspnea in dogs.Animals: Forty-eight client-owned dogs admitted to a veterinary teaching hospital for respiratory distress. Methods: Blood samples from patients were prospectively obtained. The etiology of dyspnea was determined by using physical examination, thoracic radiographs, and echocardiography.Results: CHF was diagnosed in 22 dogs, and dyspnea of noncardiac origin (noHD group) was diagnosed in 26 dogs. Analyses revealed significant difference between groups for NT-proANP (geometric mean, 95% confidence [CI]; no HD: 0.26 nmol/mL, 95% CI 0.17-1.09; CHF: 1.38 nmol/mL, 95% CI 1.09-1.74 nmol/mL; P , .0001), BNP (noHD: 12.18 pg/mL, 95% CI 10.91-16.17 pg/mL; CHF: 34.97 pg/mL, 95% CI 23.51-52.02 pg/mL; P , .0001), and ET-1 (noHD: 0.32 fmol/mL, 95% CI 0.23-0.46 fmol/mL; CHF: 1.26 fmol/mL, 95% CI 0.83-1.91 fmol/mL; P , .0001). Plasma cTnI concentrations were not significantly different between groups (noHD: 0.29 ng/mL, 95% CI 0.12-0.72 ng/mL; CHF: 0.42 ng/mL, 95% CI 0.18-0.97, P 5 .53). Receiver operating curves indicated areas under the curve for NT-proANP, BNP, and ET-1 of 0.946, 0.886, and 0.849, respectively.Conclusions and Clinical Importance: Plasma NT-proANP, BNP, and ET-1, but not cTnI, appear useful for distinguishing between dogs with cardiac and noncardiac causes of dyspnea, with plasma NT-proANP having the highest sensitivity (95.5%) and specificity (84.6%).

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Section: Figmentioning

confidence: 97%

Distinguishing Cardiac and Noncardiac Dyspnea in 48 Dogs Using Plasma Atrial Natriuretic Factor, B‐Type Natriuretic Factor, Endothelin, and Cardiac Troponin‐I

Prosek

Sisson

Oyama

et al. 2007

Veterinary Internal Medicne

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“…It is likely that much of the actions of endothelins are mediated by local concentrations (paracrine) but infusing endothelin-1 to achieve the plasma concentrations observed in disease causes vasoconstriction (Cowburn et al, 1998(Cowburn et al, , 1999, indicating that ET can also be considered an endocrine system. Infusing endothelin-3, which is more selective for the ET B receptor, has similar hemodynamic effects to endothelin-1 (Cowburn et al, 1999).…”

Section: Endothelin In Heart Failurementioning

confidence: 99%

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

et al. 2012

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In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials - except those for pulmonary arterial hypertension and scleroderma-related digital ulcers - were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.

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“…In conclusion, the novel findings of this study indicate that the activation of cardiac mast cells and subsequent MMP activation/collagen degradation during the acute stages of volume overload are prevented by blockade of the ET A receptor subtype. Furthermore, by preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits.endothelin-1; mast cell; matrix metalloproteinase; TBC-3214 ENDOTHELIN (ET)-1 is a potent neurohormone produced throughout the cardiovascular system, and the observation that plasma ET-1 is elevated in patients with heart failure is suggestive of a role in the pathophysiology of heart failure (16,19,34,40,47). The cardiovascular effects of ET-1 (a 21-amino-acid peptide) are dictated by binding to one of two G protein-linked receptor subtypes [endothelin receptor subtypes A (ET A ) or B (ET B )] (23).…”

mentioning

confidence: 99%

“…endothelin-1; mast cell; matrix metalloproteinase; TBC-3214 ENDOTHELIN (ET)-1 is a potent neurohormone produced throughout the cardiovascular system, and the observation that plasma ET-1 is elevated in patients with heart failure is suggestive of a role in the pathophysiology of heart failure (16,19,34,40,47). The cardiovascular effects of ET-1 (a 21-amino-acid peptide) are dictated by binding to one of two G protein-linked receptor subtypes [endothelin receptor subtypes A (ET A ) or B (ET B )] (23).…”

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confidence: 99%

ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

Murray¹,

McMillan²,

Brower³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Murray DB, McMillan R, Brower GL, Janicki JS. ETA selective receptor antagonism prevents ventricular remodeling in volume-overloaded rats. Am J Physiol Heart Circ Physiol 297: H109 -H116, 2009. First published May 8, 2009 doi:10.1152/ajpheart.00968.2008.-The objective of this study was to investigate the ability of selective endothelin receptor subtype A (ET A) endothelin receptor antagonism (ETA) to prevent the acute myocardial remodeling process secondary to volume overload. Left ventricular tissue from sham-operated (Sham) and untreated (Fist), and TBC-3214 (Fist ϩ ETA, 25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 )-treated fistula animals was analyzed for mast cell density, matrix metalloproteinase (MMP) activity, and extracellular collagen volume fraction (CVF) 1 and 5 days following the initiation of volume overload. Compared with Fist, ETA treatment prevented the increase in left ventricular mast cell density at 1 day and 5 days. Additionally, at 1 day postfistula, a substantial decrease in MMP-2 activity below Sham levels was observed following endothelin receptor antagonism (1.7 Ϯ 0.7 vs. 0.3 Ϯ 0.3 vs. 0.9 Ϯ 0.2 arbitrary activity units, Fist vs. Fist ϩ ETA vs. Sham, P Յ 0.05). This same effect was also seen at 5 days postfistula (1.9 Ϯ 0.3 vs. 0.5 Ϯ 0.1 arbitrary activity units, Fist vs. Fist ϩ ETA, P Յ 0.05). The marked decrease in myocardial CVF seen in Fist hearts (0.7 Ϯ 0.1 vs. 1.6 Ϯ 0.1% myocardial area, Fist vs. Sham, P Յ 0.05) was prevented by ETA (1.7 Ϯ 0.1% Fist ϩ ETA, P Ͻ 0.05 vs. Fist). This preservation of the collagen matrix was also present on day 5 in the TBC-treated group vs. the Fist group (1.0 Ϯ 0.1 vs. 1.4 Ϯ 0.1%, Fist vs. Fist ϩ ETA, P Յ 0.01). Furthermore, an 8-wk preventative treatment with ETA significantly attenuated the increase in left ventricular end systolic and diastolic volumes compared with untreated fistula hearts. In conclusion, the novel findings of this study indicate that the activation of cardiac mast cells and subsequent MMP activation/collagen degradation during the acute stages of volume overload are prevented by blockade of the ET A receptor subtype. Furthermore, by preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits.endothelin-1; mast cell; matrix metalloproteinase; TBC-3214 ENDOTHELIN (ET)-1 is a potent neurohormone produced throughout the cardiovascular system, and the observation that plasma ET-1 is elevated in patients with heart failure is suggestive of a role in the pathophysiology of heart failure (16,19,34,40,47). The cardiovascular effects of ET-1 (a 21-amino-acid peptide) are dictated by binding to one of two G protein-linked receptor subtypes [endothelin receptor subtypes A (ET A ) or B (ET B )] (23). In the heart and vasculature, binding and activation of ET A is known to mediate powerful vasoconstrictor and pressor affects, in addition to chronotropic and ionotropic effects (12,25). The ET B receptor subtype is responsible for systemic clearance of circulating ...

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Endothelin-1 has haemodynamic effects at pathophysiological concentrations in patients with left ventricular dysfunction

Abstract: Exogenous ET-1, when infused to achieve plasma concentrations similar to those in severe heart failure and pulmonary hypertension, causes systemic but not pulmonary vasoconstriction.

Cited by 20 publications

References 37 publications

Distinguishing Cardiac and Noncardiac Dyspnea in 48 Dogs Using Plasma Atrial Natriuretic Factor, B‐Type Natriuretic Factor, Endothelin, and Cardiac Troponin‐I

Distinguishing Cardiac and Noncardiac Dyspnea in 48 Dogs Using Plasma Atrial Natriuretic Factor, B‐Type Natriuretic Factor, Endothelin, and Cardiac Troponin‐I

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

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Endothelin-1 has haemodynamic effects at pathophysiological concentrations in patients with left ventricular dysfunction

Abstract: Exogenous ET-1, when infused to achieve plasma concentrations similar to those in severe heart failure and pulmonary hypertension, causes systemic but not pulmonary vasoconstriction.

Cited by 20 publications

References 37 publications

Distinguishing Cardiac and Noncardiac Dyspnea in 48 Dogs Using Plasma Atrial Natriuretic Factor, B‐Type Natriuretic Factor, Endothelin, and Cardiac Troponin‐I

Distinguishing Cardiac and Noncardiac Dyspnea in 48 Dogs Using Plasma Atrial Natriuretic Factor, B‐Type Natriuretic Factor, Endothelin, and Cardiac Troponin‐I

Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

ETAselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats

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Resources

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ET_Aselective receptor antagonism prevents ventricular remodeling in volume-overloaded rats