Positive inotropic effect of endothelin-1 in the neonatal mouse right ventricle

Nagasaka, Tsuyoshi; Izumi, Masanori; Hori, Masaru; Ozaki, Hiroshi; Karaki, Hideaki

doi:10.1016/s0014-2999(03)01936-8

Cited by 12 publications

(9 citation statements)

References 26 publications

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“…In neonatal mouse RV cardiomycytes, ET-1 increased contractility via an increase in intracellular Ca 2+ transients through activation of the ET R -A receptor and an increase in Ca 2+ influx via the Na + -Ca 2+ exchanger during the action potential. 19 In clinical trials of LV failure, where circulating levels of ET-1 are also increased like in PAH, ERAs worsened outcomes (in part as a result of early worsening of heart failure and fluid retention), prompting a premature ending of trials and the development of these drugs for congestive heart failure. 20,21 It is thus surprising that the possibility of direct effects on RV function in ERAtreated PAH patients is not typically considered.…”

mentioning

confidence: 99%

Endothelin Axis Is Upregulated in Human and Rat Right Ventricular Hypertrophy

Nagendran

Sutendra

Paterson

et al. 2013

Circulation Research

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mentioning

confidence: 99%

Endothelin Axis Is Upregulated in Human and Rat Right Ventricular Hypertrophy

Nagendran

Sutendra

Paterson

et al. 2013

Circulation Research

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“…ET‐1 does not exert an inotropic effect in adult mice and dogs, which have low levels of ET receptor expression (Takanashi and Endoh, ; Nishimaru et al ., ). However, in neonatal mice, where ET receptors are more abundant, inotropic responses to ET‐1 are observed (Nagasaka et al ., ). Moreover, the origin of the cardiac preparation studied is also a significant determinant of the response (Moravec et al ., ).…”

Section: Et‐1 In Cardiac Pacemaking and Contractilitymentioning

confidence: 97%

The role of the paracrine/autocrine mediator endothelin‐1 in regulation of cardiac contractility and growth

Drawnel

Archer

Roderick

2012

British J Pharmacology

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Endothelin-1 (ET-1) is a critical autocrine and paracrine regulator of cardiac physiology and pathology. Produced locally within the myocardium in response to diverse mechanical and neurohormonal stimuli, ET-1 acutely modulates cardiac contractility. During pathological cardiovascular conditions such as ischaemia, left ventricular hypertrophy and heart failure, myocyte expression and activity of the entire ET-1 system is enhanced, allowing the peptide to both initiate and maintain maladaptive cellular responses. Both the acute and chronic effects of ET-1 are dependent on the activation of intracellular signalling pathways, regulated by the inositol-trisphosphate and diacylglycerol produced upon activation of the ETA receptor. Subsequent stimulation of protein kinases C and D, calmodulin-dependent kinase II, calcineurin and MAPKs modifies the systolic calcium transient, myofibril function and the activity of transcription factors that coordinate cellular remodelling. The precise nature of the cellular response to ET-1 is governed by the timing, localization and context of such signals, allowing the peptide to regulate both cardiomyocyte physiology and instigate disease. LINKED ARTICLESThis article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi.org/ 10.1111/bph.2013.168.issue-2 AbbreviationsAngII, angiotensin II; CICR, calcium-induced-calcium release; Cn, calcineurin; ECC, excitation-contraction-coupling; IICR, IP3-induced calcium release; IP3R, inositol triphosphate receptor; MyBP-C, myosin binding protein C; RyR, ryanodine receptor; TnI, troponin I IntroductionEndothelin (ET)-1, ET-2 and ET-3 are a family of cyclic 21 amino acid peptides. The peptides are encoded within three separate yet highly conserved genes located on chromosomes 6, 1 and 20 in humans respectively (Inoue et al., 1989). ET-1 is the most well characterized member of this family. The peptide was initially isolated from the culture supernatant of porcine aortic endothelial cells and identified as a proteasesensitive vasoconstrictor. It remains the most potent vasoactive substance identified to date (Yanagisawa et al., 1988), performing an important function in the regulation of vascular smooth muscle tone. ET-1 also mediates effects on other cell types. Here, we discuss the role of ET-1 in the heart. We will focus on the actions of ET-1 on cardiac muscle and describe how the ET system contributes to cardiac regulation and autoregulation during health and disease. ET-1 in the heartThroughout life, ET-1 plays key roles in many aspects of cardiac physiology and pathology. It is involved in controlling aortic arch formation during development (Kurihara et al., 1995), is required for cardiomyocyte survival and prevents myocyte loss during ageing (Zhao et al., 2006). In the adult, ET-1 modulates coronary blood flow by regulation of vascular tone. Furthermore, by acting on its receptors expressed by atrial and ventricular myocytes, the peptide modulates cardiac muscle function directly (Hirata ...

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“…Unfortunately, no studies have addressed this issue. Endothelin-1 increases contractility in mouse RV cardiomyocytes via an increase in intracellular Ca 2+ transients through activation of the Endothelin Receptor-A and the Na + –Ca 2+ exchanger [97]. Upregulation of endothelin-1 in RV myocardium of patients and models of compensated hypertrophy [98] suggests a potential rationale for ERAs.…”

Section: Treatment Of Rv Failurementioning

confidence: 99%

Right ventricular failure due to chronic pressure load: What have we learned in animal models since the NIH working group statement?

et al. 2015

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Right ventricular (RV) failure determines outcome in patients with pulmonary hypertension, congenital heart diseases and in left ventricular failure. In 2006, the Working Group on Cellular and Molecular Mechanisms of Right Heart Failure of the NIH advocated the development of preclinical models to study the pathophysiology and pathobiology of RV failure. In this review, we summarize the progress of research into the pathobiology of RV failure and potential therapeutic interventions. The picture emerging from this research is that RV adaptation to increased afterload is characterized by increased contractility, dilatation and hypertrophy. Clinical RV failure is associated with progressive diastolic deterioration and disturbed ventricular–arterial coupling in the presence of increased contractility. The pathobiology of the failing RV shows similarities with that of the LV and is marked by lack of adequate increase in capillary density leading to a hypoxic environment and oxidative stress and a metabolic switch from fatty acids to glucose utilization. However, RV failure also has characteristic features. So far, therapies aiming to specifically improve RV function have had limited success. The use of beta blockers and sildenafil may hold promise, but new therapies have to be developed. The use of recently developed animal models will aid in further understanding of the pathobiology of RV failure and development of new therapeutic strategies.

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Positive inotropic effect of endothelin-1 in the neonatal mouse right ventricle

Cited by 12 publications

References 26 publications

Endothelin Axis Is Upregulated in Human and Rat Right Ventricular Hypertrophy

Endothelin Axis Is Upregulated in Human and Rat Right Ventricular Hypertrophy

The role of the paracrine/autocrine mediator endothelin‐1 in regulation of cardiac contractility and growth

Right ventricular failure due to chronic pressure load: What have we learned in animal models since the NIH working group statement?

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