Investigating the dual nature of endothelin-1: Ischemia or direct arrhythmogenic effect?

Szabó, Tamás; Gellér, László; Merkely, Béla; Selmeci, L.; Juhász‐Nagy, Alexander; Solti, F

doi:10.1016/s0024-3205(00)00587-7

Cited by 30 publications

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“…A role for ET-1 in arrhythmogenesis has been proposed early after its discovery (28). Previous in vivo studies (2,27) tried to define a direct arrhythmogenic role of ET-1 that is not solely attributable to myocardial ischemia secondary to its vasoconstrictor properties. However, these studies could not exclude the possibility that coronary ET-1 infusion caused some degree of accompanying regional, if not generalized, ischemia.…”

Section: Discussionmentioning

confidence: 99%

Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function

Zolk¹,

Münzel²,

Eschenhagen³

2004

American Journal of Physiology-Heart and Circulatory Physiology

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Zolk, Oliver, Felix Mü nzel, and Thomas Eschenhagen. Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function. Am J Physiol Heart Circ Physiol 286: H1248-H1257, 2004; 10.1152/ajpheart.00599.2003.-Endothelin-1 (ET-1) has acute positive inotropic effects, but consequences of chronically increased ET-1 on contractile function of cardiac myocytes are largely unknown. In the present study, effects of long-term treatment with ET-1 (10 nM) for 5 days on both force development [force of contraction (FOC)] and kinetics of contraction were determined in heart tissue reconstituted from rat cardiac cells. Isometric force was measured in response to cumulative concentrations of Ca 2ϩ and isoprenaline. ET-1 augmented basal FOC by 64 Ϯ 11% (P Ͻ 0.05), which was associated with a significantly blunted contractile response to Ca 2ϩ and isoprenaline. Moreover, ET-1 significantly prolonged relaxation (62 Ϯ 3 vs. 53 Ϯ 2 ms). Selective ET A (BQ-123) and ETB receptor blockade (BQ-788) demonstrated that effects of ET-1 on contractile function were mediated through the ET A receptor subtype. Effects of ET-1 were prevented by cotreatment with either Ro31-8425, a PKC inhibitor, or dimethylamiloride, an inhibitor of the Na ϩ /H ϩ exchanger. In contrast to long-term ET-1 treatment, no changes in contractile parameters were observed after ET-1 treatment for 3 h before force measurement. These data suggest that chronic ET-1 stimulation has dual effects on contractility: improvement of basal force but impairment of twitch kinetics and inotropic responsiveness to ␤-adrenoceptor stimulation. The signaling pathways involved include ET A receptors, PKC, and the Na ϩ /H ϩ exchanger. The present in vitro findings raise the possibility that ET-1 may exert both adaptive and maladaptive effects in the failing myocardium in which local accumulation of ET-1 is present. engineered heart tissue; Na ϩ /H ϩ exchanger PROGRESSION OF CONGESTIVE HEART FAILURE (CHF) is accompanied by left ventricular pump dysfunction and neurohumoral system activation. Specifically, augmented cardiac endothelin-1 (ET-1) concentrations and increased circulating levels of ET-1 have been identified as occurring with the development of left ventricular dysfunction (32, 33) and are related to the severity of heart failure (21). Activation of cardiac ET receptors in turn modulates a wide variety of biological processes including vascular tone, growth, and myocardial contractile function. In the past, the majority of studies investigating the effects of ET-1 on contractile performance concentrated on the acute actions of ET-1. These studies, performed in a multitude of cardiac preparations including isolated ventricular cardiomyocytes in vitro, have documented that acute exposure to ET-1 generally exerts positive inotropic effects (9,22,29). It remains unclear, however, whether chronic exposure to ET-1 is linked to a phenotype associated with improved or impaired contractile function. From findings that ET-1 antagonism worsens contractile function in rat an...

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Section: Discussionmentioning

confidence: 99%

Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function

Zolk¹,

Münzel²,

Eschenhagen³

2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…Indeed, ET-1 significantly increased left ventricular epicardial (LV epi ) and right ventricular endocardial (RV endo ) monophasic action potential duration (MAPD) with no change in the upstroke velocity. This was in direct contrast to coronary artery occlusion, which decreased MAPD and upstroke velocity in the ischaemic area [79]. In another study from the same group by Becker et al [80], intra-coronary administration of ET-1 induced ventricular arrhythmias that were focal in nature, without changing local refractory periods, left ventricular conduction time or the overall activation pattern.…”

Section: Mechanisms Underlying the Pro-arrhythmic Effect Of Et-1mentioning

confidence: 91%

“…The evidence from a study by Szabo et al [79] was that ET-1, given directly into the coronary artery, induced arrhythmias without any electrocardiographic or metabolic signs of ischaemia. Indeed, ET-1 significantly increased left ventricular epicardial (LV epi ) and right ventricular endocardial (RV endo ) monophasic action potential duration (MAPD) with no change in the upstroke velocity.…”

Section: Mechanisms Underlying the Pro-arrhythmic Effect Of Et-1mentioning

confidence: 99%

Endothelin and the Ischaemic Heart

Wainwright

McCabe²,

Kane³

2005

CVP

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IntroductionIt has been widely documented that plasma ET-1 and big ET-1 levels are increased in patients within a day of onset of acute myocardial infarction [1,2,3,4]. Similar changes in systemic plasma ET-1 are seen in animal models of myocardial ischaemia [5,6]. The source of the released ET-1 appears to be the area subjected to ischaemic damage, since in a study in anaesthetised pigs both short and long periods of left anterior descending (LAD) coronary artery occlusion were found to enhance overflow of ET-1 from the area of myocardium subjected to the ischaemia/reperfusion insult [7]. The myocardial tissue level of ET-1 has been found to be increased by 3 to 7 fold in the ischaemic area compared to the non-ischaemic myocardium, suggesting an increased biosynthesis of ET-1 during ischaemia/reperfusion [5,7]. Indeed, the demonstration of increased ET-1 mRNA levels in cardiomyocytes subjected to ischaemia [8], supports this notion that that the raised circulating levels of endothelin are not simply due to release of stored peptide. The observation that ischaemia and reperfusion increases 125 I-labelled ET-1 binding sites in rat cardiac membranes [9] further supports the view that the endothelin system is up-regulated during these events, although the observation that there is no difference in ET-1 mRNA levels between animals subjected to ischaemia only and hearts subjected to ischaemia followed by reperfusion, implies that it is ischaemia that stimulates enhanced ET-1 production. Taken together, these observations have led to the concept that endothelin may play an important role in determining the outcome of myocardial ischaemia/reperfusion. Based on our knowledge that ET-1 is a potent vasoconstrictor peptide, early hypotheses focused on the role of ET-1 as a detrimental factor in the 3 ischaemic/reperfused heart. However, over the last decade or so, as our understanding of the cellular effects of endothelin has extended beyond that of vasoconstriction, evidence is emerging that endothelin may play a very complex role in the setting of the ischaemic heart, with the potential to both contribute to cellular injury and cellular repair. The aim of this review therefore is to provide an overview of the effects of endothelin on the cardiomyocyte, in the setting of myocardial ischaemia, and within this to consider not only its actions mediated through vasoconstriction, but also through its effects on ion channels, cellular integrity and inflammatory cells. Contribution of endothelin to ischaemia/reperfusion-induced myocardial injury.The possibility that the coronary vasoconstrictor effects of endothelin could play a role in the development of injury resulting from myocardial ischaemia arose following a number of demonstrations that intracoronary infusion of exogenous ET-1 reduces coronary blood flow by approximately 90% [10][11][12], resulting in marked myocardial ischaemia. Substantive evidence for a contributory role of endogenous ET-1 in infarct extension subsequently emanated from studies that demonstrated that ...

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“…were observed. Furthermore, no ischemic lactate elevation Certainly, we can not rule out the role of focal ischemia in the coronary sinus could be observed [4]. Following 60 of ET-1 infusion, and the first reports on severe ventricular pmol / min ic.…”

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confidence: 76%

Arrhythmogenic action of endothelin-1

Merkely

Kiss

Vágó

et al. 2000

Cardiovascular Research

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Dear Editor, ischemic ECG changes and yielded a prompt fall in It was highly interesting to read the 'Letter to the Editor' coronary blood flow. Due to 1 nmol ET-1 bolus, MAP by Duru et al. [1] regarding the arrhythmogenic action of shortening and the decrease of the upstroke velocity in endothelin-1 (ET-1). ET-1 is supposed to act as a paracrine LV MAP signals were observed (ischemic effect) folepi hormone released due to stretch or myocardial ischaemia lowed by an increase of MAPD in the reperfusion period 90 in vivo. ET-1 prolonged action potential duration with (direct effect) [7]. early afterdepolarization (EAD) formation in right bundle When applying three dimensional mapping during 60 branch cells [2]. In in vivo experimental studies mono-and pmol / min ET-1 infusion and LAD ligation electrophysiopolymorphic nonsustained and sustained ventricular tachlogical changes, local refractory period, left ventricular ycardias (VT) often accelerating into ventricular fibrillaconduction time and total activation pattern were also tion were observed during low dose (30-60 pmol / min) different in the two groups. Besides focal mechanisms, intracoronary (ic.) ET-1 administration [3]. At the time of macroreentry was also observed in the maintenance of the the appearance of nonsustained VT-s 30% reduction of arrhythmias induced by subtotal LAD ligation, while no coronary blood flow without ischemic ECG alterations signs of reentry could be found during ET-1 infusion [8]. were observed. Furthermore, no ischemic lactate elevation Certainly, we can not rule out the role of focal ischemia in the coronary sinus could be observed [4]. Following 60 of ET-1 infusion, and the first reports on severe ventricular pmol / min ic. ET-1 infusion, a continuous prolongation of arrhythmias due to high-dose bolus administration of ET-1 monophasic action potential (MAP) signs at 90% repolaripresumably referred to the secondary arrhythmogenic sation (MAPD ) was detected before arrhythmia formaeffect of ET-1 via strong coronary vasoconstriction, cor-90 tion in all investigated regions (right and left ventricular onary spasm or reperfusion. Presumably, ischemia can also apical / septal endocardial and right and left ventricular play an important role in the maintenance of ET-1 induced anterior epicardial sites). This was associated with EAD arrhythmias. However, direct arrhythmogenic effect of ETformation in approximately 50% of cases. However, the 1 infusion was proven by both in vivo and in vitro typical ischemic MAP changes, shortening of MAPD , experimental models.

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Investigating the dual nature of endothelin-1: Ischemia or direct arrhythmogenic effect?

Cited by 30 publications

References 30 publications

Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function

Effects of chronic endothelin-1 stimulation on cardiac myocyte contractile function

Endothelin and the Ischaemic Heart

Arrhythmogenic action of endothelin-1

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