Positive inotropic responses mediated by endothelin ETA and ETB receptors in human myocardial trabeculae

Opgaard, Ole Saetrum; Möller, Sebastian; Vries, René de; Edvinsson, Lars; Saxena, Pramod R.

doi:10.1042/cs19990302

Cited by 18 publications

(16 citation statements)

References 54 publications

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“…The ET A knockout mice also have similar cardiac contractility (as measured by Vp), aortic velocity time integral, ejection time, and heart rate) as the genetic controls. Although ET-1 has been reported to have a positive inotropic and chronotropic effect via the ET A receptor (5,17,19,27), our results suggest that ET A receptor on murine cardiomyocytes is dispensable for the maintenance of basal cardiac anatomy, inotropy, and chronotropy.…”

Section: Discussionmentioning

confidence: 45%

“…The cardiomyocytes predominantly express ET A receptor (9). The binding of ET-1 to both ET A and ET B receptors on cardiomyocytes results in activation of Gq signaling, increased intracellular calcium, and positive inotropy and chronotropy (5,17,19,27; for review, see reference 8). In addition, ET-1 and its receptors mediate stress-induced remodeling in the mammalian heart (for a review, see reference 21).…”

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confidence: 99%

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Cardiomyocyte-Specific Endothelin A Receptor Knockout Mice Have Normal Cardiac Function and an Unaltered Hypertrophic Response to Angiotensin II and Isoproterenol

Kedzierski

Grayburn

Kisanuki

et al. 2003

Molecular and Cellular Biology

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Even though endothelin is recognized as an important vasoregulatory molecule, the roles of endothelin receptors in specific cell types are not yet fully understood. Mice with a null mutation in endothelin A receptor gene (ET A ) or in the gene of its ligand (endothelin 1) die neonatally due to craniofacial and cardiac abnormalities. This early lethality has in the past hindered studies on the role of endothelin in cardiovascular physiology and pathophysiology. To overcome this obstacle, we utilized the cre/loxP technology to generate mice in which the ET A gene could be deleted specifically in cardiomyocytes. The cre recombinase transgene driven by the ␣-myosin heavy-chain promoter deleted the floxed ET A allele specifically in the hearts of these mice, resulting in a 78% reduction in cardiac ET A mRNA level compared to wild-type controls. Cardiomyocytespecific ET A knockout animals are viable and exhibit normal growth, cardiac anatomy, and cardiac contractility, as assessed by echocardiography. In addition, these animals exhibit hypertrophic and contractile responses to 10-day infusion of angiotensin II or isoproterenol similar to those observed in control animals. These results indicate that in adult mice cardiac ET A receptors are not necessary for either baseline cardiac function or stress-induced response to angiotensin II or isoproterenol.Endothelin 1 (ET-1) was identified as an endothelium-derived, vasoactive 21-amino-acid peptide (34). The hormone activates two G-protein-coupled receptors, endothelin A (ET A ) and endothelin B (ET B ), with approximately equal affinity (2, 30). Complex physiology of the endothelin system is suggested by broad tissue distribution of the ligand and its receptors. ET-1 is secreted by many cell types, including endothelial cells and cardiomyocytes (28, 34), whereas ET A and ET B receptors are expressed by cells such as vascular and nonvascular smooth muscle cells, cardiomyocytes, neurons, and renal tubular epithelial cells (2,9,28,30). The circulating levels of ET-1 in plasma are 2 orders of magnitude below the concentration needed for receptor activation, suggesting that ET-1 functions locally (4).In the heart, ET-1 is produced by cardiomyocytes, fibroblasts, and endothelial cells (9, 28, 34). The cardiomyocytes predominantly express ET A receptor (9). The binding of ET-1 to both ET A and ET B receptors on cardiomyocytes results in activation of Gq signaling, increased intracellular calcium, and positive inotropy and chronotropy (5, 17, 19, 27; for review, see reference 8). In addition, ET-1 and its receptors mediate stress-induced remodeling in the mammalian heart (for a review, see reference 21). In vitro experiments show that ET-1-mediated activation of either ET A or ET B receptors on cardiomyocytes results in cellular hypertrophy (7,18). In vivo studies demonstrate that levels of ET-1 and ET A are elevated in animal models of congestive heart failure (29,35,36). Providing the final proof of endothelins' molecular role in cardiac pathology, endothelin receptor antagonis...

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Section: Discussionmentioning

confidence: 45%

mentioning

confidence: 99%

Cardiomyocyte-Specific Endothelin A Receptor Knockout Mice Have Normal Cardiac Function and an Unaltered Hypertrophic Response to Angiotensin II and Isoproterenol

Kedzierski

Grayburn

Kisanuki

et al. 2003

Molecular and Cellular Biology

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“…In the studies showing pro-arrhythmic effects of ET-1 on contractility [9,11] and (Ca 2+ ) i handling [7,8,10], the atrial tissues were not under adrenergic stimulation. However, ET-1 produced marked negative inotropism in human atrium in the presence of catecholamines [29]. Therefore, ET-1 exerts marked anti-adrenergic effects on atrial contractility, as well as on CADs.…”

Section: /25mentioning

confidence: 96%

Anti-adrenergic effects of endothelin on human atrial action potentials are potentially anti-arrhythmic

Redpath

Rankin

Kane

et al. 2006

Journal of Molecular and Cellular Cardiology

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Abstract.Endothelin-1 (ET-1) is elevated in patients with atrial fibrillation (AF) and heart failure. We investigated effects of ET-1 on human atrial cellular electrophysiological measurements expected to influence the genesis and maintenance of AF. Action potential characteristics and L-type Ca 2+ current (I CaL ) were recorded by whole cell patch clamp, in atrial isolated myocytes obtained from patients in sinus rhythm. Isoproterenol (ISO) at 0.05 µM prolonged the action potential duration at 50% repolarisation (APD 50 : 54±10 vs 28±5 ms; P<0.05, n=15 cells, 10 patients), but neither late repolarisation nor cellular effective refractory period (ERP) were affected. ET-1 (10 nM) reversed the effect of ISO on APD 50 , and had no basal effect (in the absence of ISO) on repolarisation or ERP. During repetitive stimulation, ISO (0.05 µM) produced arrhythmic depolarisations (P<0.05). Each was abolished by ET-1 at 10 nM (P<0.05). ISO (0.05 µM) increased peak I CaL from -5.5±0.4 to -14.6±0.9 pA/pF (P<0.05; n=79 cells, 34 patients). ET-1 (10 nM) reversed this effect by 98±10% (P<0.05), with no effect on basal I CaL . Chronic treatment of patients with a β-blocker did not significantly alter basal APD 50 or I CaL , the increase in APD 50 or I CaL by 0.05 µM ISO, nor the subsequent reversal of this effect on APD 50 by 10 nM ET-1. The marked anti-adrenergic effects of ET-1 on human atrial cellular action potential plateau, arrhythmic depolarisations and I CaL , without affecting ERP and independently of β-blocker treatment, may be expected to contribute a potentially anti-arrhythmic influence in the atria of patients with AF and heart failure.

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“…However, the response of atrial myocardium to various agents could be different from that of the ventricular myocardium. Endothelin [16], calcitonin gene-related peptide [17], and adrenomedulin (ADM) [18] all show pronounced inotropic effects on the atrial myocardium but smaller or even no (angiotensin II) effect on the ventricular myocardium. Flagg et al [19] found a previously unidentified K ATP channel heterogeneity: SUR1 is an essential component of the K ATP channels in atrial but not ventricular cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Opens the K<sub>ATP </sub>Channel on Rat Atrial and Ventricular Myocytes

Zhong¹,

Li²,

Liu³

et al. 2009

Cardiology

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Objective: Hydrogen sulfide (H₂S), an endogenous gaseous transmitter, was found to protect the heart from various forms of injury, but the underlying mechanism is not known. H₂S can open the K_ATP channel on vascular smooth muscle cells, and the objective of this study was to determine whether H₂S can open the K_ATP channel on myocardiocytes. Methods: The whole-cell patch-clamp technique was used to record I_K,ATP and action potentials of atrial and ventricular myocytes isolated from the hearts of male Wistar rats. Sodium hydrogen sulfide (NaHS) was used as a donor of H₂S to observe the effect of exogenous H₂S on I_K,ATP. DL-propargylglycine (PPG), an inhibitor of the synthesis of H₂S, was used at a concentration of 200 µM to observe the effect of endogenous H₂S on I_K,ATP. Results: NaHS at concentrations (in µM) of 9.375, 18.75, 37.5, 75 and 150 increased I_K,ATP by 12.8% (p > 0.05), 28.4% (p < 0.05), 38.8% (p < 0.01), 51.2% (p < 0.01) and 58.6% (p< 0.01) on ventricular myocytes, respectively, and by 6.8% (p > 0.05), 10.4% (p > 0.05), 18.9% (p < 0.01), 24.8% (p < 0.01) and 37.2% (p < 0.01) on atrial myocytes, respectively. The H₂S-induced decrease in the duration of action potentials (APD₉₀) of ventricular myocytes was concentration-dependent, although only NaHS at a concentration of 150 µM decreased the APD₉₀ significantly (15%, p < 0.05). The H₂S-induced decrease in APD₉₀ on atrial myocytes was concentration dependent, but the statistical difference was not significant. Inhibition of I_K,ATP by PPG was time dependent and the level of inhibition was: ventricular myocytes, 7% (p > 0.05), 10% (p < 0.05), 15.3% (p < 0.01), 24.0% (p < 0.01) and 28.9% (p < 0.01); atrial myocytes, 15.8% (p > 0.05), 21.3% (p > 0.05), 26.5% (p < 0.01), 34.0% (p < 0.01) and 43.2% (p < 0.01) measured at 5, 10, 15, 20 and 25 min, respectively. The increase in the APD₉₀, by PPG was time dependent for ventricular myocytes [increased by 12.8% (p < 0.05) at 25 min]. The same was true for atrial myocytes, although only the value at 25 min was significant (15%, p < 0.05). Conclusions: H₂S decreased the APD₉₀,and both the endogenous and exogenous H₂S-induced increase in I_K,ATP on both atrial and ventricular myocytes was concentration dependent. These results may help to explain, at least in part, how H₂S protects heart cells from various forms of injury.

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Positive inotropic responses mediated by endothelin ETA and ETB receptors in human myocardial trabeculae

Cited by 18 publications

References 54 publications

Cardiomyocyte-Specific Endothelin A Receptor Knockout Mice Have Normal Cardiac Function and an Unaltered Hypertrophic Response to Angiotensin II and Isoproterenol

Cardiomyocyte-Specific Endothelin A Receptor Knockout Mice Have Normal Cardiac Function and an Unaltered Hypertrophic Response to Angiotensin II and Isoproterenol

Anti-adrenergic effects of endothelin on human atrial action potentials are potentially anti-arrhythmic

Hydrogen Sulfide Opens the K<sub>ATP </sub>Channel on Rat Atrial and Ventricular Myocytes

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