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

Zolk, Oliver; Münzel, Felix; Eschenhagen, Thomas

doi:10.1152/ajpheart.00599.2003

Cited by 37 publications

(20 citation statements)

References 31 publications

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“…Originally, ET-1 was thought to have positive ionotropic and chronotropic effects in vitro (16). This remains controversial, however, since a deleterious role for ET-1 has been observed in isolated cardiomyocytes chronically treated with ET-1 (45). These findings of ET-1-induced diminished contractile function are parallel with previously reported in vivo effects (26).…”

Section: Effect Of Et Receptor Antagonism On Postfistula Remodeling Amentioning

confidence: 64%

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Murray

Gardner²,

Brower³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Murray DB, Gardner JD, Brower GL, Janicki JS. Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cellmediated ventricular remodeling in rats. Am J Physiol Heart Circ Physiol 294: H1251-H1257, 2008. First published January 4, 2008 doi:10.1152/ajpheart.00622.2007.-The objective of this study was to investigate the effect a nonselective endothelin-1 (ET-1) receptor antagonist (bosentan) had on the acute myocardial remodeling process including left ventricular (LV) mast cells and matrix metalloproteinase (MMP) activity secondary to volume overload. Additionally, we investigated the overall functional outcome of preventative endothelin receptor antagonism during 14 days of chronic volume overload. LV tissue from sham-operated (Sham), untreated-fistula (Fist), and bosentan (100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 )-treated animals (Fist ϩ Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction at 1 and 5 days after the creation of an aortocaval fistula. When compared with untreated fistulas, bosentan treatment prevented the marked increase in LV mast cell density at 1 day postfistula (3.1 Ϯ 0.3 vs. 1.3 Ϯ 0.3 LV mast cells/mm 2 , Fist vs. Fist ϩ Bos, P Յ 0.01). Additionally, the substantial increase in MMP-2 activation in the untreated fistula at 1 day was prevented following bosentan treatment (1.6 Ϯ 0.3 vs. 0.9 Ϯ 0.1 arbitrary activity units, Fist vs. Fist ϩ Bos, P Յ 0.01). The marked decrease in collagen volume fraction seen in the Fist group (1.4 Ϯ 0.1 vs. 0.8 Ϯ 0.1% myocardial tissue, Sham vs. Fist, P Յ 0.01) was significantly attenuated following bosentan treatment at both the 1-and 5-day time points. Lastly, a 2-wk preventative treatment with bosentan resulted in significant attenuation of the increase in LV end-systolic and -diastolic volumes compared with those in untreated fistula hearts. In summary, nonselective ET-1 antagonism prevents the acute increases in cardiac mast cell density and MMP activation induced secondary to chronic volume overload. By preventing these events, ET-1 antagonism was efficacious in attenuating ventricular dilatation and limiting the development of structural and functional deficits in the first 2 wk of chronic volume overload. Accordingly, these results are the first to demonstrate that cardiac mast cells are responsive to the endogenous endothelin system in vivo. Another novel finding from this study is that chronic nonspecific endothelin antagonism may inadvertently potentiate ET-1-mediated signaling.bosentan; heart; extracellular matrix; cardiac function DISCOVERED ONLY 16 years ago, the neurohormone endothelin-1 (ET-1) has been intensely investigated due to its potent cardiovascular effects and strong association with the pathophysiological worsening of cardiac function in congestive heart failure (7,13,16,29,35). ET-1 is a 21 amino acid peptide predominantly synthesized and secreted by endothelial cells. The effects of ET-1 are dictated by binding to one of two G protein-linked receptor subtypes A or B (ET A or ET B ) (16). In th...

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Section: Effect Of Et Receptor Antagonism On Postfistula Remodeling Amentioning

confidence: 64%

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Murray

Gardner²,

Brower³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…/H ? exchanger [51]. Lower heart rate, LVP max and LV dysfunction under the stress of anesthesia and surgical manipulation could well be partly the consequence of refractoriness to adrenergic stimulation mentioned above.…”

Section: Edlvp) B End Diastolic LV Dimensions (Edlvd)mentioning

confidence: 98%

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

et al. 2009

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Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged s and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.

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“…Hence, our results demonstrate a novel function for MEK1-ERK1/2 signaling whereby it regulates myocardial contractility in addition to influencing cell growth and survival. Previously, ET-1 has been suggested to increase cardiac contractility 8,10,16 and ERK1/2 phosphorylation 24 via a PKCdependent pathway. However, our data indicate that PKC is unlikely to mediate the inotropic effect of ET-1 in the intact adult rat heart.…”

Section: Szokodi Et Al Map Kinases and Cardiac Contractilitymentioning

confidence: 99%

Functionally Opposing Roles of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in the Regulation of Cardiac Contractility

et al. 2008

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Background-Extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38-MAPK) have been shown to regulate various cellular processes, including cell growth, proliferation, and apoptosis in the heart. However, the function of these signaling pathways in the control of cardiac contractility is unclear. Here, we characterized the contribution of ERK1/2 and p38-MAPK to the inotropic effect of endothelin-1 (ET-1). Methods and Results-In isolated perfused rat hearts, infusion of ET-1 (1 nmol/L) for 10 minutes increased contractility and phosphorylation of ERK1/2 and their downstream target p90 ribosomal S6 kinase (p90RSK). Suppression of ERK1/2 activation prevented p90RSK phosphorylation and attenuated the inotropic effect of ET-1. Pharmacological inhibition of epidermal growth factor receptor kinase activity abolished ET-1-induced epidermal growth factor receptor transactivation and ERK1/2 and p90RSK phosphorylation and reduced ET-1-mediated inotropic response. Moreover, inhibition of the p90RSK target Na ϩ -H ϩ exchanger 1 attenuated the inotropic effect of ET-1. In contrast to ERK1/2 signaling, suppression of p38-MAPK activity further augmented ET-1-enhanced contractility, which was accompanied by increased phosphorylation of phospholamban at Ser-16. Conclusions-MAPKs play opposing roles in the regulation of cardiac contractility in that the ERK1/2-mediated positive inotropic response to ET-1 is counterbalanced by simultaneous activation of p38-MAPK. Hence, selective activation of ERK1/2 signaling and inhibition of p38-MAPK signaling may represent novel means to support cardiac function in

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

Cited by 37 publications

References 31 publications

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

Functionally Opposing Roles of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in the Regulation of Cardiac Contractility

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