Inhibition of myocardial endothelin pathway improves long-term survival in heart failure

Sakai, Satoshi; Miyauchi, Takashi; Kobayashi, Masahiko; Yamaguchi, Iwao; Goto, Katsutoshi; Sugishita, Yasuro

doi:10.1038/384353a0

Cited by 586 publications

(329 citation statements)

References 20 publications

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“…24,25 There are several studies showing beneficial effects of the ET receptor blockade on survival, hemodynamic parameters, and histological remodeling. [11][12][13] This study has demonstrated for the first time that long-term treatment with an ET A receptor antagonist prevents electrical remodeling such as reduction of I to , I K , and I Ca,L and prolongation of APD in ventricular cells and improves QT prolongation in the ECG of cardiomyopathic hamsters. Beneficial effects of the ET A antagonist TA-0201 on survival rate might be partly ascribed to the inhibition of ventricular arrhythmias by lessening electrical inhomogeneity resulting from downregulation of ion channels.…”

Section: Matsumoto Et Al Et a Receptor Blockade On Electrical Remodelingmentioning

confidence: 99%

“…9 -11 It has been reported that long-term blockade of the endothelin-A (ET A ) receptor ameliorates ventricular contractile dysfunction in various animal models of congestive heart failure. 12,13 More recently it has been found that long-term treatment with TA-0201, a selective ET A antagonist, 14 improved cardiac function and survival rate in cardiomyopathic Syrian hamsters. 11 Since the BIO 14.6 cardiomyopathic hamsters were reported to have ventricular arrhythmias in the late stage, 15 the ET A receptor antagonist might prevent sudden cardiac death by inhibiting electrophysiological alterations associated with cardiomyopathic contractile dysfunction.…”

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confidence: 99%

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Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

Matsumoto

Aihara²,

Yamauchi-Kohno³

et al. 2002

Circulation

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Background-The endothelin (ET) system is activated in failing hearts. Congestive heart failure frequently is associated with ventricular arrhythmias, which may result from electrical remodeling such as changes of ionic current density and heterogeneous action potential prolongation. We examined the effects of long-term ET A receptor blockade on the electrophysiological properties of ventricular cells, the surface ECG, and the survival in BIO 14.6 cardiomyopathic hamsters. Methods and Results-Membrane currents and action potentials were recorded from left ventricular cells isolated from normal F1␤ hamsters and cardiomyopathic BIO 14.6 hamsters untreated and chronically treated with TA-0201, an ET A receptor antagonist. In ventricular cells of untreated BIO 14.6 hamsters, the action potential duration was prolonged and the densities of the L-type Ca 2ϩ current (I Ca,L ), the transient outward current (I to ), the delayed rectifier K ϩ current (I K ), and the inward rectifier K ϩ current (I K1 ) were decreased compared with those of F1␤ hamsters. Long-term treatment with the ET A receptor antagonist significantly attenuated action potential duration prolongation and reduction of I to , I K , and I Ca,L in BIO 14.6 ventricular cells. Long-term ET A receptor blockade prevented the QT prolongation and ventricular arrhythmias and improved the survival rate in the cardiomyopathic hamsters. Conclusions-Long-term treatment with an ET

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Section: Matsumoto Et Al Et a Receptor Blockade On Electrical Remodelingmentioning

confidence: 99%

mentioning

confidence: 99%

Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

Matsumoto

Aihara²,

Yamauchi-Kohno³

et al. 2002

Circulation

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“…ET-1 is the main isoform released from the endothelium and acts in a paracrine or autocrine fashion by interacting with ET receptors in vascular smooth muscle (VSM) and endothelial cells, and thereby modifying vascular function and cell growth and proliferation [10]. ET-1 is also produced by airway epithelial cells, macrophages, fibroblasts, cardiomyocytes and neurons [9,[11][12][13]. ET-2 is expressed by intestinal epithelial cells, while ET-3 is produced by intestinal epithelial cells, brain neurons and renal tubular epithelial cells [9,14].…”

Section: Et Synthesismentioning

confidence: 99%

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Hynynen

Khalil²

2006

PRC

102

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The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ET A and ET B2 receptors in vascular smooth muscle, and stimulate [Ca 2+ ] i , protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ET B1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ET B1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.

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“…We used the left coronary artery-ligated rat model of CHF, which is well established (24,(26)(27)(28). To produce rats with CHF, left ventricular free wall myocardial infarction was induced in 7-wk-old male rats (CHF group) according to the method described in our previous papers (26)(27)(28).…”

Section: Animals and Protocolmentioning

confidence: 99%

Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training

Iemitsu

Miyauchi

Maeda

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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149

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Peroxisome proliferator-activated receptor (PPAR)-␣, a transcriptional activator, regulates genes of fatty acid (FA) metabolic enzymes. To study the contribution of PPAR-␣ to exercise training-induced improvement of FA metabolic capacity in the aged heart, we investigated whether PPAR-␣ signaling and expression of its target genes in the aged heart are affected by exercise training. We used hearts of sedentary young rat (4 mo old), sedentary aged rat (23 mo old), and swim-trained aged rat (23 mo old, training for 8 wk). The mRNA and protein expression of PPAR-␣ in the heart was significantly lower in the sedentary aged rats compared with the sedentary young rats and was significantly higher in the swim-trained aged rats compared with the sedentary aged rats. The activity of PPAR-␣ DNA binding to the transcriptional regulating region on the FA metabolic enzyme genes, the mRNA expression of 3-hydroxyacyl CoA dehydrogenase (HAD) and carnitine palmitoyl transferase-I, which are PPAR-␣ target genes, and the enzyme activity of HAD in the heart altered in association with changes of the myocardial PPAR-␣ mRNA and protein levels. These findings suggest that exercise training improves aging-induced downregulation in myocardial PPAR-␣-mediated molecular system, thereby contributing to the improvement of the FA metabolic enzyme activity in the trained-aged hearts.peroxisome proliferator-activated receptor-␣; swimming training; aged rat; fatty acid THE HEART is known for its ability to produce energy from fatty acids (FA) because of its important ␤-oxidation equipment, but it can also derive energy from several other substrates, including glucose and lactate (10, 23). On a physiological condition, FA is considered to account for 60-70% of oxygen consumption for energy production in the heart (23). However, FA metabolic capacity in the heart is reduced by aging (19, 32).It has been reported that exercise training improved an aging-induced decrease of FA metabolic capacity in the heart (7, 18, 25, 32). However, the mechanisms for improving FA metabolic capacity in the heart by exercise training are unclear.Peroxisome proliferator-activated receptor (PPAR)-␣ is a member of the nuclear receptor transcription factor superfamily and is mainly expressed in the heart, liver, and kidney (2,13,29). The recent studies indicated that PPAR-␣ plays a critical role in the expression of genes involved in FA metabolism (13). PPAR-␣ heterodimerizes with the retinoid X receptor (RXR-␣) to bind to peroxisome proliferator-response elements (PPRE) in the upstream regions of a number of genes involved in metabolic homeostasis (13,29). PPAR-␣ regulates target genes encoding FA metabolic (␤-oxidation) enzymes and FA transporters such as FA binding protein, carnitine palmitoyl transferase-I (CPT-I), acyl-CoA synthase, 3-hydroxyacyl CoA dehydrogenase (HAD), apolipoproteins, and so on, suggesting that PPAR-␣ plays an important role in FA metabolic homeostasis (2,5,17,29). However, it is unknown whether the aging and subsequent exercise training affect...

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Inhibition of myocardial endothelin pathway improves long-term survival in heart failure

Cited by 586 publications

References 20 publications

Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

Long-Term Endothelin A Receptor Blockade Inhibits Electrical Remodeling in Cardiomyopathic Hamsters

The Vascular Endothelin System in Hypertension - Recent Patents and Discoveries

Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training

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