Role of endogenous endothelin-1 in post-ischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Tawa, Masashi; Fukumoto, Taiki; Ohkita, Mamoru; Matsumura, Yasuo

doi:10.1016/j.ejphar.2008.06.039

Cited by 15 publications

(19 citation statements)

References 43 publications

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“…We and others have demonstrated that cardiac ET-1 production is increased by ischemia, followed by reperfusion 6,23 and that increased ET-1 is involved in the postischemic cardiac dysfunction by enhancing NE overflow via the stimulation of ET A receptor existing in the sympathetic nerve endings. [7][8][9][10]14 In addition, we obtained evidence that exogenously applied ET-1 to the ischemic heart further enhanced the NE overflow and exacerbates the postischemic cardiac dusfunction.…”

Section: Discussionmentioning

confidence: 85%

“…5 In addition, we have recently noted that left ventricular ET-1 content is increased by ischemia/reperfusion in isolated rat hearts, and postischemic cardiac dysfunction is improved by suppressing the ET-1 biosynthesis. 6 These findings imply that endogenously generated ET-1 plays an important role in the pathophysiology of myocardial ischemia/reperfusion. Indeed, both selective ET A receptor antagonists and non-selective ET A /ET B receptor antagonists exhibited protective effects against the postischemic cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 93%

“…6 Isolation of total RNA, synthesis of cDNA and quantitative realtime reverse transcriptase-PCR analysis Total RNA was extracted from isolated rat left ventricle by TRI REAGENT (Molecular Research Center, Cincinnati, OH, USA) according to the instructions from the manufacturer. RNA was purified by TURBO DNA-free kit (Applied Biosystems/Ambion, Austin, TX, USA).…”

Section: Ne Assaymentioning

confidence: 99%

“…[11][12][13] We have found that endogenously generated ET-1 evokes NE overflow via the stimulation of ET A receptors, and this contributes to cardiac deterioration after ischemia/reperfusion. 6,10 Moreover, Isaka et al have demonstrated that both ET A and ET B receptors exist in the sympathetic nerve varicosities of guinea pig hearts, and modulate NE release in association with reperfusion arrhythmias. 14 Taken together, it is considered that endogenously generated ET-1 promotes postischemic NE overflow, and this is contributive, at least in part, to subsequent cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

et al. 2010

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Endothelin-1 (ET-1) is involved in norepinephrine (NE) overflow and cardiac dysfunction after myocardial ischemia/reperfusion via the activation of ET A receptors. As ET-1 is generated from big ET-1 via endothelin-converting enzyme (ECE), ischemia/ reperfusion-induced cardiac injury may be exacerbated by exogenous big ET-1. The aim of this study was to investigate the influence of exogenously applied big ET-1 on ischemia/reperfusion-induced NE overflow and cardiac dysfunction. According to the Langendorff technique, isolated rat hearts were subjected to 40-min global ischemia followed by 30-min reperfusion. Exogenous big ET-1 (0.1, 0.3 and 1 nM) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1 nM) of big ET-1 significantly improved indices of left ventricular function after ischemia/reperfusion, such as left ventricular developed pressure (LVDP), the maximum value of the first derivative of left ventricular pressure (dP/dt max ) and left ventricular end diastolic pressure (LVEDP). In addition, big ET-1 significantly suppressed excessive NE overflow in the coronary effluent from the postischemic heart. These effects of big ET-1 were markedly attenuated by treatment with SM-19712 (selective ECE inhibitor) or A-192621 (selective ET B receptor antagonist). On the other hand, those were not potentiated even though combined with ABT-627 (selective ET A receptor antagonist). From these findings, we suggest that exogenous big ET-1 has beneficial effects on ischemia/reperfusion-induced cardiac injury. It seems likely that big ET-1 is converted to ET-1, locally in the heart, and this ET-1 preferentially binds to ET B receptors to exert its related beneficial actions. Keywords: big endothelin-1; endothelin-1; ischemia/reperfusion; norepinephrine INTRODUCTION Endothelin-1 (ET-1) was originally found as a 21-amino-acid vasoconstrictor peptide produced by vascular endothelial cells. 1 This peptide is most abundant in the cardiovascular system, and at least two distinct ET receptors, ET A and ET B , have been identified. ET A receptors mediate vasoconstriction and cell proliferation, whereas ET B receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin. 2 There is accumulating evidence that ET-1 is closely related to the pathogenesis and development of several cardiovascular diseases. 3,4 It has been demonstrated that ischemia increases ET-1-binding sites in cardiac membranes. 5 In addition, we have recently noted that left ventricular ET-1 content is increased by ischemia/reperfusion in isolated rat hearts, and postischemic cardiac dysfunction is improved by suppressing the ET-1 biosynthesis. 6 These findings imply that endogenously generated ET-1 plays an important role in the pathophysiology of myocardial ischemia/reperfusion. Indeed, both selective

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 93%

Section: Ne Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

et al. 2010

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“…Accumulating evidence indicates the crucial role of ET-1 in the pathogenesis and/or development of several cardiovascular diseases [14]. It has been reported that an ischemic event results in increases in ET-1 levels [15–18] and its binding sites [19, 20]. Additionally, blockade of its effects has been shown to act protectively against postischemic cardiac and/or coronary dysfunction both in animal studies [18, 21–29] and human clinical trials [30, 31].…”

Section: Introductionmentioning

confidence: 99%

Endothelin-1 and Norepinephrine Overflow from Cardiac Sympathetic Nerve Endings in Myocardial Ischemia

Tawa

Yamamoto

Ohkita

et al. 2012

Cardiology Research and Practice

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In protracted myocardial ischemia, sympathetic activation with carrier-mediated excessive norepinephrine (NE) release from its nerve endings due to reversal of NE transporter in an outward direction is a prominent cause of arrhythmias and cardiac dysfunction. Endothelin-1 (ET-1) and its receptors are intimately involved in the regulation of this carrier-mediated NE overflow in protracted myocardial ischemia. The ET-1 system is often complex, sometimes involving opposing actions depending on which receptor subtype is activated, which cells are affected, and whether stimuli are endogenously generated or exogenously applied. Therefore, a detailed understanding of the ET-1 system is important for applying drugs acting on this system in clinical settings for the treatment of ischemic cardiac disease. This article provides a detailed analysis of how the ET-1 system is involved in the regulation of carrier-mediated NE release from sympathetic nerve endings in protracted myocardial ischemia.

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Gender and Cardiovascular Disease in the Post-Genomic Era

Marı́n-Garcı́a

2014

Post-Genomic Cardiology

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Role of endogenous endothelin-1 in post-ischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Cited by 15 publications

References 43 publications

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

Endothelin-1 and Norepinephrine Overflow from Cardiac Sympathetic Nerve Endings in Myocardial Ischemia

Gender and Cardiovascular Disease in the Post-Genomic Era

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