Endothelin receptors, localized in sympathetic nerve terminals of the heart, modulate norepinephrine release and reperfusion arrhythmias

Isaka, Mitsuhiro; Kudo, Akihiko; Imamura, Michiaki; Kawakami, Hayato; Yasuda, Keishu

doi:10.1007/s00395-006-0623-2

Cited by 51 publications

(63 citation statements)

References 37 publications

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“…We found that CPU0213 is more effective than PD156707 and IRL-1038 in modulating FKBP12.6/12, which is consistent with the findings in a previous study [18] . Our findings are supported by evidence that ET A and ET B are located on the sympathetic nerve ending in the myocardium and control release of norepinephrine individually [26] .…”

Section: Discussionsupporting

confidence: 83%

Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein

Zhang

Dai

et al. 2011

Acta Pharmacol Sin

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Aim: To investigate which endothelin receptors mediated isoproterenol (ISO)-induced downregulation of FKBP12.6/12 in cardiomyocytes and study whether argirhein, a novel compound containing rhein and L-arginine that has anti-inflammatory activity, could reverse the downregulation of FKBP12.6/12 induced by ISO. Methods: Neonatal rat cardiomyocytes were incubated with ISO to downregulate FKBP12.6/12. Then the cells were treated with a selective ET A blocker (PD156707) and a ET B blocker (IRL1038), a dual ET A /ET B antagonist (CPU0213), and argirhein, respectively. FKBP12.6/12 expression was assayed by RT-PCR, Western blot, and immunocytochemistry. Results: The expression of FKBP12.6 mRNA was reduced by 37.7% (P<0.01) and 28.9% (P<0.05) relative to the control by ISO 1 and 0.1 μmol/L, respectively, but no response to ISO 0.01 μmol/L was observed in vitro. FKBP12.6/12 protein expression was reduced by 47.2% (P<0.01) and 37.8% (P<0.05) by ISO 1 and 0.1 μmol/L, respectively. This decrease was reversed significantly by PD156707, or IRL1038, and CPU0213. CPU0213 was more potent than either PD156707 or IRL-1038. Argirhein 10 µmol/L blunted the downregulation of FKBP12.6/12 by ISO, as demonstrated by the rising mRNA and protein levels and by the fluorescent density of the ISOincubated cardiomyocytes. Conclusion: In cardiomyocytes, the ISO induced downregulation of FKBP12.6/12 is modulated by both ET A and ET B . A new compound, argirein, reversed the down-regulation of FKBP12.6/12 expression in myocardial cells stimulated with ISO.

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Section: Discussionsupporting

confidence: 83%

Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein

Zhang

Dai

et al. 2011

Acta Pharmacol Sin

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“…It has been mentioned that ET-1 plays a critical role in heart injury mostly through the activation of ET A receptors. 7,9,10,14 However, our present data showed that ET-1 generated from exogenously applied big ET-1 preferentially acts on ET B receptors rather than ET A receptors in the postischemic heart. In the present study, we have chosen the doses of exogenous big ET-1 in the ranges from 0.1 to 1 nM.…”

Section: Discussioncontrasting

confidence: 63%

“…[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. 10 In the present study, we expected that exogenously applied big ET-1 would cause deterioration of cardiac function following the global ischemia and reperfusion, because exogenously applied big ET-1 exerts qualitatively similar effects to ET-1, in the cardiovascular system in vivo and in vitro.…”

Section: Discussionmentioning

confidence: 69%

“…Two subtypes of ET-1 receptor, named ET A and ET B , are known to mediate opposite physiological actions in several organs, including NE release from sympathetic nerve endings of the postischemic heart; ET A receptors evoke NE release, whereas ET B receptors prevent it. 10,14 Most recently, Oikonomidis et al found a prominent role of ET B receptor on sympathetic hyperactivity during the early phase of myocardial infarction. 13 In this study, they have demonstrated that NE level during the early phase of myocardial infarction is much higher in ET B deficient rats than wild-type rats and this contributes to incidence of ventricular arrhythmogenesis.…”

Section: Discussionmentioning

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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“…ET A is also expressed in neural crest derived tissue such as sympathetic neurons (SNs) that innervate the heart and release norepinephrine (NE) (14,15), one of the neurotransmitters that regulate cardiac function and growth. The success of HF therapy with adrenergic receptor antagonists that inhibit the target receptor of NE in adult CMs underscores the pivotal role of NE in HF (16).…”

mentioning

confidence: 99%

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

Lehmann

Rostosky

Buss

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance In failing hearts, norepinephrine (NE) net release and endothelin-1 (ET1) levels are increased. ET1 receptor antagonists were successfully used in preclinical heart failure (HF) studies, but clinical studies did not show beneficial effects in HF patients. We found that mice lacking endothelin receptor A (ET A ) only in sympathetic neurons but not in cardiomyocytes were protected from the development of HF. Mechanistically, the presynaptic reuptake of NE within the heart was preserved in mice lacking ET A only in sympathetic neurons. These data provide an explanation of why patients in clinical studies do not benefit from ET1 receptor antagonists, because these patients are usually treated with β blockers, which interfere with the mechanism of action identified here.

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Endothelin receptors, localized in sympathetic nerve terminals of the heart, modulate norepinephrine release and reperfusion arrhythmias

Cited by 51 publications

References 37 publications

Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein

Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein

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

Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

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