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
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DOI：
10.1038/hr.2010.213
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发表时间：
2011-02
影响因子：
5.4
通讯作者：
Masashi Tawa;T. Fukumoto;M. Ohkita;N. Yamashita;A. Geddawy;T. Imamura;K. Ayajiki;T. Okamura;Y. Matsumura
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文献类型：
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作者：
Masashi Tawa;T. Fukumoto;M. Ohkita;N. Yamashita;A. Geddawy;T. Imamura;K. Ayajiki;T. Okamura;Y. Matsumura
内皮素1（ET 1）通过激活ET A受体参与心肌缺血再灌注后去甲肾上腺素（NE）溢出和心功能不全的发生。由于ET-1是由大ET-1通过内皮素转换酶（ECE）产生的，因此外源性大ET-1可加重缺血/再灌注诱导的心脏损伤。本研究旨在探讨外源性大内皮素-1（big ET-1）对缺血/再灌注所致去甲肾上腺素（NE）溢出及心功能不全的影响。根据Langendorff技术，离体大鼠心脏进行40分钟的全脑缺血，然后再灌注30分钟。缺血前15 min开始灌注外源性大ET-1（0.1、0.3和1 nM）。高剂量（0.3和1 nM）大ET-1可显著改善缺血/再灌注后左室功能指标，如左室发展压（LVDP）、左室压一阶导数最大值（dP/dt max）和左室舒张末压（LVEDP）。此外，大ET-1显着抑制过量的NE溢出冠状动脉流出物从缺血后的心脏。用选择性ECE抑制剂SM-19712或选择性ET B受体拮抗剂A-192621处理可明显减弱大ET-1的上述作用。另一方面，即使与ABT-627（选择性ET A受体拮抗剂）联合使用，也没有增强这些作用。从这些发现，我们认为，外源性大ET-1对缺血/再灌注诱导的心脏损伤有有益的作用。似乎大ET-1在心脏局部转化为ET-1，并且该ET-1优先结合ET B受体以发挥其相关的有益作用。
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 n M) was perfused, beginning 15 min before ischemia. Unexpectedly, higher doses (0.3 and 1 n M) 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.