内皮素-1抑制雄性大鼠心脏中的神经元去甲肾上腺素转运体。
Endothelin-1 inhibits the neuronal norepinephrine transporter in hearts of male rats.
作者信息
Backs Johannes, Bresch Elke, Lutz Matthias, Kristen Arnt V, Haass Markus
机构信息
Department of Cardiology, University of Heidelberg, INF 410, D-69120 Heidelberg, Germany.
出版信息
Cardiovasc Res. 2005 Aug 1;67(2):283-90. doi: 10.1016/j.cardiores.2005.03.018.
OBJECTIVE
Endothelin-1 (ET-1) potentiates norepinephrine (NE)-induced contractile responses. An impairment of cardiac NE re-uptake by the neuronal NE transporter (NET) contributes to an increased NE net release in failing hearts. We hypothesized that both phenomena are caused by ET-1-mediated inhibition of NET.
METHODS
[3H]-NE-uptake, electrical field stimulation-evoked NE overflow and left ventricular contractility (LV-dp/dt(max)) were measured in isolated perfused rat hearts. NET density on cardiac plasma membranes was determined by [3H]-mazindol binding. Experimental heart failure in rats was induced by transverse aortic constriction (TAC).
RESULTS
ET-1 inhibited cardiac [3H]-NE-uptake in a concentration- and time-dependent manner. The endothelin A receptor (ET(A)) antagonist BQ123 but not the endothelin B receptor (ET(B)) antagonist BQ788 abolished ET-1-induced reduction of [3H]-NE-uptake. Likewise, ET-1, but not the ET(B) agonist sarafotoxin S6c, enhanced the stimulated overflow of endogenous NE. In contrast, ET-1 inhibited the stimulated NE overflow during NET blockade (exocytotic NE release) via activation of ET(B). In isovolumically contracting healthy hearts, ET-1 potentiated the NE- but not isoprenaline-induced increase in LV-dp/dt(max). Since isoprenaline is not a NET substrate, the enhanced LV-dp/dt(max) response to NE thus depends on NET. In TAC rats, ET(A) antagonism by darusentan improved both impairment of cardiac [3H]-NE-uptake and reduction of [3H]-mazindol binding sites.
CONCLUSION
ET-1 inhibits cardiac NE re-uptake via ET(A) but attenuates exocytotic NE release via ET(B), resulting in opposite effects on cardiac NE net release. In healthy hearts, ET(A)-mediated inhibition of NE re-uptake exceeds ET(B)-mediated silencing of NE release and potentiates the NE-induced increase in left ventricular contractility. In TAC rats, endogenous ET-1 impairs NE re-uptake and promotes sympathetic overstimulation of failing hearts.
目的
内皮素 -1（ET -1）可增强去甲肾上腺素（NE）诱导的收缩反应。神经元去甲肾上腺素转运体（NET）对心脏NE再摄取的损害导致衰竭心脏中NE净释放增加。我们推测这两种现象均由ET -1介导的NET抑制所致。
方法
在离体灌注大鼠心脏中测量[³H]-NE摄取、电场刺激诱发的NE溢出以及左心室收缩力（LV - dp/dt(max)）。通过[³H]-马吲哚结合法测定心脏质膜上的NET密度。采用横断主动脉缩窄（TAC）诱导大鼠实验性心力衰竭。
结果
ET -1以浓度和时间依赖性方式抑制心脏[³H]-NE摄取。内皮素A受体（ET(A)）拮抗剂BQ123可消除ET -1诱导的[³H]-NE摄取减少，而内皮素B受体（ET(B)）拮抗剂BQ788则无此作用。同样，ET -1可增强内源性NE的刺激溢出，而ET(B)激动剂沙拉新毒素S6c则无此作用。相反，ET -1通过激活ET(B)在NET阻断期间（胞吐性NE释放）抑制刺激的NE溢出。在等容收缩的健康心脏中，ET -1增强NE诱导的LV - dp/dt(max)增加，但不增强异丙肾上腺素诱导的增加。由于异丙肾上腺素不是NET底物，因此对NE增强的LV - dp/dt(max)反应依赖于NET。在TAC大鼠中，达芦生坦对ET(A)的拮抗作用改善了心脏[³H]-NE摄取受损和[³H]-马吲哚结合位点减少的情况。
结论
ET -1通过ET(A)抑制心脏NE再摄取，但通过ET(B)减弱胞吐性NE释放，对心脏NE净释放产生相反作用。在健康心脏中，ET(A)介导的NE再摄取抑制超过ET(B)介导的NE释放沉默，并增强NE诱导的左心室收缩力增加。在TAC大鼠中，内源性ET -1损害NE再摄取并促进衰竭心脏的交感神经过度刺激。
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