Levi R, Smith N C
Department of Pharmacology, Cornell University, Weill Medical College, New York, New York, USA.
J Pharmacol Exp Ther. 2000 Mar;292(3):825-30.
In protracted myocardial ischemia, sympathetic nerve endings undergo ATP depletion, hypoxia and pH(i) reduction. Consequently, norepinephrine (NE) accumulates in the axoplasm, because it is no longer stored in synaptic vesicles, and intraneuronal Na(+) concentration increases, as the Na(+)/H(+) exchanger (NHE) is activated. This forces the reversal of the Na(+)- and Cl(-)-dependent NE transporter, triggering a massive carrier-mediated release of NE and thus, arrhythmias. Indeed, NE overflow in myocardial ischemia directly correlates with the severity of arrhythmias. Histamine H(3)-receptors (H(3)R) have been identified as inhibitory heteroreceptors in adrenergic nerve endings of the heart. In addition to inhibiting NE exocytosis from sympathetic nerve endings, selective H(3)R agonists attenuate carrier-mediated release of NE in both animal and human models of protracted myocardial ischemia. Whereas H(3)R-mediated attenuation of exocytotic NE release involves an inhibition of N-type Ca(2+)-channels, H(3)R-mediated reduction of carrier-mediated NE release is associated with diminished NHE activity. In addition to inhibiting NE release, H(3)R stimulation significantly attenuates the incidence and duration of ventricular fibrillation. Although other presynaptic receptors also modulate NE release from sympathetic nerve endings, H(3)R stimulation reduces both exocytotic and carrier-mediated NE release, whereas alpha(2)-adrenoceptor agonists attenuate NE exocytosis but enhance carrier-mediated NE release. Furthermore, unlike adenosine A(1)-receptors, whose activation reduces both exocytotic and carrier-mediated NE release, H(3)R stimulation is devoid of negative chronotropic and dromotropic effects (i.e., sinoatrial and atrioventricular nodal functions are unaffected). Because excess NE release can trigger severe arrhythmias and sudden cardiac death, negative modulation of NE release by H(3)R agonists may offer a novel therapeutic approach to myocardial ischemia.
在持续性心肌缺血中，交感神经末梢会出现三磷酸腺苷（ATP）耗竭、缺氧和细胞内pH值降低。因此，去甲肾上腺素（NE）在轴浆中蓄积，因为它不再储存在突触小泡中，并且由于钠/氢交换体（NHE）被激活，神经元内钠离子浓度升高。这迫使依赖钠和氯的NE转运体发生逆转，引发大量载体介导的NE释放，进而导致心律失常。事实上，心肌缺血时NE的溢出与心律失常的严重程度直接相关。组胺H3受体（H3R）已被确定为心脏肾上腺素能神经末梢中的抑制性异源受体。除了抑制交感神经末梢的NE胞吐作用外，选择性H3R激动剂在持续性心肌缺血的动物和人体模型中均能减弱载体介导的NE释放。虽然H3R介导的NE胞吐释放减弱涉及对N型钙通道的抑制，但H3R介导的载体介导的NE释放减少与NHE活性降低有关。除了抑制NE释放外，H3R刺激还能显著降低室颤的发生率和持续时间。尽管其他突触前受体也能调节交感神经末梢的NE释放，但H3R刺激可减少胞吐和载体介导的NE释放，而α2肾上腺素能受体激动剂可减弱NE胞吐作用，但增强载体介导的NE释放。此外，与腺苷A1受体不同，腺苷A1受体激活后可减少胞吐和载体介导的NE释放，而H3R刺激没有负性变时和变传导作用（即窦房结和房室结功能不受影响）。由于过量的NE释放可引发严重心律失常和心源性猝死，H3R激动剂对NE释放的负性调节可能为心肌缺血提供一种新的治疗方法。
