Hatta E, Yasuda K, Levi R
Department of Pharmacology, Cornell University Medical College, New York, New York 10021, USA.
J Pharmacol Exp Ther. 1997 Nov;283(2):494-500.
During protracted myocardial ischemia, ATP depletion promotes Na+ accumulation in sympathetic terminals and prevents vesicular storage of norepinephrine (NE). This forces the reversal of the neuronal uptake1 transporter, and NE is massively released (carrier-mediated release). We had shown that histamine H3 receptors (H3Rs) modulate ischemic NE release in animals. We have now used a human model of protracted myocardial ischemia to investigate whether H3Rs may control carrier-mediated NE release. Surgical specimens of human atrium were incubated in anoxic conditions. NE release increased approximately 7-fold within 70 min of anoxia. This release was carrier mediated because it was Ca++ independent and inhibited by the uptake1 inhibitor desipramine. Furthermore, the Na+/H+ exchanger (NHE) inhibitors ethyl-isopropyl-amiloride and HOE 642, and the Na+ channel blocker tetrodotoxin inhibited NE release, whereas the Na+ channel activator aconitine potentiated it. The selective H3R agonist imetit decreased NE release, an effect that was blocked by each of the H3R antagonists thioperamide and clobenpropit. Notably, imetit acted synergistically with ethyl-isopropyl-amiloride, HOE 642 and tetrodotoxin to reduce anoxic NE release. Thus, activation of H3R appears to result in an inhibition of both NHE- and voltage-dependent Na+ channels. Most importantly, endogenous histamine was released from the anoxic human heart, and thioperamide and clobenpropit each alone increased NE release, indicating that H3R become activated in myocardial ischemia. Our findings indicate that H3Rs are likely to mitigate sympathetic overactivity in the ischemic human heart and suggest new therapeutic strategies to alleviate dysfunctions associated with myocardial ischemia.
在持续性心肌缺血期间，三磷酸腺苷（ATP）耗竭促使钠离子在交感神经末梢积聚，并阻止去甲肾上腺素（NE）的囊泡储存。这迫使神经元摄取1转运体发生逆转，大量去甲肾上腺素被释放（载体介导的释放）。我们已经证明，组胺H3受体（H3Rs）可调节动物缺血时去甲肾上腺素的释放。我们现在使用持续性心肌缺血的人体模型来研究H3Rs是否可以控制载体介导的去甲肾上腺素释放。将人心房手术标本在缺氧条件下孵育。缺氧70分钟内，去甲肾上腺素释放增加了约7倍。这种释放是由载体介导的，因为它不依赖于钙离子，并且被摄取1抑制剂地昔帕明所抑制。此外，钠/氢交换体（NHE）抑制剂乙基异丙基阿米洛利和HOE 642以及钠通道阻滞剂河豚毒素抑制去甲肾上腺素释放，而钠通道激活剂乌头碱则增强其释放。选择性H3R激动剂碘美替啶减少去甲肾上腺素释放，该作用被H3R拮抗剂硫代哌啶和氯苯丙哌嗪所阻断。值得注意的是，碘美替啶与乙基异丙基阿米洛利、HOE 642和河豚毒素协同作用，以减少缺氧时去甲肾上腺素的释放。因此，H3R的激活似乎导致对NHE和电压依赖性钠通道的抑制。最重要的是，内源性组胺从缺氧的人心脏中释放出来，硫代哌啶和氯苯丙哌嗪各自单独增加去甲肾上腺素释放，表明H3R在心肌缺血时被激活。我们的研究结果表明，H3Rs可能减轻缺血人心脏中的交感神经过度活动，并提出新的治疗策略以减轻与心肌缺血相关的功能障碍。
