Vesicular monoamine transport inhibitors. Novel action at calcium channels to prevent catecholamine secretion.
Vesicular monoamine transport inhibitors. Novel action at calcium channels to prevent catecholamine secretion.
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囊泡单胺转运抑制剂。
DOI：
10.1161/01.hyp.28.3.414
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
O'Connor,DT
中科院分区：
文献类型：
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作者：
Mahata,M;Mahata,SK;Parmer,RJ;O'Connor,DT
囊泡单胺转运（VMAT）抑制剂，如利血平和丁苯那嗪，损害嗜铬细胞和交感神经元中的囊泡儿茶酚胺储存，从而降低血压。在这里，我们描述了一种新的行动VMAT的拮抗剂的L-型电压门控钙通道，也可能影响从PC 12大鼠嗜铬细胞瘤细胞和牛肾上腺嗜铬细胞释放的儿茶酚胺。当单独给药时，VMAT抑制剂以剂量依赖性方式从嗜铬细胞中急性释放儿茶酚胺。然而，VMAT抑制剂阻断由烟碱胆碱能激动剂或细胞膜去极化刺激的儿茶酚胺分泌，其中每一种都依赖于L型通道的开放;长期暴露于VMAT抑制剂后，抑制作用更强（IC 50 <100 nmol/L）。利血平阻断尼古丁刺激的神经突PC 12细胞释放的儿茶酚胺。利血平还拮抗由组合膜去极化和二氢吡啶L型通道激动剂Bay K8644引发的儿茶酚胺释放，利血平阻断细胞对尼古丁的细胞外45 Ca 2+的摄取。总之，这些结果表明VMAT抑制剂也是L型电压门控钙通道的拮抗剂。经典的L型通道拮抗剂（维拉帕米或硝苯地平）也表现出相互作用;急性时，它们从嗜铬细胞释放去甲肾上腺素，慢性时，它们耗尽细胞中的儿茶酚胺储存，尽管摩尔效价低于利血平（IC 50 <1 nmol/L）。我们得出结论，VMAT抑制剂和L-型钙通道拮抗剂发挥相互抑制作用，对方的更经典的药理学目标。此外，在这些化合物的浓度下观察到这些新的作用，这些化合物在体外经常被认为是特异性的，并且可能在体内抗高血压治疗期间发生。
Vesicular monoamine transport (VMAT) inhibitors, such as reserpine and tetrabenazine, impair vesicular catecholamine storage in chromaffin cells and sympathetic neurons, thereby lowering blood pressure. Here we describe a novel action of VMAT inhibitors—blockade of L-type voltage-gated calcium channels—that may also influence catecholamine release from both PC12 rat pheochromocytoma cells and bovine adrenal chromaffin cells. When given alone, VMAT inhibitors acutely release catecholamines from chromaffin cells in a dose-dependent fashion. However, VMAT inhibitors block catecholamine secretion stimulated by either nicotinic cholinergic agonists or cell membrane depolarization, each of which rely on the opening of L-type channels; the inhibition was more potent after long-term exposure to VMAT inhibitors (IC50<100 nmol/L). Reserpine blocked nicotinic-stimulated catecholamine release from neurite-bearing PC12 cells. Reserpine also antagonized catecholamine release triggered by combined membrane depolarization and the dihydropyridine L-type channel agonist Bay K8644, and reserpine blocked cellular uptake of extracellular45Ca2+in response to nicotine. Taken together, these results indicate that VMAT inhibitors are also antagonists at L-type voltage-gated calcium channels. Classic L-type channel antagonists (verapamil or nifedipine) also exhibited the reciprocal actions; acutely, they released norepinephrine from chromaffin cells, and chronically, they depleted cellular catecholamine stores, albeit with inferior molar potency to reserpine (IC50<1 nmol/L). We conclude that VMAT inhibitors and L-type calcium channel antagonists exert reciprocal inhibitory actions on each other's more classic pharmacological targets. Furthermore, these novel actions are seen at concentrations of these compounds frequently taken to be specific in vitro and likely to occur during antihypertensive treatment in vivo.