Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase - A new action for an old drug
Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase - A new action for an old drug
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DOI：
10.1172/jci118935
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发表时间：
1996-09-15
影响因子：
15.9
通讯作者：
Harrison, DG
中科院分区：
文献类型：
--
作者：
Munzel, T;Kurz, S;Harrison, DG
肼苯达嗪与硝酸异山梨酯同时给药可降低充血性心力衰竭患者的死亡率。最近，我们证明了硝酸盐耐受性部分是由于增强血管超氧化物。O-2（-）产生。我们试图确定肼苯哒嗪可能阻止耐受的机制。兔子或者不接受治疗，或者接受硝酸甘油贴片（1.5 μ g/kg/min × 3 d），或者单独接受肼苯哒嗪（10 mg/kg/d，溶于饮用水），或者接受肼苯哒嗪和硝酸甘油。在器官腔室和血管相对速率中研究主动脉段。用光泽精增强化学发光法测定O-2（-）的产生。硝酸甘油治疗显著抑制硝酸甘油的舒张作用（未治疗患者的最大舒张作用：92+/-1 vs.硝酸甘油治疗患者的64+/-3%），并增加血管舒张。O-2（-）产生量增加2倍以上（P < 0.05）。肼苯哒嗪在未接受硝酸甘油的家兔中的治疗显著降低。完整兔主动脉中O-2（-）的产生和对硝酸甘油的敏感性增加。当与硝酸甘油同时给药时，肼苯哒嗪完全阻止了硝酸盐耐受性的发展，并使血管内源性速率正常化。O-2（-）产生。血管匀浆的研究表明，主要来源。O-2（-）是一种NADH依赖性膜相关氧化酶，活性为67+/-12 nmol vs. 28+/-2 nmol。O-2（-）。min（-1）。硝酸甘油处理与未处理的主动脉匀浆中的蛋白质mg（-1）。在另外的研究中，我们发现，急性添加肼苯哒嗪（10 μ M）的硝酸甘油耐受血管立即抑制。血管匀浆中O-2（-）的产生和NADH氧化酶的活性。化学发光信号被重组肝素结合超氧化物歧化酶（HB-SOD）抑制，证明了该检测方法的特异性。O-2（-）。这些观察结果表明，一个特定的膜相关氧化酶被激活的慢性硝酸甘油治疗，这种氧化酶的活性被肼苯哒嗪抑制，肼苯哒嗪可能会防止耐受提供了一种机制。肼苯哒嗪抑制血管生成的能力。O-2（-）阴离子的产生代表了这种药物的一种新的作用机制。
Hydralazine has been shown to reduce mortality in patients with congestive heart failure when given concomitantly with isosorbide dinitrate. Recently, we demonstrated that nitrate tolerance is in part due to enhanced vascular superoxide . O-2(-) production. We sought to determine mechanisms whereby hydralazine may prevent tolerance. Rabbits either received no treatment, nitroglycerin patches (1.5 mu g/kg/min X 3 d), hydralazine alone (10 mg/kg/d in drinking water), or hydralazine and nitroglycerin. Aortic segments were studied in organ chambers and relative rates of vascular . O-2(-) production were determined using lucigenin-enhanced chemiluminescence. Nitroglycerin treatment markedly inhibited relaxations to nitroglycerin (maximum relaxations in untreated: 92+/-1 vs. 64+/-3% in nitroglycerin-treated patients and increased vascular . O-2(-) production by over twofold (P < 0.05). Treatment with hydralazine in rabbits not receiving nitroglycerin significantly decreased . O-2(-) production in intact rabbit aorta and increased sensitivity to nitroglycerin. When given concomitantly with nitroglycerin, hydralazine completely prevented the development of nitrate tolerance and normalized endogenous rates of vascular . O-2(-) production. Studies of vessel homogenates demonstrated that the major source of . O-2(-) was an NADH-dependent membrane-associated oxidase displaying activities of 67+/-12 vs. 28+/-2 nmol . O-2(-) . min(-1). mg protein(-1) in nitroglycerin-treated vs. untreated aortic homogenates. In additional studies, we found that acute addition of hydralazine (10 mu M) to nitroglycerin-tolerant vessels immediately inhibited . O-2(-) production and NADH oxidase activity in vascular homogenates. The chemiluminescence signal was inhibited by a recombinant heparin-binding superoxide dismutase (HB-SOD) demonstrating the specificity of this assay for . O-2(-). These observations suggest that a specific membrane-associated oxidase is activated by chronic nitroglycerin treatment, and the activity of this oxidase is inhibited by hydralazine, providing a mechanism whereby hydralazine may prevent tolerance. The ability of hydralazine to inhibit vascular . O-2(-) anion production represents a novel mechanism of action for this drug.