EVIDENCE FOR ENHANCED VASCULAR SUPEROXIDE ANION PRODUCTION IN NITRATE TOLERANCE - A NOVEL MECHANISM UNDERLYING TOLERANCE AND CROSS-TOLERANCE
EVIDENCE FOR ENHANCED VASCULAR SUPEROXIDE ANION PRODUCTION IN NITRATE TOLERANCE - A NOVEL MECHANISM UNDERLYING TOLERANCE AND CROSS-TOLERANCE
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DOI：
10.1172/jci117637
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发表时间：
1995-01-01
影响因子：
15.9
通讯作者：
HARRISON, DG
中科院分区：
文献类型：
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作者：
MUNZEL, T;SAYEGH, H;HARRISON, DG
我们试图研究硝酸甘油（NTG）耐受性和对其他硝基血管扩张剂的“交叉耐受性”的机制。用NTG贴片（0.4 mg/h）治疗家兔3 d，并在器官室中研究其主动脉节段。用苯乙醯胺预收缩后检查松弛。在NTG耐受的兔主动脉中，对cGMP依赖性血管扩张剂如NTG（45+/-6%）、SIN-1（69+/-7%）和乙酰胆碱（ACh，64+/-5%）的舒张作用与对照组相比减弱（分别为90+/-2，94+/-3和89+/-2%，P均< 0.05），而对cAMP依赖性血管扩张剂毛喉素的反应保持不变。在耐受性主动脉中，内皮去除显著增强NTG和SIN-1的舒张作用（分别为82+/-4和95+/-3%）。进行其他研究以确定内皮如何增强耐受性。血管稳态O-2-自由基-阴离子水平（通过光泽精化学发光评估）在具有内皮的耐受血管与对照血管中增加两倍（0.31+/-0.01 vs. 0.61+/-0.01 nmol/mg/min）。内皮剥脱后，这种差异在血管中较小。二亚苯基碘鎓，一种黄素蛋白氧化酶抑制剂，和Tiron，一种直接的O-2-自由基阴离子清除剂，标准化O-2-自由基阴离子水平。与此相反，oxypurinol（1 mM）的黄嘌呤氧化酶的抑制剂，鱼藤酮（50 μ M）的线粒体电子传递的抑制剂和N-G-硝基-L-精氨酸（100 μ M）的一氧化氮合酶的抑制剂没有影响的NTG-耐受性arrhetas的化学发光信号。用脂质体包埋的pH敏感性超氧化物歧化酶（600 U/ml）预处理耐受的主动脉显著增强对NTG、SIN-1和ACh的最大舒张反应，并有效地降低化学发光信号。这些研究表明，连续NTG治疗与增加血管O-2-自由基-阴离子-产生和随后的抑制NO介导的血管舒张产生的外源性和内源性硝基血管扩张剂。
We sought to examine mechanisms underlying nitroglycerin (NTG) tolerance and ''cross-tolerance'' to other nitrovasodilators. Rabbits were treated for 3 d with NTG patches (0.4 mg/h) and their aortic segments studied in organ chambers. Relaxations were examined after preconstriction with phenylephrine. In NTG tolerant rabbit aorta, relaxations to cGMP-dependent vasodilators such as NTG (45+/-6%), SIN-1 (69+/-7%), and acetylcholine (ACh, 64+/-5%) were attenuated vs. controls, (90+/-2, 94+/-3, and 89+/-2% respectively, P < 0.05 for all), while responses to the cAMP-dependent vasodilator forskolin remained unchanged. In tolerant aorta, endothelial removal markedly enhanced relaxations to NTG and SIN-1 (82+/-4 and 95+/-3%, respectively). Other studies were performed to determine how the endothelium enhances tolerance. Vascular steady state O-2-radical-anion levels (assessed by lucigenin chemiluminescence) was increased twofold in tolerant vs. control vessels with endothelium (0.31+/-0.01 vs. 0.61+/-0.01 nmol/mg per minute). This difference was less in vessels after denudation of the endothelium. Diphenylene iodonium, an inhibitor of flavoprotein containing oxidases, and Tiron a direct O-2-radical anion scavenger normalized O-2-radical anions levels. In contrast, oxypurinol (1 mM) an inhibitor of xanthine oxidase, rotenone (50 mu M) an inhibitor of mitochondrial electron transport and N-G-nitro-L-arginine (100 mu M) an inhibitor of nitric oxide synthase did not affect the chemiluminescence signals from NTG-tolerant aortas. Pretreatment of tolerant aorta with liposome-entrapped, pH sensitive superoxide dismutase (600 U/ml) significantly enhanced maximal relaxation in response to NTG, SIN-1, and ACh, and effectively reduced chemiluminescence signals. These studies show that continuous NTG treatment is associated with increased vascular O-2-radical-anion-production and consequent inhibition of NO. mediated vasorelaxation produced by both exogenous and endogenous nitrovasodilators.