Rongen G A, Smits P, Thien T
Department of Medicine, University Hospital Nijmegen, The Netherlands.
Circulation. 1994 Oct;90(4):1891-8. doi: 10.1161/01.cir.90.4.1891.
Animal data indicate that ATP derived from aggregating thrombocytes or endothelium induces an endothelium-dependent vasodilator response that is mediated by P2y-purinergic receptors and is reduced when high dosages are administered. This reduced vasodilator response to high ATP doses has been associated with the concomitant release of endothelium-derived contracting factors. In contrast to the endothelium-dependent vasodilator response, ATP as released from sympathetic nerve endings induces a P2x-purinergic receptor-mediated vasoconstrictor response that may contribute to the attenuated vasodilator response to high dosages of luminally applied ATP. The dual action of ATP might be important in the pathophysiology of disease states characterized by an impaired endothelial function and increased thrombocyte aggregation. This study was performed to characterize the vascular response to ATP in humans.
The brachial artery was cannulated in 50 healthy male volunteers (age, 18 to 44 years) for drug infusion and measurement of mean arterial pressure. Forearm blood flow was recorded by venous occlusion strain-gauge plethysmography. ATP induced a dose-dependent vasodilator response that was significantly higher than the effect of equimolar adenosine infusion and that was not reduced by concomitant infusion of the P1-purinergic receptor antagonist theophylline. The infusion of the NO synthase antagonist NG-monomethyl-L-arginine (L-NMMA) reduced the average fall in forearm vascular resistance (FVR) to acetylcholine (-59 +/- 6% [mean +/- SEM] versus -42 +/- 8%; P < .05; N = 10) but did not affect the vasodilator response to ATP (-68 +/- 3% versus -64 +/- 6%; P > .1; N = 10) or sodium nitroprusside (SNP; -53 +/- 3% versus -49 +/- 4%; P > .01; N = 6). The L-NMMA-induced increase in FVR appeared to be related to the type of vasodilator pretreatment, being 94.7 +/- 16.7%, 44.9 +/- 8.7%, and 40.8 +/- 7.3% for acetylcholine, ATP, and SNP pretreatment, respectively (P < .01 for acetylcholine versus ATP and SNP; P > .1 for ATP versus SNP). In contrast to animal data, high dosages of intra-arterially infused ATP (up to 1000 micrograms.100 mL forearm-1.min-1) did not reveal a reduction in the forearm vasodilator response but appeared to be similar to the maximal forearm vasodilation as observed during postocclusive reactive hyperemia.
These observations indicate that ATP induces a potent dose-dependent vasodilator response that is not mediated by P1-purinergic receptor stimulation or by the release of nitric oxide. Moreover, in healthy volunteers, the vasodilator response to high intra-arterial dosages of ATP is not reduced by the release of endothelium-derived contracting factors or by the stimulation of P2x-purinergic receptors on the smooth muscle cells.
动物实验数据表明，聚集的血小板或内皮细胞产生的ATP可诱导内皮依赖性血管舒张反应，该反应由P2y嘌呤能受体介导，高剂量给药时反应减弱。高剂量ATP时这种血管舒张反应减弱与内皮源性收缩因子的同时释放有关。与内皮依赖性血管舒张反应不同，交感神经末梢释放的ATP可诱导P2x嘌呤能受体介导的血管收缩反应，这可能导致对高剂量经腔应用ATP的血管舒张反应减弱。ATP的双重作用在以内皮功能受损和血小板聚集增加为特征的疾病病理生理过程中可能很重要。本研究旨在描述人体对ATP的血管反应。
对50名健康男性志愿者（年龄18至44岁）的肱动脉进行插管，用于药物输注和平均动脉压测量。通过静脉阻断应变片体积描记法记录前臂血流量。ATP诱导剂量依赖性血管舒张反应，该反应显著高于等摩尔腺苷输注的效果，且不受P1嘌呤能受体拮抗剂茶碱同时输注的影响。一氧化氮合酶拮抗剂N-甲基-L-精氨酸（L-NMMA）的输注降低了乙酰胆碱引起的前臂血管阻力（FVR）平均下降幅度（-59±6%[平均值±标准误]对-42±8%；P<.05；N=10），但不影响对ATP的血管舒张反应（-68±3%对-64±6%；P>.1；N=10）或硝普钠（SNP；-53±3%对-49±4%；P>.01；N=6）。L-NMMA诱导的FVR升高似乎与血管舒张剂预处理类型有关，乙酰胆碱、ATP和SNP预处理后的升高分别为94.7±16.7%、44.9±8.7%和40.8±7.3%（乙酰胆碱与ATP和SNP相比，P<.01；ATP与SNP相比，P>.1）。与动物实验数据不同，高剂量动脉内输注ATP（高达1000μg·100mL前臂-1·min-1）并未显示前臂血管舒张反应减弱，而是与闭塞后反应性充血期间观察到的最大前臂血管舒张相似。
这些观察结果表明，ATP诱导强效的剂量依赖性血管舒张反应，该反应不是由P1嘌呤能受体刺激或一氧化氮释放介导的。此外，在健康志愿者中，内皮源性收缩因子的释放或平滑肌细胞上P2x嘌呤能受体的刺激不会降低对高剂量动脉内ATP的血管舒张反应。
