Shen J Z, Zheng X F, Kwan C Y
Department of Pharmacology, School of Medicine, Zhejiang University, Hubin Campus, 353 Yanan Road, 310031, Hangzhou, PR China.
Cardiovasc Res. 2000 Aug 18;47(3):574-85. doi: 10.1016/s0008-6363(00)00123-1.
H(2)O(2) can contract many arteries, however the underlying mechanisms are not fully understood. This study aims to test whether H(2)O(2)-induced vasoconstriction could be functionally attributed to the activation of P(2)-purinoceptors in rat aorta and to explore its possible signaling mechanisms.
Isometric tension recording of H(2)O(2) and ATP-induced contractions of rat aortic rings were compared in the absence or presence of various pharmacological tools to identify their possible common signaling pathways.
Both H(2)O(2) and ATP induced transient phasic contractions in a concentration-dependent manner (1-1000 microM). Removal of endothelium potentiated the contractile responses to H(2)O(2) and to ATP. H(2)O(2) (30 microM)-induced phasic contraction could be abolished by catalase (800 U/ml), but not affected by SOD (150 U/ml), DMSO (5 mM) and apyrase (5 U/ml), suggesting no involvement of O(2)(-), hydroxyl free radicals and ATP release. Also, several receptor antagonists including phentolamine, atropine, methysergide and chlorpheniramine (each 3 microM) were without effect on H(2)O(2) (30 microM)-induced phasic contraction, suggesting no involvement of typical neurotransmitter release. However, both H(2)O(2) (30 microM) and ATP (1 mM)-induced phasic contractions not only presented homologous desensitization, but also showed heterogeneous desensitization. Furthermore, the phasic contractions in response to H(2)O(2) (30 microM) or ATP (100 microM) could be inhibited or abolished in a concentration dependent manner by RB-2 and suramin (10-100 microM), two widely used P(2)-purinoceptor antagonists, with only partial inhibition by Evans blue (300 microM), a moderately selective P(2x) receptor blocker, or by alpha-beta-methylene-ATP (100 microM), a selective P(2x) receptor desensitizer. On the other hand, both H(2)O(2) (30 microM) and ATP (100 microM)-induced phasic contractions were also attenuated, to different degree, by inhibitors of several enzymes including PLC, PKC, PLA(2) and cyclooxygenase. Lastly, removal of extracellular Ca(2+) or pretreatment with procaine (10 mM) and dantrolene (30 microM), two putative intracellular Ca(2+) release blockers, or with Ni(2+) (100 microM) and tetrandrine (5 microM), two Ca(2+) channel blockers, all significantly inhibited H(2)O(2) and ATP-induced contractions. However, nifedipine (1 microM), a voltage-dependent L-type Ca(2+) channel blocker, was without effect.
Our results demonstrate that H(2)O(2)-induced phasic contraction of rat aorta involves, at least in part, the activation of P(2)-purinoceptors in the aortic smooth muscle cells
过氧化氢（H₂O₂）可使多种动脉收缩，但其潜在机制尚未完全明确。本研究旨在检测H₂O₂诱导的血管收缩在功能上是否归因于大鼠主动脉中P₂ -嘌呤受体的激活，并探讨其可能的信号传导机制。
在有无各种药理学工具的情况下，比较H₂O₂和ATP诱导的大鼠主动脉环等长张力记录，以确定它们可能的共同信号传导途径。
H₂O₂和ATP均以浓度依赖性方式（1 - 1000微摩尔）诱导短暂的相性收缩。去除内皮可增强对H₂O₂和ATP的收缩反应。过氧化氢酶（800单位/毫升）可消除H₂O₂（30微摩尔）诱导的相性收缩，但超氧化物歧化酶（150单位/毫升）、二甲基亚砜（5毫摩尔）和腺苷三磷酸双磷酸酶（5单位/毫升）对其无影响，提示不涉及超氧阴离子、羟自由基和ATP释放。此外，几种受体拮抗剂，包括酚妥拉明、阿托品、甲基麦角新碱和氯苯那敏（各3微摩尔）对H₂O₂（30微摩尔）诱导的相性收缩无影响，提示不涉及典型神经递质释放。然而，H₂O₂（30微摩尔）和ATP（1毫摩尔）诱导的相性收缩不仅表现出同源脱敏，还表现出异源脱敏。此外，RB - 2和苏拉明（10 - 100微摩尔）这两种广泛使用的P₂ -嘌呤受体拮抗剂可浓度依赖性地抑制或消除对H₂O₂（30微摩尔）或ATP（100微摩尔）的相性收缩，而中度选择性P₂x受体阻滞剂伊文思蓝（300微摩尔）或选择性P₂x受体脱敏剂α - β -亚甲基 - ATP（100微摩尔）仅产生部分抑制。另一方面，H₂O₂（30微摩尔）和ATP（100微摩尔）诱导的相性收缩也不同程度地被几种酶的抑制剂所减弱，这些酶包括磷脂酶C、蛋白激酶C、磷脂酶A₂和环氧化酶。最后，去除细胞外钙或用普鲁卡因（10毫摩尔）和丹曲林（30微摩尔）这两种假定的细胞内钙释放阻滞剂，或用镍离子（100微摩尔）和粉防己碱（5微摩尔）这两种钙通道阻滞剂预处理，均显著抑制H₂O₂和ATP诱导的收缩。然而，电压依赖性L型钙通道阻滞剂硝苯地平（1微摩尔）无作用。
我们的结果表明，H₂O₂诱导的大鼠主动脉相性收缩至少部分涉及主动脉平滑肌细胞中P₂ -嘌呤受体的激活
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