Agonist-specific differences in mechanisms mediating eNOS-dependent pial arteriolar dilation in rats.
Agonist-specific differences in mechanisms mediating eNOS-dependent pial arteriolar dilation in rats.
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介导大鼠 eNOS 依赖性软脑膜小动脉扩张机制的激动剂特异性差异。
DOI：
10.1152/ajpheart.2002.282.1.h237
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Pelligrino,DA
中科院分区：
文献类型：
--
作者：
Xu,H-L;Feinstein,DL;Santizo,RA;Koenig,HM;Pelligrino,DA
一氧化氮（NO）是一种重要的脑血管舒张介质，来源于内皮型一氧化氮合酶（eNOS）。在本研究中，我们解决的问题，是否负责激动剂诱导的eNOS激活的机制不同，根据特定的受体被刺激。因此，我们研究是否热休克蛋白90（HSP 90），磷脂酰肌醇-3-激酶（PI 3 K），酪氨酸激酶参与ACh与ADP诱导的eNOS激活在体内脑小动脉。本实验观察了在连续应用乙酰胆碱（ACh）和二磷酸腺苷（ADP）的麻醉雄性大鼠中，在无和有非选择性NOS激活剂N ω-硝基-L-精氨酸甲酯（l-NAME）、神经元型NOS（nNOS）选择性抑制剂ARR-17477、热休克蛋白90（HSP 90）阻断剂17-（烯丙基氨基）-17-去甲氧基格尔德霉素（AAG）、PI 3 K抑制剂渥曼青霉素（Wort）或酪氨酸激酶阻断剂tyrphostin 47（T-47）。只有用l-NAME（而不是ARR-17477）抑制NOS才能降低ACh和ADP反应（65-75%），这表明这些激动剂的血管舒张作用中的所有NO依赖性都来自eNOS。AAG，麦芽汁和T-47的窒息伴随着ACh诱导的扩张大幅减少，但对ADP的反应没有变化。这些结果表明，毒蕈碱（ACh）和嘌呤能（ADP）受体介导的eNOS激活在脑小动脉涉及明显不同的信号转导途径。
Nitric oxide (NO), derived from the endothelial isoform of NO synthase (eNOS), is a vital mediator of cerebral vasodilation. In the present study, we addressed the issue of whether the mechanisms responsible for agonist-induced eNOS activation differ according to the specific receptor being stimulated. Thus we examined whether heat shock protein 90 (HSP90), phosphatidylinositol-3-kinase (PI3K), and tyrosine kinase participate in ACh- versus ADP-induced eNOS activation in cerebral arterioles in vivo. Pial arteriolar diameter changes in anesthetized male rats were measured during sequential applications of ACh and ADP in the absence and presence of the nonselective NOS inhibitorNω-nitro-l-arginine methyl ester (l-NAME), the neuronal NOS (nNOS)-selective inhibitor ARR-17477, the HSP90 blocker 17-(allylamino)-17-demethoxygeldanamycin (AAG), the PI3K inhibitor wortmannin (Wort), or the tyrosine kinase blocker tyrphostin 47 (T-47). Only NOS inhibition withl-NAME (not ARR-17477) reduced ACh and ADP responses (by 65–75%), which suggests that all of the NO dependence in the vasodilating actions of those agonists derived from eNOS. Suffusions of AAG, Wort, and T-47 were accompanied by substantial reductions in ACh-induced dilations but no changes in the responses to ADP. These findings suggest that muscarinic (ACh) and purinergic (ADP) receptor-mediated eNOS activation in cerebral arterioles involve distinctly different signal transduction pathways.