Dual role of PKC in modulating pharmacomechanical coupling in fetal and adult cerebral arteries.
Dual role of PKC in modulating pharmacomechanical coupling in fetal and adult cerebral arteries.
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DOI：
10.1152/ajpregu.2000.279.4.r1419
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发表时间：
2000-10
期刊：
影响因子：
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通讯作者：
L. Longo;Y. Zhao;W. Long;C. Miguel;R. S. Windemuth;A. Cantwell;A. T. Nanyonga;T. Saito;L. Zhang
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文献类型：
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作者：
L. Longo;Y. Zhao;W. Long;C. Miguel;R. S. Windemuth;A. Cantwell;A. T. Nanyonga;T. Saito;L. Zhang
本研究在近足月（约140胎龄）和成年绵羊脑动脉中验证了蛋白激酶C（PKC）对去甲肾上腺素（NE）介导的三磷酸肌醇[Ins（1，4，5）P（3）]途径和血管收缩具有双重调节作用的假说。胎儿和成人脑动脉的基础PKC活性值（%膜结合）分别为38 +/- 4%和32 +/-4%。在两个年龄组的血管中，PKC亚型α、β（I）、β（II）和δ相对丰富。相反，与成人相比，胎儿脑动脉中PKC-β的水平较低。10（-4）M佛波醇12，13-二丁酸酯（PDBu; PKC激动剂）可使胎儿和成人脑动脉中的PKC活性增加40- 50%。去甲肾上腺素（NE）刺激后，PDBu激活PKC对两个年龄组动脉Ins（1，4，5）P（3）和细胞内Ca（2+）浓度（[Ca（2+）]（i））均产生负反馈。反过来，用staurosporine抑制PKC导致NE诱导的Ins（1，4，5）P（3）和[Ca（2+）]（i）反应在成人脑动脉中增强，而不是在胎儿脑动脉中。在成人组织中，PDBu刺激PKC可增加血管张力，但不增加[Ca（2+）]（i）。相反，在胎儿动脉中，PKC刺激与张力和[Ca（2+）]（i）的增加相关。在细胞外[Ca（2+）]为零的情况下，这些PDBu-induced反应在胎儿血管中不存在，而在成人中保持不变。我们的结论是，虽然基础的PKC活性是相似的胎儿和成人脑动脉，PKC的作用NE介导的药物力学耦合显着不同的两个年龄组。在胎儿和成人脑动脉中，PKC对NE诱导的信号转导反应的调节似乎在血管张力的调节中起重要作用。然而，这两个年龄组的机制不同，这可能与胎儿血管中相对缺乏PKC β有关。
This study tested the hypothesis that protein kinase C (PKC) has dual regulation on norepinephrine (NE)-mediated inositol 1,4, 5-trisphosphate [Ins (1,4,5)P(3)] pathway and vasoconstriction in cerebral arteries from near-term fetal ( approximately 140 gestational days) and adult sheep. Basal PKC activity values (%membrane bound) in fetal and adult cerebral arteries were 38 +/- 4% and 32 +/- 4%, respectively. In vessels of both age groups, the PKC isoforms alpha, beta(I), beta(II), and delta were relatively abundant. In contrast, compared with the adult, cerebral arteries of the fetus had low levels of PKC-epsilon. In response to 10(-4) M phorbol 12,13-dibutyrate (PDBu; PKC agonist), PKC activity in both fetal and adult cerebral arteries increased 40-50%. After NE stimulation, PKC activation with PDBu exerted negative feedback on Ins(1,4,5)P(3) and intracellular Ca(2+) concentration ([Ca(2+)](i)) in arteries of both age groups. In turn, PKC inhibition with staurosporine resulted in augmented NE-induced Ins(1,4,5)P(3) and [Ca(2+)](i) responses in adult, but not fetal, cerebral arteries. In adult tissues, PKC stimulation by PDBu increased vascular tone, but not [Ca(2+)](i). In contrast, in the fetal artery, PKC stimulation was associated with an increase in both tone and [Ca(2+)](i). In the presence of zero extracellular [Ca(2+)], these PDBu-induced responses were absent in the fetal vessel, whereas they remained unchanged in the adult. We conclude that, although basal PKC activity was similar in fetal and adult cerebral arteries, PKC's role in NE-mediated pharmacomechanical coupling differed significantly in the two age groups. In both fetal and adult cerebral arteries, PKC modulation of NE-induced signal transduction responses would appear to play a significant role in the regulation of vascular tone. The mechanisms differ in the two age groups, however, and this probably relates, in part, to the relative lack of PKC-epsilon in fetal vessels.