Bauer J, Dau C, Cavarape A, Schaefer F, Ehmke H, Parekh N
Physiologisches Institut and Universitäts-Kinderklinik, Ruprecht-Karls-Universität Heidelberg, D-69120 Heidelberg, Germany.
Am J Physiol. 1999 Jul;277(1):H1-7. doi: 10.1152/ajpheart.1999.277.1.H1.
Studies in vitro have demonstrated that vasoconstrictor agents increase intracellular Ca(2+) and activate protein kinase C (PKC) to elevate vascular tone. The aim of the present study was to determine the importance of these signaling pathways for angiotensin II (ANG II) and thromboxane A(2) (TxA(2)) in regulating mesenteric blood flow (MBF) in vivo. In anesthetized rats increasing doses of ANG II or the TxA(2) agonist U-46619 were administered into the superior mesenteric artery to reduce MBF. Intra-arterial infusion of inhibitors served to examine the contribution of different pathways: 8-(diethylamino)octyl 3,4,5-trimethoxybenoate hydrochloride (TMB-8) to inhibit intracellular Ca(2+) release, nifedipine to block transmembrane Ca(2+) influx through the L-type Ca(2+) channel, and staurosporine to inhibit PKC. Each of the inhibitors attenuated ANG II-induced reductions in MBF, and all dose-response curves were shifted to the right to an approximately threefold higher ANG II dose. Combinations of the inhibitors revealed that their effects were additive; together they abolished the vasoconstrictor action of ANG II completely. In contrast, the dose-response curve for U-46619 was not affected by any of the inhibitors infused either separately or together. The results demonstrate that a rise in intracellular Ca(2+) and activation of PKC are major mediators of the vasoconstrictor effect of ANG II in mesenteric circulation, but they play a subordinate role, if any, for the effects of TxA(2). Because TxA(2) plays a major role only under pathological conditions, the uncontrolled vasoconstriction appears to be associated with the recruitment of novel signal transduction pathways.
体外研究表明，血管收缩剂可增加细胞内钙离子浓度并激活蛋白激酶C（PKC），从而提高血管张力。本研究的目的是确定这些信号通路对于体内血管紧张素II（ANG II）和血栓素A2（TxA2）调节肠系膜血流量（MBF）的重要性。在麻醉大鼠中，将递增剂量的ANG II或TxA2激动剂U-46619注入肠系膜上动脉以减少MBF。动脉内输注抑制剂用于研究不同途径的作用：8-（二乙氨基）辛基3,4,5-三甲氧基苯甲酸盐酸盐（TMB-8）抑制细胞内钙离子释放，硝苯地平阻断通过L型钙离子通道的跨膜钙离子内流，以及星形孢菌素抑制PKC。每种抑制剂均减弱了ANG II诱导的MBF降低，所有剂量-反应曲线均向右移动至ANG II剂量约高三倍处。抑制剂的组合显示它们的作用是相加的；它们共同完全消除了ANG II的血管收缩作用。相比之下，U-46619的剂量-反应曲线不受单独或联合注入的任何抑制剂的影响。结果表明，细胞内钙离子浓度升高和PKC激活是ANG II在肠系膜循环中血管收缩作用的主要介质，但它们对TxA2的作用（如果有）起次要作用。由于TxA2仅在病理条件下起主要作用，因此不受控制的血管收缩似乎与新信号转导途径的募集有关。
