The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension
The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension
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DOI：
10.1152/ajpheart.00679.2010
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发表时间：
2011-01-01
影响因子：
4.8
通讯作者：
Iadecola, Costantino
中科院分区：
文献类型：
--
作者：
Capone, Carmen;Faraco, Giuseppe;Iadecola, Costantino
Capone C，Faraco G，Park L，Cao X，Davisson RL，Iadecola C.缓慢升压剂量的血管紧张素II诱导的脑血管功能障碍先于高血压的发展。美国生理学杂志心脏循环生理学300：H397-H407，2011年。首次发表于2010年10月22日; doi：10.1152/ajpheart.00679.2010.-高血压改变了脑血管的调节，增加了大脑对中风和痴呆的易感性。我们研究了由“慢升压”血管紧张素II（ANG II）输注引起的动脉压（AP）升高与脑血管功能障碍之间的时间关系。将递送盐水或ANG II 14天的微型泵皮下植入C57 BL/6小鼠（n = 5/组）中。在配备有颅窗的麻醉小鼠中通过激光多普勒血流仪评估脑血流。对于ANG II（600 ng.kg（-1）.min（-1）），AP在9天后开始升高（与生理盐水相比P < 0.05），在11-17天保持升高，并在21天恢复至基线（P > 0.05）。ANG II减弱了由神经活动（晶须刺激）或内皮依赖性血管扩张剂引起的脑血流量增加，这是在AP升高（7天）之前以及高血压消退（21天）之后观察到的效果。非升压剂量的ANG II（200 ng.kg（-1）.min（-1））诱导脑血管功能障碍和氧化应激，而不升高AP（与生理盐水相比，P < 0.05），而苯肾上腺素升高AP，而不诱导脑血管效应。ANG II（600 ng.kg（-1）.min（-1））增加了新皮质活性氧（ROS），其时间过程与脑血管功能障碍相似。ROS清除剂锰（I-II）meso-四（4-苯甲酸）卟啉或NADPH氧化酶肽抑制剂gp 91 ds-tat的新皮质应用减弱了ROS和脑血管功能障碍。我们的结论是缓慢升压型ANG II引起的神经血管调节的改变发生在高血压之前，并持续超过AP正常化，但不是永久性的。这些发现揭示了脑血管功能对ANG II有害作用的显著易感性，并提高了ANG II依赖性高血压患者脑血管失调先于AP升高的可能性。
Capone C, Faraco G, Park L, Cao X, Davisson RL, Iadecola C. The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension. Am J Physiol Heart Circ Physiol 300: H397-H407, 2011. First published October 22, 2010; doi: 10.1152/ajpheart.00679.2010.-Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by "slow pressor" angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice (n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng.kg(-1).min(-1)), AP started to rise after 9 days (P < 0.05 vs. saline), remained elevated at 11-17 days, and returned to baseline at 21 days (P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng.kg(-1).min(-1)) induced cerebrovascular dysfunction and oxidative stress without elevating AP (P < 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng.kg(-1).min(-1)) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension.