A peripherally administered, centrally acting angiotensin II AT2 antagonist selectively increases brain AT1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH.
A peripherally administered, centrally acting angiotensin II AT2 antagonist selectively increases brain AT1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH.
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DOI：
10.1016/j.brainres.2008.11.006
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发表时间：
2009-01-23
期刊：
影响因子：
2.9
通讯作者：
Saavedra JM
中科院分区：
文献类型：
--
作者：
Macova M;Pavel J;Saavedra JM
脑血管紧张素II AT2受体的生理作用及其与血管紧张素II AT1受体的关系仍然存在争议。为了进一步阐明它们的作用，我们确定了全身给药AT2受体拮抗剂对脑内AT2受体结合和AT1受体表达的影响程度。为此，我们通过渗透微型泵皮下给药AT2受体拮抗剂PD123319 （1mg /kg/天）给成年雄性大鼠两周。我们还研究了代表下丘脑-垂体-肾上腺轴激活的垂体促肾上腺皮质激素和加压素的含量，以及作为中枢去甲肾上腺素功能指标的蓝斑中酪氨酸羟化酶基因的表达。我们发现在血脑屏障内的脑区、下橄榄区和蓝斑区AT2受体结合明显减少。AT2受体阻断不仅使位于血脑屏障外的皮质下器官和正中隆起以及位于血脑屏障内的下丘脑室旁核的AT1受体结合和mRNA表达增加。这些变化与蓝斑中酪氨酸羟化酶mRNA表达的降低以及垂体促肾上腺皮质激素和加压素含量的降低相一致。我们的研究结果表明，持续外周给药AT2拮抗剂会减少与大脑AT2受体的结合，这表明该药物是研究其核心作用的有用工具。AT2受体活性抑制上调特定脑区AT1受体表达。脑AT2受体的阻断与下丘脑-垂体-肾上腺轴增强和中枢交感系统活性降低是相容的。
The physiological actions of brain Angiotensin II AT2 receptors and their relationship to Angiotensin II AT1 receptors remain controversial. To further clarify their role, we determined to what extent systemic administration of an AT2 receptor antagonist affected AT2 receptor binding within the brain and the expression of AT1 receptors. For this purpose, we subcutaneously administered the AT2 receptor antagonist PD123319 (1 mg/kg/day) to adult male rats for two weeks via osmotic minipumps. We also studied the content of pituitary adrenocorticotropic hormone and vasopressin, representative of hypothalamic–pituitary–adrenal axis activation, and the tyrosine hydroxylase gene expression in the locus coeruleus as a measure of central norepinephrine function. We found significant decreases in AT2 receptor binding in brain areas inside the blood brain barrier, the inferior olive and the locus coeruleus. AT2 receptor blockade increased AT1 receptor binding and mRNA expression not only in the subfornical organ and the median eminence, situated outside the blood brain barrier, but also in the hypothalamic paraventricular nucleus, located inside the blood brain barrier. These changes paralleled decreased expression of tyrosine hydroxylase mRNA in the locus coeruleus and decreased pituitary adrenocorticotropic and vasopressin content. Our results demonstrate that sustained peripheral administration of an AT2 antagonist decreases binding to brain AT2 receptors, indicating that this drug is a useful tool for the study of their central role. AT2 receptor activity inhibition up-regulates AT1 receptor expression in specific brain areas. Blockade of brain AT2 receptors is compatible with enhanced hypothalamic–pituitary–adrenal axis and decreased central sympathetic system activity.
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影响因子：
64.8
作者：
ICHIKI, T;LABOSKY, PA;INAGAMI, T
通讯作者：
INAGAMI, T
影响因子：
3.4
作者：
Kerr, DS;Bevilaqua, LRM;Cammarota, M
通讯作者：
Cammarota, M
影响因子：
2.9
作者：
HOGARTY, DC;SPEAKMAN, EA;PHILLIPS, MI
通讯作者：
PHILLIPS, MI
DOI：
10.1073/pnas.82.2.617
发表时间：
1985-01-01
影响因子：
11.1
作者：
GRIMA, B;LAMOUROUX, A;MALLET, J
通讯作者：
MALLET, J
影响因子：
4.1
作者：
Armando, I;Terrón, JA;Saavedra, JM
通讯作者：
Saavedra, JM