Excessive leukotriene B4 in nucleus tractus solitarii is prohypertensive in spontaneously hypertensive rats.
Excessive leukotriene B4 in nucleus tractus solitarii is prohypertensive in spontaneously hypertensive rats.
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DOI：
10.1161/hypertensionaha.112.192252
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Paton JF
中科院分区：
文献类型：
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作者：
Waki H;Hendy EB;Hindmarch CC;Gouraud S;Toward M;Kasparov S;Murphy D;Paton JF
脑干微血管内的炎症与慢性心血管疾病有关。我们发现，在 SHR 的 NTS 中，参与花生四烯酸 (AA) - 白三烯 B4 (LTB4) 生产的几种酶的表达发生了改变。 LTB4 由 AA 通过 5-脂氧合酶 (5LOX) 产生，是一种有效的白细胞趋化剂。与 Wistar-Kyoto 大鼠 (WKY) 相比，降解白三烯 B4 (LTB4) 的白三烯 B4-12-羟基脱氢酶 (LTB4-12-HD) 下调。定量 RT-PCR 显示，与年龄匹配的 WKY 大鼠 (n=6) 相比，成年 SHR 和高血压前期 (PH) SHR 的 NTS 中 LTB4-12-HD 分别降低了 63% 和 58%。 5LOX 基因表达在 SHR 的 NTS 中上调（~50%；n=6）。 SHR 的 NTS 中 LTB4 水平增加（17%；n=10，p<0.05）。 LTB4 受体 BLT1（但不是 BLT2）在 NTS 中的星形胶质细胞上表达，但在神经元或血管上不表达。将 LTB4 显微注射到 WKY 大鼠的 NTS 中可增加白细胞粘附和动脉压，持续 4 天以上（峰值：+15 mmHg；P<0.01）。相反，阻断 NTS BLT1 受体可降低 SHR 大鼠的血压（峰值：-13 mmHg；P<0.05），但不会降低 WKY 大鼠的血压。因此，SHR NTS 中过量的 LTB4 可能是由于 5LOX 上调和 LTB412-HD 下调所致，可诱发炎症。由于NTS BLT1受体的阻断降低了SHR中的动脉压，因此它们的内源性活性可能导致该啮齿动物模型的高血压状态。因此，脑干的炎症反应与神经源性高血压有因果关系。
Inflammation within the brainstem microvasculature has been associated with chronic cardiovascular diseases. We found that the expression of several enzymes involved in arachidonic acid (AA) - leukotriene B4 (LTB4) production was altered in NTS of SHR. LTB4 produced from AA by 5-lipoxygenase (5LOX) is a potent chemoattractant of leukocytes. Leukotriene B4-12-hydroxydehydrogenase (LTB4-12-HD), which degrades leukotriene B4 (LTB4), was down-regulated compared to Wistar-Kyoto rats (WKY). Quantitative RT-PCR revealed that LTB4-12-HD was reduced by 63 and 58% in the NTS of adult SHR and pre-hypertensive (PH) SHR respectively, compared to age-matched WKY rats (n=6). 5LOX gene expression was up-regulated in the NTS of SHR (~50%; n=6). LTB4 levels were increased in the NTS of the SHR (17%; n=10, p<0.05). LTB4 receptors BLT1 (but not BLT2), were expressed on astroglia in the NTS but not neurons or vessels. Microinjection of LTB4 into the NTS of WKY rats increased both leukocyte adherence and arterial pressure for over 4 days (peak: +15 mmHg; P<0.01). In contrast, blockade of NTS BLT1 receptors lowered blood pressure in the SHR (peak: -13 mmHg; P<0.05) but not WKY rats. Thus, excessive amounts of LTB4 in NTS of SHR possibly as a result of up-regulation of 5LOX and down regulation of LTB412-HD, can induce inflammation. Since blockade of NTS BLT1 receptors lowered arterial pressure in the SHR their endogenous activity may contribute to the hypertensive state of this rodent model. Thus, inflammatory reactions in the brainstem are causally associated with neurogenic hypertension.