Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat.
Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat.
复制标题
DOI：
10.1161/hypertensionaha.114.04683
复制
发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Gourine AV
中科院分区：
文献类型：
--
作者：
Marina N;Ang R;Machhada A;Kasymov V;Karagiannis A;Hosford PS;Mosienko V;Teschemacher AG;Vihko P;Paton JF;Kasparov S;Gourine AV
补充数字内容可在正文中找到。系统性动脉高压以前被认为是中枢神经灌流/氧合受损时的一种代偿性疾病。延髓头端腹外侧区的主要交感兴奋性C1神经元(其激活增加交感冲动和动脉血压)对低氧高度敏感，但这种O2敏感性的机制尚不清楚。在这里，我们研究了自发性高血压大鼠脑干缺氧和全身动脉血压升高之间的可能机制。自发性高血压大鼠的脑干实质氧分压在相同的动脉血氧饱和度和全身动脉压水平下，比正常血压的大鼠低15≈ 汞。ATP受体拮抗剂MRS2179或糖原分解抑制剂1，4-二脱氧-1，4-亚氨基-d-阿拉伯糖醇可抑制缺氧诱导的延髓头端腹外侧神经元的激活，提示这些神经元对低PO2的敏感性是通过细胞外ATP和乳酸的作用而调节的。脑干缺氧引起乳酸和三磷酸腺苷的释放，从而在体外产生对C1神经元的兴奋，并在体内增加交感神经活性和动脉血压。病毒驱动的跨膜前列腺酸性磷酸酶高表达促进了延髓头端腹外侧区细胞外ATP的分解，导致自发性高血压大鼠的动脉血压显著降低(但在正常血压动物中不是)。这些结果提示，自发性高血压大鼠脑干实质氧分压降低可能与交感前环路内环境三磷酸腺苷和L-乳酸水平升高有关，从而导致中枢交感神经驱动增强，并伴随全身动脉压持续升高。
Supplemental Digital Content is available in the text. Systemic arterial hypertension has been previously suggested to develop as a compensatory condition when central nervous perfusion/oxygenation is compromised. Principal sympathoexcitatory C1 neurons of the rostral ventrolateral medulla oblongata (whose activation increases sympathetic drive and the arterial blood pressure) are highly sensitive to hypoxia, but the mechanisms of this O2 sensitivity remain unknown. Here, we investigated potential mechanisms linking brainstem hypoxia and high systemic arterial blood pressure in the spontaneously hypertensive rat. Brainstem parenchymal PO2 in the spontaneously hypertensive rat was found to be ≈15 mm Hg lower than in the normotensive Wistar rat at the same level of arterial oxygenation and systemic arterial blood pressure. Hypoxia-induced activation of rostral ventrolateral medulla oblongata neurons was suppressed in the presence of either an ATP receptor antagonist MRS2179 or a glycogenolysis inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol, suggesting that sensitivity of these neurons to low PO2 is mediated by actions of extracellular ATP and lactate. Brainstem hypoxia triggers release of lactate and ATP which produce excitation of C1 neurons in vitro and increases sympathetic nerve activity and arterial blood pressure in vivo. Facilitated breakdown of extracellular ATP in the rostral ventrolateral medulla oblongata by virally-driven overexpression of a potent ectonucleotidase transmembrane prostatic acid phosphatase results in a significant reduction in the arterial blood pressure in the spontaneously hypertensive rats (but not in normotensive animals). These results suggest that in the spontaneously hypertensive rat, lower PO2 of brainstem parenchyma may be associated with higher levels of ambient ATP and l-lactate within the presympathetic circuits, leading to increased central sympathetic drive and concomitant sustained increases in systemic arterial blood pressure.