Blockade of central orexin 2 receptors reduces arterial pressure in spontaneously hypertensive rats
Blockade of central orexin 2 receptors reduces arterial pressure in spontaneously hypertensive rats
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DOI：
10.1113/expphysiol.2013.072298
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发表时间：
2013-07-01
影响因子：
2.7
通讯作者：
Hwang, Ling-Ling
中科院分区：
文献类型：
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作者：
Lee, Yen-Hsien;Dai, Yu-Wen E.;Hwang, Ling-Ling
新发现中心点本研究的中心问题是什么？中枢食欲素能活动参与心血管稳态的紧张性和阶段性控制。在自发性高血压大鼠（SHR）中，中枢食欲素能活性升高在维持高血压中的潜在作用尚未被探索。中心点什么是主要的发现，它的重要性是什么？我们发现，中枢或头端腹外侧延髓阻断食欲素2受体可显著降低SHR的动脉压，但对Wistar-Kyoto大鼠没有影响。这项研究证实了食欲素2受体在维持SHR高血压中的一个先前未被认识的作用。食欲素可升高动脉压和交感神经活性，并参与心血管稳态的紧张性和阶段性控制。我们假设中枢食欲素能活性升高有助于维持自发性高血压大鼠（SHR）的高血压。我们通过抑制SHR和Wistar-Kyoto大鼠（WKYs）的中枢食欲素能活性来验证这一假设，这些大鼠具有针对食欲素1（OX 1 R）和2受体（OX 2 R）的特异性拮抗剂或抗体。脑室内给予OX 1 R拮抗剂SB-334867（30和100 nmol），在SHR和WKY中未诱导平均动脉压（MAP）和心率（HR）发生显著变化，但在100 nmol时降低了WKY的HR。相比之下，OX 2 R拮抗剂TCS-OX 2 -29（3-30 nmol）在SHR中诱导MAP和HR的长期降低（30 nmol时为21 +/- 3 mmHg和22 +/- 2次心跳min-1），但在WKY中则不然。侧脑室注射抗OX 2 R IgG可显著降低SHR的MAP和HR，而抗OX 1 R IgG或非免疫山羊IgG则无此作用。三种IgG均不影响WKY的MAP或HR。SHR延髓头端腹外侧区（RVLM）的OX 2 R蛋白水平低于WKY，而下丘脑室旁核、背内侧-穹窿周围区和孤束尾侧核的OX 2 R蛋白水平在SHR和WKY之间无差异。在这四个区域中的OX 1 R蛋白水平在SHR和WKY之间没有差异。将TCS-OX 2 -29（50 pmol）注射到RVLM中，在SHR中产生比WKY中更大的MAP降低。我们的结论是，升高的OX 2 R介导的活动在大脑中，特别是在RVLM，可能有助于高血压的SHR。
New Findings center dot What is the central question of this study? Central orexinergic activity is involved in tonic and phasic control of cardiovascular homeostasis. A potential role for elevated central orexinergic activity in the maintenance of hypertension in spontaneously hypertensive rats (SHRs) has not previously been explored. center dot What is the main finding and what is its importance? We show that central or intra-rostral ventrolateral medulla blockade of orexin 2 receptors produces a significant reduction of arterial pressure in SHRs, but not Wistar-Kyoto rats. This study demonstrates a previously unrecognized role of orexin 2 receptors in maintaining hypertension in SHRs. Orexins can raise arterial pressure and sympathetic activity and are involved in tonic and phasic control of cardiovascular homeostasis. We hypothesized that elevated central orexinergic activity contributes to the maintenance of hypertension in spontaneously hypertensive rats (SHRs). We examined this hypothesis by suppressing central orexinergic activity in SHRs and Wistar-Kyoto rats (WKYs) with specific antagonists or antibodies against orexin 1 (OX1R) and 2 receptors (OX2R). Intracerebroventricular administration of an OX1R antagonist, SB-334867 (30 and 100 nmol), induced no significant change in mean arterial pressure (MAP) and heart rate (HR) in SHRs and WKYs except that at 100 nmol it reduced HR in WKYs. In contrast, an OX2R antagonist, TCS-OX2-29 (3-30 nmol) induced long-lasting reductions of MAP and HR in SHRs (21 +/- 3 mmHg and 22 +/- 2 beats min-1 at 30 nmol), but not in WKYs. Intracerebroventricular anti-OX2R IgG, but not anti-OX1R IgG or non-immune goat IgG, significantly lowered MAP and HR in SHRs. None of the three IgGs affected MAP or HR in WKYs. The OX2R protein level in the rostral ventrolateral medulla (RVLM) was lower in SHRs than in WKYs, whereas no differences were found between SHRs and WKYs in the paraventricular hypothalamic nucleus, dorsomedial-perifornical hypothalamic area or caudal nucleus tractus solitarii. The OX1R protein levels in these four regions did not differ between SHRs and WKYs. Injection of TCS-OX2-29 (50 pmol) into the RVLM produced a larger reduction of MAP in SHRs than in WKYs. We conclude that elevated OX2R-mediated activity in the brain, especially in the RVLM, may contribute to hypertension in SHRs.