Department of Physiology and Pathophysiology, Shanghai Medical College of Fudan University, Shanghai, China.
PLoS One. 2013 Jul 26;8(7):e69840. doi: 10.1371/journal.pone.0069840. Print 2013.
Hypocretin/orexin-producing neurons, located in the perifornical region of the lateral hypothalamus area (LHA) and projecting to the brain sites of rostral ventrolateral medulla (RVLM), involve in the increase of sympathetic activity, thereby regulating cardiovascular function. The current study was designed to test the hypothesis that the central orexin-A (OXA) could be involved in the cardiovascular dysfunction of acute myocardial infarction (AMI) by releasing NAD(P)H oxidase-derived superoxide anion (O2 (-)) generation in RVLM, AMI rat model established by ligating the left anterior descending (LAD) coronary artery to induce manifestation of cardiac dysfunction, monitored by the indicators as heart rate (HR), heart rate variability (HRV), mean arterial pressure (MAP) and left intraventricular pressure. The results showed that the expressions of OXA in LHA and orexin 1 receptor (OX1R) increased in RVLM of AMI rats. The double immunofluorescent staining indicated that OX1R positive cells and NAD(P)H oxidative subunit gp91phox or p47phox-immunoreactive (IR) cells were co-localized in RVLM. Microinjection of OXA into the cerebral ventricle significantly increased O2 (-) production and mRNA expression of NAD(P)H oxidase subunits when compared with aCSF-treated ones. Exogenous OXA administration in RVLM produced pressor and tachycardiac effects. Furthermore, the antagonist of OX1R and OX2R (SB-408124 and TCS OX2 29, respectively) or apocynin (APO), an inhibitor of NAD(P)H oxidase, partly abolished those cardiovascular responses of OXA. HRV power spectral analysis showed that exogenous OXA led to decreased HF component of HRV and increased LF/HF ratio in comparison with aCSF, which suggested that OXA might be related to sympathovagal imbalance. As indicated by the results, OXA might participate in the central regulation of cardiovascular activities by disturbing the sympathovagal balance in AMI, which could be explained by the possibility that OXR and NAD(P)H-derived O2 (-) in RVLM mediates OXA-induced cardiovascular responses.
下丘脑外侧区（LHA）穹隆周围区的下丘脑外侧区（LHA）和投射到延髓头端腹外侧区（RVLM）的脑部位的下丘脑外侧区（LHA）中的下丘脑外侧区（LHA）产生的下丘脑外侧区（LHA），涉及交感活动的增加，从而调节心血管功能。本研究旨在通过在 RVLM 中释放 NAD（P）H 氧化酶衍生的超氧阴离子（O2（-））生成来测试中枢阿片样物质-A（OXA）可能通过释放 NAD（P）H 氧化酶衍生的超氧阴离子（O2（-））生成来参与急性心肌梗死（AMI）心血管功能障碍的假说，通过结扎左前降支冠状动脉（LAD）来建立 AMI 大鼠模型，从而诱发心脏功能障碍的表现，通过心率（HR）、心率变异性（HRV）、平均动脉压（MAP）和左室内压等指标进行监测。结果表明，AMI 大鼠 RVLM 中 LHA 和阿片样物质 1 受体（OX1R）的 OXA 表达增加。双免疫荧光染色表明，OX1R 阳性细胞与 NAD（P）H 氧化亚单位 gp91phox 或 p47phox-免疫反应性（IR）细胞在 RVLM 中存在共定位。与 aCSF 处理组相比，脑室注射 OXA 可显著增加 O2（-）产生和 NAD（P）H 氧化酶亚单位的 mRNA 表达。RVLM 中给予外源性 OXA 可产生升压和心动过速作用。此外，OX1R 和 OX2R 的拮抗剂（分别为 SB-408124 和 TCS OX2 29）或 APO（NAD（P）H 氧化酶抑制剂）部分消除了 OXA 的这些心血管反应。HRV 功率谱分析表明，与 aCSF 相比，外源性 OXA 导致 HRV 的 HF 成分减少和 LF/HF 比值增加，这表明 OXA 可能与交感神经迷走神经平衡有关。结果表明，OXA 可能通过扰乱 AMI 中心血管活动的交感神经迷走神经平衡参与心血管活动的中枢调节，这可以通过 RVLM 中的 OXR 和 NAD（P）H 衍生的 O2（-）介导 OXA 诱导的心血管反应的可能性来解释。
