Abstract
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.
Highlights
Studies have revealed that Hypocretin/orexin (OX)-producing neurons, located in the perifornical region of the lateral hypothalamus, project to brain sites important in behavioral [1,2], cardiovascular [3,4] and endocrine function [4,5]
In 1999, Shirasaka T et al reported that intracerebroventricular administration of high dose (3.0nmol) of OXA rapidly increased mean arterial pressure (MAP) and heart rate (HR) in conscious and anesthetized rats [12]
We employed acute myocardial infarction (AMI) rat models to test the central regulation of cardiovascular activities in rostral ventrolateral medulla (RVLM), and observed that the expression of OXA-IR neurons and the mRNA expression of PPO in AMI rats’ lateral hypothalamus area (LHA) were higher than that of the control group
Summary
Studies have revealed that Hypocretin/orexin (OX)-producing neurons, located in the perifornical region of the lateral hypothalamus, project to brain sites important in behavioral [1,2], cardiovascular [3,4] and endocrine function [4,5]. Orexinproducing neurons are localized to the lateral hypothalamic and perifornical nucleus, OX-containing nerve terminals and receptors are widely distributed throughout the brain, including the brainstem area that includes the RVLM [7,8,9]. They have many pharmacological effects in common, OXA and OXB present some actions unique to each other [10]. The data have indicated that RVLM, a key neural structure involved in mediating the sympathetic activity of OXA in the brain, plays an important role in regulating cardiovascular function
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