The effect of orexin-A on cardiac dysfunction mediated by NADPH oxidase-derived superoxide anion in ventrolateral medulla.
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.
Department of Physiology and Pathophysiology, Shanghai Medical College of Fudan University, Shanghai, China.
Jun
J
Chen
Chunmei
C
Xia
Jin
J
Wang
Meiyan
M
Jiang
Huanhuan
H
Zhang
Chengrong
C
Zhang
Minxia
M
Zhu
Linlin
L
Shen
Danian
D
Zhu
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006334:Heart Function Tests; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008026:Ligation; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins; D010671:Phenylurea Compounds / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism*
C572065:1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone; D000098:Acetophenones; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D010671:Phenylurea Compounds; D021122:Protein Subunits; D011725:Pyridines; C542397:SB 408124; D013481:Superoxides; C056165:acetovanillone; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1