title: Centrally administered lipopolysaccharide elicits sympathetic excitation via NAD(P)H oxidase-dependent mitogen-activated protein kinase signaling.
abstract: OBJECTIVE
  The mechanisms by which inflammation activates sympathetic drive in heart failure and hypertension remain ill-defined. In this study, an intracerebroventricular injection of lipopolysaccharide (LPS) was used to induce the expression of cytokines and other inflammatory mediators in the brain, in the absence of other excitatory mediators, and the downstream signaling pathways leading to sympathetic activation were examined using intracerebroventricular injections of blocking or inhibiting agents.
  
  
  RESULTS
  In anesthetized rats, intracerebroventricular injection of LPS (5 microg) increased (P < 0.05) renal sympathetic nerve activity, blood pressure and heart rate. LPS increased (P < 0.05) hypothalamic mRNA for NAD(P)H oxidase subunits p47 and gp91, NAD(P)H oxidase-dependent superoxide generation, hypothalamic mRNA for tumor necrosis factor-alpha, cyclooxygenase-2 and cerebrospinal fluid levels of tumor necrosis factor-alpha and prostaglandin E2. In the paraventricular nucleus of hypothalamus, dihydroethidium staining for superoxide expression and c-Fos activity (indicating neuronal excitation) increased. The superoxide scavenger tempol significantly (P < 0.05) diminished the expression of inflammatory mediators, as well as superoxide expression and neuronal excitation in paraventricular nucleus. SB203580 (p38 mitogen-activated protein kinase inhibitor) also reduced the expression of inflammatory mediators in hypothalamus and cerebrospinal fluid. Tempol, apocynin [NAD(P)H oxidase inhibitor], SB203580 and NS398 (cyclooxygenase-2 inhibitor) all reduced cerebrospinal fluid prostaglandin E2 and the sympathoexcitatory response to LPS. LPS also increased angiotensin II type 1 receptor mRNA, a response blocked by apocynin and tempol but not by SB203580.
  
  
  CONCLUSIONS
  These findings suggest that central inflammation in pathophysiological conditions activates the sympathetic nervous system via NAD(P)H oxidase and p38 mitogen-activated protein kinase-dependent synthesis of prostaglandin E2.
authors.affiliation: Medical Service, Department of Veterans Affairs Medical Center, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa52242, USA.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Shun-Guang
authors.initials: SG
authors.lastname: Wei
authors.forename: Robert B
authors.initials: RB
authors.lastname: Felder
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000134:cerebrospinal fluid / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000502:physiology* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D000098:Acetophenones; D003497:Cyclic N-Oxides; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D044140:Receptor, Angiotensin, Type 1; D013113:Spin Labels; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C056165:acetovanillone; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases; C001803:tempol