title: Ghrelin inhibits sympathetic nervous activity in sepsis.
abstract: Our previous studies have shown that norepinephrine (NE) upregulates proinflammatory cytokines by activating alpha(2)-adrenoceptor. Therefore, modulation of the sympathetic nervous system represents a novel treatment for sepsis. We have also shown that a novel stomach-derived peptide, ghrelin, is downregulated in sepsis and that its intravenous administration decreases proinflammatory cytokines and mitigates organ injury. However, it remains unknown whether ghrelin inhibits sympathetic activity through central ghrelin receptors [i.e., growth hormone secretagogue receptor 1a (GHSR-la)] in sepsis. To study this, sepsis was induced in male rats by cecal ligation and puncture (CLP). Ghrelin was administered through intravenous or intracerebroventricular injection 30 min before CLP. Our results showed that intravenous administration of ghrelin significantly reduced the elevated NE and TNF-alpha levels at 2 h after CLP. NE administration partially blocked the inhibitory effect of ghrelin on TNF-alpha in sepsis. GHSR-la inhibition by the administration of a GHSR-la antagonist, [d-Arg(1),d-Phe(5), d-Trp(7,9),Leu(11)]substance P, significantly increased both NE and TNF-alpha levels even in normal animals. Markedly elevated circulating levels of NE 2 h after CLP were also significantly decreased by intracerebroventricular administration of ghrelin. Ghrelin's inhibitory effect on NE release was completely blocked by intracerebroventricular injection of the GHSR-1a antagonist or a neuropeptide Y (NPY)/Y(1) receptor antagonist. However, ghrelin's downregulatory effect on TNF-alpha release was only partially diminished by these agents. Thus ghrelin has sympathoinhibitory properties that are mediated by central ghrelin receptors involving a NPY/Y1 receptor-dependent pathway. Ghrelin's inhibitory effect on TNF-alpha production in sepsis is partially because of its modulation of the overstimulated sympathetic nerve activation.
authors.affiliation: The Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030, USA.
authors.forename: Rongqian
authors.initials: R
authors.lastname: Wu
authors.forename: Mian
authors.initials: M
authors.lastname: Zhou
authors.forename: Padmalaya
authors.initials: P
authors.lastname: Das
authors.forename: Weifeng
authors.initials: W
authors.lastname: Dong
authors.forename: Youxin
authors.initials: Y
authors.lastname: Ji
authors.forename: Derek
authors.initials: D
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Miksa
authors.forename: Fangming
authors.initials: F
authors.lastname: Zhang
authors.forename: Thanjavur S
authors.initials: TS
authors.lastname: Ravikumar
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D054439:Ghrelin / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D009638:Norepinephrine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000502:physiology; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000502:physiology; D018805:Sepsis / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C092926:BIBP 3226; D054439:Ghrelin; D054440:Receptors, Ghrelin; D017476:Receptors, Neuropeptide Y; D014409:Tumor Necrosis Factor-alpha; D013373:Substance P; D001120:Arginine; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-; D009638:Norepinephrine