Participation of iNOS-derived NO in hypothalamic activation and vasopressin release during polymicrobial sepsis.
Clinical and experimental studies with LPS injection have shown an increase in vasopressin (AVP) secretion in the early phase of severe sepsis, which is subsequently reduced despite persistent hypotension. The aim of this study was to evaluate the role of inducible nitric oxide synthase (iNOS)-derived NO in hypothalamic activation and in AVP release during severe sepsis induced by cecal ligation and puncture (CLP). Male Wistar rats received i.p. injections of aminoguanidine, an iNOS inhibitor, or saline 30 min before CLP or sham surgeries (controls). CLP led to increased plasma nitrate levels, protein leakage and hypotension and caused mortality of 80% by 24 h. Expression of c-fos in paraventricular (PVN), supraoptic (SON) and organum vasculosum of lamina terminalis (OVLT) nuclei, as well as plasma AVP concentration were increased at 6 h but reduced to basal levels 24 h after CLP. Aminoguanidine pre-treatment prevented the increase in plasma nitrate levels and hypotension in the first 6 h. It also reduced AVP secretion and hypothalamic c-fos expression. After 24 h, the pre-treatment reduced plasma nitrate levels, protein leakage and caused a partial recovery of c-fos expression in SON and OVLT but did not affect AVP release. Furthermore, mortality was reduced to 43%. We conclude that during the early phase of severe sepsis hypotension caused by the iNOS-derived NO is partially responsible for the hypothalamic activation and AVP release. In the late phase, however, the iNOS-derived NO prevents brain activation blunting AVP secretion contributing to hypotension, irreversible shock and animal death.
Corrêa
Pollyanna Barbosa Farias
PB
Departamento de Morfologia, Estomatologia e Fisiologia da Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Avenida do Café s/n, CEP 14049-900 Ribeirão Preto-SP, Brazil.
Pancoto
João Alexandre Trés
JA
de Oliveira-Pelegrin
Gabriela Ravanelli
GR
Cárnio
Evelin Capellari
EC
Rocha
Maria José Alves
MJ
D000818:Animals; D001424:Bacterial Infections / Q000150:complications; D001794:Blood Pressure; D004326:Drinking; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006146:Guanidines / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D009994:Osmolar Concentration; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism / Q000382:microbiology / Q000473:pathology* / Q000503:physiopathology; D013997:Time Factors; D014667:Vasopressins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006146:Guanidines; D016760:Proto-Oncogene Proteins c-fos; D014667:Vasopressins; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine