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Role of central NO-cGMP pathway in vasopressin and oxytocin gene expression
Gabriela Ravanelli Oliveira-Pelegrin, Fábio Alves Aguila, Paulo José Basso, Maria José Alves Rocha ∗
Departamento de Morfologia, Estomatologia e Fisiologia,Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
Received 29 March 2010
Received in revised form 26 June 2010
Accepted 28 June 2010
Available online 16 July 2010
Soluble guanylate cyclase
Sepsis induces massiveproduction of inﬂammatory mediators, such as nitric oxide (NO), and causes
neuroendocrine and cardiovascular alterations. This study investigates the involvement of the central NOcGMP pathway in arginine vasopressin (AVP) and oxytocin (OXY) gene expression during sepsis induced
by cecal ligation and puncture (CLP). Male Wistar rats received an i.c.v. injection of ODQ (0.25 g/ L),
a selectiveinhibitor of the heme site of soluble guanylate cyclase, or of 1% dymethilsulfoxide (DMSO),
as vehicle. Thirty minutes after the injections, sepsis was induced by cecal ligation and puncture or the
animals were sham operated. The ODQ pre-treatment did not alter the progressive NO increase observed
after CLP. In the supraoptic nucleus (SON), this pretreatment increased the relative gene expressionratio of AVP and OXY in the initial phase of sepsis, but in the late phase, the gene expression of both
hormones was reduced. In the paraventricular nucleus (PVN), soluble guanylate cyclase inhibition caused
an even larger decrease in the relative gene expression ratio of AVP and OXY during sepsis. These results
are indicative of a role of the NO-cGMP pathway in hormonal synthesis in the SON andPVN of the
hypothalamus during polymicrobial sepsis.
© 2010 Elsevier Inc. All rights reserved.
Sepsis is the systemic response that results from a complex
interaction between host and infectious agents. The excessive
response to infection leads to a high production of inﬂammatory
mediators such as nitric oxide (NO) that is reported to affect autonomic and neuroendocrinefunctions during sepsis [6,19,23,26,28].
NO is a gaseous mediator synthesized by NO synthases (NOS)
from the semi-essential amino acid l-arginine [11,24,27]. In the
central nervous system, NO has been reported to participate
in the modulation of arginine vasopressin (AVP) and oxytocin
(OXY) secretion, showing either stimulatory or inhibitory effects
[5,6,14,39,40]. AVP and OXY arenonapeptides hormones synthesized in magnocellular neurons of the supraoptic (SON) and
paraventricular (PVN) nuclei of the hypothalamus [7,10]. Clinical and experimental sepsis studies have reported high AVP
plasma levels in the initial phase of sepsis, whereas in the late
phase, despite continued hypotension, the levels of these hormones are inappropriately low, contributing to vasodilatory shock[6,21,26,28,34]. As regards OXY secretion, similar patterns release
∗ Corresponding author at: Departamento de MEF – Faculdade de Odontologia
de Ribeirão Preto, USP, Avenida do Café s/n, Monte Alegre, CEP 14040-904 Ribeirão
Preto, SP, Brazil. Tel.: +55 16 3602 3974; fax: +55 16 3633 0999.
E-mail address: email@example.com (M.J.A. Rocha).
0196-9781/$ – see front matter © 2010 Elsevier Inc. Allrights reserved.
was observed during lipopolysaccharides-induced endotoxemia
[2,5,8,14]. The reasons underlying the relative deﬁcient secretion of
neurohypophyseal hormones during sepsis remain unclear [15,32].
One hypothesis suggests that hormonal synthesis is impaired due
to NO overproduction by inducible NOS (iNOS), which, is activated