Abstract
Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor is a counter-regulatory axis that counteracts detrimental renin-angiotensin system (RAS) effects, especially regarding systemic inflammation, vasopressin (AVP) release, and hypothalamic-pituitary-adrenal (HPA) activation. However, it is not completely understood whether this system may control centrally or systemically the late phase of systemic inflammation. Thus, the aim of this study was to determine whether intracerebroventricular (i.c.v.) administration of Ang-(1-7) can modulate systemic inflammation through the activation of humoral pathways in late phase of endotoxemia. Endotoxemia was induced by systemic injection of lipopolysaccharide (LPS) (1.5 mg/kg, i.v.) in Wistar rats. Ang-(1-7) (0.3 nmol in 2 µL) promoted the release of AVP and attenuated interleukin-6 (IL-6) and nitric oxide (NO) levels but increased interleukin-10 (IL-10) in the serum of the endotoxemic rats. The central administration of Mas receptor antagonist A779 (3 nmol in 2 µL, i.c.v.) abolished these anti-inflammatory effects in endotoxemic rats. Furthermore, Ang-(1-7) applied centrally restored mean arterial blood pressure (MABP) without affecting heart rate (HR) and prevented vascular hyporesponsiveness to norepinephrine (NE) and AVP in animals that received LPS. Together, our results indicate that Ang-(1-7) applied centrally promotes a systemic anti-inflammatory effect through the central Mas receptor and activation of the humoral pathway mediated by AVP.
Highlights
Introduction nal affiliationsEndotoxemia, a classical model of systemic inflammation, is characterized by the amplified production of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) by immune cells and vascular endothelium [1].The overproduction of inflammatory mediators has been involved in hypotension, hyporesponsiveness to vasoactive agents, and alterations in the hypothalamic-neurohypophyseal axis during systemic inflammation [2,3]
The main findings obtained in the present study were that Ang-(1-7) applied centrally prevented vascular hyporesponsiveness and hypotension by improving a marked decrease in vasopressin (AVP) impairment and systemic inflammation in endotoxemic rats
Mas receptor located in the central nervous system (CNS), and it appears to be dependent on humoral pathway mediated by AVP
Summary
Introduction nal affiliationsEndotoxemia, a classical model of systemic inflammation, is characterized by the amplified production of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) by immune cells and vascular endothelium [1].The overproduction of inflammatory mediators has been involved in hypotension, hyporesponsiveness to vasoactive agents, and alterations in the hypothalamic-neurohypophyseal axis during systemic inflammation [2,3]. Other ways to control the hypothalamic-neurohypophyseal axis, including osmolality, hypotensive stimulus, and activation of the renin-angiotensin system (RAS) [12]. Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor, the counter-regulatory axis of the RAS, exerts beneficial effects against the pathophysiologic conditions [13,14]. In addition to neuroendocrine actions, the activation of Ang-(1-7)/Mas receptor axis attenuates inflammation in several experimental models, including polymicrobial sepsis and cerebral ischemia [18,19,20]. In our most recent study, it has been shown that central administration of Ang-(1-7) prevented LPS-induced vascular hyporesponsiveness and hypotension due to an anti-inflammatory effect via activation of sympathetic signaling during the initial phase of endotoxemia [21].
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