Central angiotensin-(1–7) attenuates systemic inflammation via activation of sympathetic signaling in endotoxemic rats

• Published in: Brain, behavior, and immunity Vol. 88; pp. 606 - 618
• Main Authors: Passaglia, Patrícia, de Lima Faim, Felipe, Batalhão, Marcelo Eduardo, Bendhack, Lusiane Maria, Antunes-Rodrigues, José, Ulloa, Luis, Kanashiro, Alexandre, Carnio, Evelin Capellari
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.08.2020
• Subjects: Angiotensin I; Angiotensin-(1–7); Animals; Endotoxemia - drug therapy; Hypotension; Inflammatory reflex; Lipopolysaccharide; Male; Neuroimmunomodulation; Peptide Fragments; Rats; Rats, Wistar; Sympathetic nervous system; Vascular reactivity; Angiotensin-(1–7); Vascular reactivity; Inflammatory reflex; Lipopolysaccharide; Sympathetic nervous system; Neuroimmunomodulation; Hypotension
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2020.04.059

•Central administration of Ang-(1–7) decreases serum, splenic, and hepatic TNF and NO levels of endotoxemic rats.•Central administration of Ang-(1–7) increases serum, splenic, and hepatic IL-10 levels of endotoxemic rats.•Central administration of Ang-(1–7) tampers systemic inflammation in endotoxemia via sympathetic activation.•Central Ang-(1–7) injection prevents hypotension and vascular hyporesponsiveness by inhibiting PVAT-derived NO production. Angiotensin-(1–7) [Ang-(1–7)] is an angiotensin-derived neuropeptide with potential anti-hypertensive and anti-inflammatory properties. However, a possible action of Ang-(1–7) in neuroimmune interactions to regulate inflammatory response has not been explored. Thus, the aim of this study was to determine whether the intracerebroventricular (i.c.v.) administration of Ang-(1–7) can modulate systemic inflammation via sympathetic efferent circuits. Wistar male rats received systemic administration of lipopolysaccharide (LPS) (1.5 mg/Kg). Ang-(1–7) (0.3 nmol in 2 µL) promoted the release of splenic norepinephrine and attenuated tumor necrosis factor (TNF) and nitric oxide (NO), but increased interleukin-10 (IL-10), levels in the serum, spleen, and liver in endotoxemic rats. Furthermore, 6-hydroxydopamine-induced chemical sympathectomy (100 mg/Kg, intravenous) or i.c.v. administration of Mas receptor antagonist A779 (3 nmol in 2 µL) abolished the anti-inflammatory effects of central Ang-(1–7) injection. Moreover, this treatment did not alter the plasmatic LPS-induced corticosterone and vasopressin. The administration of Ang-(1–7) reverted the low resistance in response to catecholamines of rings of thoracic aorta isolated from endotoxemic rats, treated or not, with this peptide by a mechanism dependent on the regulation of NO released from perivascular adipose tissue. Together, our results indicate that Ang-(1–7) regulates systemic inflammation and vascular hyporesponsiveness in endotoxemia via activation of a central Mas receptors/sympathetic circuits/norepinephrine axis and provide novel mechanistic insights into the anti-inflammatory Ang-(1–7) properties.