Adjuvant potential of angiotensin-(1-7) in attenuating organ injury in rats with endotoxemia

[Speaker] Cheng-Ming Tsao:1
[Co-author] Mei-Hui Liao:2, Chin-Chen Wu:2
1:Department of Anesthesiology, National Yang-Ming University, Taiwan, 2:Department of Pharmacology, National Defense Medical Center, Taiwan

Background: Sepsis is a systemic inflammatory reaction that may lead to multiple organ damage, shock and death. The renin-angiotensin system consists of two opposing axes; the 'classical axis' mediated primarily by angiotensin II (Ang II), and the 'alternative axis' mediated mainly by angiotensin-(1-7) (Ang-(1-7)). Ang-(1-7), a counter-regulatory mediator of Ang II, appears to be protective against cardiovascular disease. In addition, Ang-(1-7) has been proposed to improve acute lung injury and fibrosis induced by endotoxin. However, its effect on multiple organ injury induced by sepsis remains unclear. Therefore, this study was to evaluate the Ang-(1-7) effect on the development of multiple organ dysfunction in endotoxemic rats and to explore its mechanisms.
Methods: Endotoxemia was induced by an intravenous administration of lipopolysaccharide (LPS, 10 mg/kg) in male Wistar rats. Then, the animals were randomly assigned to receive an intravenous infusion of Ang-(1-7) (2 mg/kg for 3 h) or an equivalent volume of vehicle (0.9% saline) solution after LPS administration. All hemodynamic and biochemical parameters were measured during the 6-hour observation.
Results: Endotoxemia induced hypotension, low blood glucose, as well as elevated serum levels of lactate dehydrogenase (LDH), creatinine, alanine aminotransferase (ALT), interleukin-6 and nitrate/nitrite in rats at 6 hours after LPS administration. However, Ang-(1-7) attenuated these worsened hemodynamic and biochemical parameters induced by endotoxemia. In addition, Ang-(1-7) attenuated the LPS-induced raised iNOS and decreased IkB expressions in livers.
Conclusions: Ang-(1-7) prevented circulatory failure and attenuated multiple organ dysfunction in endotoxemic rats induced by LPS. These beneficial effects of Ang-(1-7) may be attributed to its anti-inflammation by reducing interleukin-6 and nitrate/nitrite levels. Therefore, Ang-(1-7) could be a potential therapeutic adjuvant in the early sepsis.

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