Antagonist of the type-1 ANG II receptor prevents against LPS-induced septic shock in rats.
OBJECTIVE
Type 1 angiotensin II (AT1) receptor antagonists have anti-inflammatory effects in vitro and in patients. The purpose of this study was to investigate whether losartan (LOS), an AT1 receptor antagonist, reduces lung damage by inhibiting the induction of high mobility group box 1 (HMGB1) protein and cytokines by lipopolysaccharide (LPS; serotype: O127:B8) in a rat model.


METHODS
We used male Wistar rats. Control group rats received a 0.9% NaCl solution. The LOS + LPS group rats received LOS (50 mg kg(-1)) before LPS (7.5 mg kg(-1)) administration. LPS group rats received injection of LPS (7.5 mg kg(-1)).


RESULTS
We performed immunohistochemistry, ELISA, and western blot analysis to examine the suppressive effects of LOS on LPS-induced cytokine induction. Plasma concentrations of cytokines (IL-6 and TNF-alpha) and HMGB1 (p < 0.05) were markedly reduced in the LOS + LPS group compared to the LPS group. LOS also inhibited the LPS-mediated decrease in angiotensin-converting enzyme 2 (ACE2) activity (p < 0.05). Immunohistochemical analysis revealed positive staining for ACE2 in lungs from both control and LOS + LPS groups. The intensity and degree of ACE2 labeling in lung tissue sections from the LPS group were markedly reduced compared to the control and LOS + LPS groups (p < 0.05). Additionally, RAW264.7 murine macrophages were stimulated with LPS, with or without simultaneous LOS treatment, resulting in inhibition of IkappaB phosphorylation.


CONCLUSIONS
Treatment with LOS improved lung injury in an endotoxin shock model system by an anti-inflammatory action that inhibits reduction of ACE2.
Hagiwara
Satoshi
S
Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, 1-1 Idaigaoka-Hasamamachi, Yufu, Oita 879-5593, Japan. saku@med.oita-u.ac.jp
Iwasaka
Hideo
H
Hidaka
Seigo
S
Hasegawa
Akira
A
Koga
Hironori
H
Noguchi
Takayuki
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000097:blood / Q000187:drug effects; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D019808:Losartan / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D055370:Lung Injury / Q000188:drug therapy; D008297:Male; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000139:chemically induced* / Q000517:prevention & control*
D047228:Angiotensin II Type 1 Receptor Blockers; D016207:Cytokines; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D019808:Losartan