Angiotensin II type 1 receptor antagonist improves the prognosis in rats displaying liver cirrhosis induced by a choline-deficient diet.
BACKGROUND
Angiotensin II type 1 receptor (AT1) antagonists are known to suppress TGFbeta and lipid peroxidation. An experimental rat model made by feeding rats a choline-deficient diet (CDD) showed severe steatosis, fibrosis and infiltration of inflammatory cells in the liver resembling nonalcoholic steatohepatitis (NASH). NASH causes fibrosis by lipid peroxidation. In this study, we assess whether AT1 antagonists and angiotensin II type 2 receptor (AT2) antagonists can suppress the hepatic fibrosis and lipid peroxidation in CDD rats that lead to the development of NASH.


METHODS
Both study groups received subcutaneously aqueous solutions of AT2 antagonist (PD123319 - 1 mg/kg/day) and AT1 antagonist (L158809 - 1 mg/kg/day), respectively, 6 times per week. On day 90, some rats (5 /group) were sacrificed by excision of the liver under anesthesia, in order to assess the hepatic hydroxyproline (HP), malondialdehyde (MDA), total glutathione, superoxide dismutase (SOD) activity and TGFbeta-1. The remaining rats were maintained to observe the survival rate.


RESULTS
All CDD rats developed liver cirrhosis. However, the tissue TGF and HP decreased in AT1 antagonist group in comparison with the other two groups. All groups of CDD rats showed strong adipose hyperoxidation. The AT1 antagonist group demonstrated a markedly improved survival rate in comparison to the other two groups.


CONCLUSIONS
Hepatic fibrosis progression in the AT1 antagonist group was slower than that in the other groups. This observation suggests that AT1 antagonists delayed the progression of liver failure, which thus led to an improved survival rate.
Iwata
Kaoru
K
Department of Gastroenterology and Medicine, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Johan-ku, Fukuoka City 814-0180, Japan. iwata-k@fukuoka-u.ac.jp
Sohda
Tetsuro
T
Irie
Makoto
M
Takeyama
Yasuaki
Y
Anan
Akira
A
Shakado
Satoshi
S
Sakisaka
Shotaro
S
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D002794:Choline; D004195:Disease Models, Animal; D007093:Imidazoles / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D013777:Tetrazoles / Q000627:therapeutic use*; D014662:Vasoconstrictor Agents / Q000627:therapeutic use
D057912:Angiotensin II Type 2 Receptor Blockers; D000959:Antihypertensive Agents; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C073402:PD 123319; C070967:L 158809; D002794:Choline