Prostacyclin inhibition by indomethacin aggravates hepatic damage and encephalopathy in rats with thioacetamide-induced fulminant hepatic failure.
OBJECTIVE
Vasodilatation and increased capillary permeability have been proposed to be involved in the pathogenesis of acute and chronic form of hepatic encephalopathy. Prostacyclin (PGI2) and nitric oxide (NO) are important contributors to hyperdynamic circulation in portal hypertensive states. Our previous study showed that chronic inhibition of NO had detrimental effects on the severity of encephalopathy in thioacetamide (TAA)-treated rats due to aggravation of liver damage. To date, there are no detailed data concerning the effects of PGI2 inhibition on the severity of hepatic encephalopathy during fulminant hepatic failure.


METHODS
Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/(kg.d) for 3 d. Rats were divided into two groups to receive intraperitoneal injection of indomethacin (5 mg/(kg.d), n = 20) or normal saline (N/S, n = 20) for 5 d, starting 2 d before TAA administration. Severity of encephalopathy was assessed by the counts of motor activity measured with Opto-Varimex animal activity meter. Plasma tumor necrosis factor-alpha (TNF-alpha, an index of liver injury) and 6-keto-PGF(1alpha) (a metabolite of PGI2) levels were measured by enzyme-linked immunosorbent assay.


RESULTS
As compared with N/S-treated rats, the mortality rate was significantly higher in rats receiving indomethacin (20% vs 5%, P<0.01). Inhibition of PGI2 created detrimental effects on total movement counts (indomethacin vs N/S: 438+/-102 vs 841+/-145 counts/30 min, P<0.05). Rats treated with indomethacin had significant higher plasma levels of TNF-alpha (indomethacin vs N/S: 22+/-5 vs 10+/-1 pg/mL, P<0.05) and lower plasma levels of 6-keto-PGF1alpha (P<0.001), but not total bilirubin or creatinine (P>0.05), as compared with rats treated with N/S.


CONCLUSIONS
Chronic indomethacin administration has detrimental effects on the severity of encephalopathy in TAA-treated rats and this phenomenon may be attributed to the aggravation of liver injury. This study suggests that PGI2 may provide a protective role in the development of fulminant hepatic failure.
Chu
Chi-Jen
CJ
Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, China.
Hsiao
Ching-Chin
CC
Wang
Teh-Fang
TF
Chan
Cho-Yu
CY
Lee
Fa-Yauh
FY
Chang
Full-Young
FY
Chen
Yi-Chou
YC
Huang
Hui-Chun
HC
Wang
Sun-Sang
SS
Lee
Shou-Dong
SD
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D007213:Indomethacin / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced / Q000473:pathology*; D009043:Motor Activity / Q000187:drug effects; D044062:Prostaglandins I / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013853:Thioacetamide / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D044062:Prostaglandins I; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D015121:6-Ketoprostaglandin F1 alpha; D003404:Creatinine; D001663:Bilirubin; D007213:Indomethacin