The effect of a
thromboxane (Tx) A2 receptor antagonist,
ONO 3708, on
cholestasis and injury related to
ischemia and subsequent reperfusion (I-R) was investigated in the dog liver by assessing changes in
insulin and
glucagon metabolism. The left hepatic duct was ligated for 4 weeks to create a cholestatic lobe. Sixty-minute
ischemia was induced by Pringle's procedure.
ONO 3708 (200 micrograms/kg/min) was initiated 60 min before induction of
ischemia and continued throughout the experiment. The rate of
insulin metabolism was higher in the right noncholestatic lobe than in the left cholestatic lobe. There was no significant difference in the rate of
glucagon metabolism between the right and left lobes. After induction of I-R, the rate of
insulin metabolism, but not
glucagon metabolism, decreased. The
lipid peroxide level was higher and the
glutathione level was lower in the cholestatic lobe than in the noncholestatic lobe. There was no significant difference in the
alpha-tocopherol level between lobes. After induction of I-R, the
lipid peroxide level increased and the
alpha-tocopherol level decreased. There was no change in the
glutathione level. I-R accelerated the release of 6-keto-prostaglandin (PG) F1 alpha, a stable metabolite of PGI2, and of TxB2, a stable metabolite of TxA2, from the liver. After I-R,
cholestasis accelerated the release of TxB2, but not
6-keto-PGF1 alpha. I-R also increased the TxB2/
6-keto-PGF1 alpha ratio.
ONO 3708 reduced these metabolic changes in the
cholestasis and after I-R. These findings suggest that
ONO 3708 protects liver function, especially in the cholestatic lobe, from I-R-related injury by reducing peroxidation of
lipids and the TxA2/PGI2 ratio, which predicts cellular damage, and by increasing levels of
alpha-tocopherol and
glutathione.