The aim of the investigation was to explore whether ursodeoxycholate, a tertiary bile acid with potential for treatment of chronic cholestasis in cirrhotic liver disease, has the same physiological effects in cirrhotic as in normal rats. Furthermore, we wanted to investigate whether ductular proliferation, as it occurred in this situation, increases the bicarbonate stimulatory effect of ursodeoxycholate. Rats (n = 16) were rendered cirrhotic by continuous exposure to phenobarbital—carbon tetrachloride; untreated animals (n = 13) served as controls. In cirrhotic rats in vivo, ursodeoxycholate (20 μmoles/min/kg) stimulated bile salt secretion and bile flow less than in controls. Nevertheless, the increment in ursodeoxycholate-induced biliary bicarbonate—the bicarbonate stimulatory potency—was increased by 29% in cirrhotic animals (0.55 ± 0.08 mmol vs. 0.71 ± 0.11 mmol; p < 0.05). This finding could be related to ductular proliferation because the volume fraction of bile ductules, determined stereologically, increased from 0.3% ± 0.1% to 2.7% ± 0.6% in cirrhotic rats (p < 0.005). To explore further the behavior of ductules during ursodeoxycholate stimulation, we carried out experiments in the in situ perfused rat liver. In the portally perfused organ, replacement of bicarbonate by tricine-acetate abolished ursodeoxycholate-induced hypercholeresis. In the dually perfused organ (perfusion of both portal vein and hepatic artery) perfusion of the hepatic artery with bicarbonate-containing buffer, ursodeoxycholate had a similar stimulatory effect as in vivo in both control and cirrhotic rats. When bicarbonate in the hepatic artery was replaced by tricine-acetate, a decrease in biliary bicarbonate and bile flow occurred in controls but not in cirrhotic rats. During ursodeoxycholate stimulation, a decrease in biliary bicarbonate occurred in both experimental groups. We conclude that ursodeoxycholate maintains its hypercholeretic properties in cirrhosis and that the ductular proliferation found in this model of cirrhosis conveys a larger bicarbonate-stimulating capacity to this tertiary bile acid. These results lend further support the cholehepatic shunt hypothesis to explain ursodeoxycholate-induced bicarbonate-rich hypercholeresis in rodents.(HEPATOLOGY 1994;20:1048-1054)
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