Ursodeoxycholate-induced hypercholeresis in cirrhotic rats: further evidence for cholehepatic shunting.
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 mumoles/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Elsing
C
C
Department of Clinical Pharmacology, University of Berne, Switzerland.
Sägesser
H
H
Reichen
J
J
D000704:Analysis of Variance; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D001646:Bile / Q000378:metabolism* / Q000502:physiology; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000473:pathology; D002256:Carbonic Anhydrases / Q000502:physiology; D004573:Electrolytes / Q000378:metabolism; D004896:Erythritol / Q000493:pharmacokinetics; D006965:Hyperplasia; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D010477:Perfusion / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
D001639:Bicarbonates; D001647:Bile Acids and Salts; D004573:Electrolytes; D014580:Ursodeoxycholic Acid; D002256:Carbonic Anhydrases; D004896:Erythritol