Devazepide-induced hyperplasia in the rat liver and bile ducts.
Cholecystokinin (CCK) is a potent stimulus of pancreatic enzyme secretion and growth and is known to influence the flow of biliary secretions. It has also been suggested as a trophic stimulus of the biliary tract and liver, but confirmatory studies are lacking. The aim of the present experiment was to study the effects on the rat liver and biliary tract of long-term stimulation of CCK-8S and the CCK-A receptor antagonist devazepide, respectively. Sprague-Dawley male rats had an infusion of sulfated CCK-8, devazepide or sodium chloride by subcutaneously implanted osmotic minipumps. The animals were sacrified 36 h and 3, 7 or 28 days after the start of infusion, and all had an injection of tritiated thymidine (1 mCi/kg) intraperitoneally 1 h prior to death. The liver was dissected out, weighed and processed for its content of protein, DNA and water. After autoradiography, histologic samples were examined for labeled hepatocytes and bile duct epithelium. Devazepide caused an increase in liver protein content from 36 h on. After 3 days labeling index of hepatocytes and liver DNA concentration were increased. On day 7, induced cell proliferation was also seen in the bile duct epithelium, and the increase in liver DNA content and concentration was now more pronounced and persisted throughout the study. After 28 days devazepide also induced increased crude and relative liver weight. A transient reduction in liver weight and liver protein content and concentration was seen after 7 days of CCK-8S infusion. There were no changes of the labeling index of hepatocytes or bile duct epithelial cells or in liver DNA content in the rats receiving CCK-8S infusion. Devazepide induced hyperplastic changes in both the liver and the biliary tract, probably by interfering with the bile secretion, whereas CCK-8S did not exert any similar effects. The results do not support CCK as a hepatotrophic factor.
Ohlsson
B
B
Department of Surgery, University Hospital, Lund, Sweden.
Axelson
J
J
Rehfeld
J F
JF
Ihse
I
I
D000818:Animals; D001570:Benzodiazepinones / Q000633:toxicity*; D001652:Bile Ducts / Q000187:drug effects* / Q000473:pathology; D002766:Cholecystokinin / Q000097:blood / Q000494:pharmacology; D004247:DNA / Q000032:analysis; D020109:Devazepide; D006727:Hormone Antagonists / Q000633:toxicity*; D006965:Hyperplasia; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012844:Sincalide / Q000037:antagonists & inhibitors*
D001570:Benzodiazepinones; D006727:Hormone Antagonists; D004247:DNA; D002766:Cholecystokinin; D020109:Devazepide; D012844:Sincalide