THE EFFECT OF PROSTANOIDS ON HEPATIC BILE-FLOW IN DOGS WITH NORMAL LIVER AND BILE-DUCT CELL HYPERPLASIA

Bile flow rates and composition are subject to a wide variety of neura l, endocrine and paracrine influences. The effects of these multiple f actors may be different in the diseased liver compared to the response produced in the normal liver. As prostanoids may have a therapeutic r ole in liver disease it was intended to evaluate the effects oi two pr incipal therapeutic prostanoids, prostaglandin E(2) and prostacyclin, on bile flow in dogs with a normal liver and in dogs with hepatotoxin- induced liver injury. Initially, in awake animals with chronic biliary and gastric fistulas the bile flow response to prostaglandin E(2) and prostacyclin was evaluated and compared to the response produced by b ile salt infusion alone and to that produced by the standard cholereti c hormones, secretin and glucagon. The animals were then fed alpha-nap hthylisothiocyanate (ANIT) and the studies repeated. ANIT is a hepatot oxin that produces bile duct cell hyperplasia which was confirmed in d ogs by demonstrating that ANIT increased [H-3]thymidine incorporation by isolated canine bile duct cells. In normal dogs, the prostanoids, s ecretin, and glucagon increased hepatic bile flow. 10 days of ANIT fee ding produced a hypercholeresis. While secretin was able to stimulate the hyperplastic biliary epithelium and increase bile flow over values produced by the hyperplastic biliary epithelium alone, neither prosta glandin E(2), prostacyclin, or glucagon appeared to stimulate the hype rplastic biliary epithelium. As ANIT produced evidence of cholestasis and hepatocellular damage, only secretin would seem to have a potentia l therapeutic role in increasing bile flow in cholestatic liver disord ers associated with bile duct cell hyperplasia.