HEPATOBILIARY FUNCTION IN SENESCENT MALE SPRAGUE-DAWLEY RATS

The purpose of these studies was to investigate intrahepatic changes u nderlying age-related decreases in bile flow by evaluating the effects of aging on bile acid-dependent and -independent flow, canalicular ve rsus ductular flow and hepatic tight junction permeability. The isolat ed perfused liver was used to assess age-related changes in intrinsic hepatobiliary function without the complications of extrahepatic facto rs such as circulating hormones or hemodynamics. Livers from young adu lts (3 to 6 mo old) or senescent (22 to 26 mo old) male Sprague-Dawley rats were isolated and perfused in a nonrecirculating, hemoglobin-fre e system to assess oxygen uptake, bile acid-dependent and -independent bile flow, bile acid uptake, carbon 14-labeled erythritol clearance a s a measure of canalicular how, tight junction permeability and transc ellular transport into bile. Rates of oxygen uptake by livers from sen escent rats were significantly lower than those of young adults (75 +/ - 8 mu mol/gm/hr vs. 121 +/- 5 mu mol/gm/hr). Age-related decreases in total bile flow were observed and were associated with similar reduct ions in C-14 erythritol clearance suggestive of decreased canalicular bile how. Bile acid-dependent and -independent how was decreased by 50 % and 60%, respectively, in isolated perfused livers from senescent ra ts. Hepatocellular uptake of taurocholate and rates of bile acid excre tion also were about 50% lower in senescent than in young adult rats. Tight junction permeability and transcellular transport were assessed by monitoring appearance of tritiated inulin and horseradish peroxidas e in bile after bolus injections of these compounds through the portal vein. Tritiated inulin appearance in bile was decreased slightly in s enescent compared with young rats. No age-related differences in tight junction permeability to horseradish peroxidase were observed. In add ition, biliary excretion of horseradish peroxidase in livers from sene scent rats was not affected by colchicine, suggesting that microtubule -related transport was minimal or absent in the senescent rats. Taken together, these data indicate that decreased rates of bile how in sene scent compared with young rats are caused by age-related effects on in trinsic hepatobiliary function, specifically decreases in canalicular bile how associated with decreased bile acid-dependent and -independen t bile flow. The decreased canalicular bile how appears to be a result in part of impairment of energy-dependent transport processes and mic rotubule-dependent transcellular transport across cells. These finding s suggest that changes in intrinsic hepatobiliary function occur in ag ed populations and are not caused exclusively by extrahepatic effects such as altered blood how or changes in hormonal status. Further, age- related decreases in bile how may be caused at least in part by decrea sed active transport of osmotically active solutes into bile.