The effect of cisapride on total parenteral nutrition-associated cholestasis in rats.

BACKGROUND: Cholestasis is a frequent problem in patients on total parenteral nutrition. Cisapride has a prokinetic effect on the biliary system, but its effect on hepatic excretory function is unknown. OBJECTIVES: To study the effect of cisapride on TPN-induced cholestasis in a rat model. METHODS: Bile flow and bile salt secretion rate were measured in rats given TPN. There were four groups of 8 to 13 animals each. After a one hour baseline period during which all four groups received i.v. saline infusion, two groups received a TPN solution for another 2 hours, while saline was infused in the two control groups. At the beginning of the second hour, 2 mg/kg cisapride was injected i.v. as a bolus into one experimental and one control group. Bile was collected from the common bile duct. RESULTS: At the end of the third hour, TPN caused a significant reduction in bile flow (P < 0.02) and bile salt secretion rate (P < 0.001) (61.24 vs. 50.74 microliters/min/kg, and 1.173 vs. 0.799 mumol/min/kg, respectively). Addition of cisapride abolished the cholestatic effect of TPN. CONCLUSIONS: Cisapride has a protective effect against TPN-associated cholestasis. This may have clinical significance, and further studies are warranted.

Oxygen radical scavengers are protective against indomethacin-induced intestinal ulceration in the rat.

Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used and may cause small intestinal inflammation and damage. Reactive oxygen metabolites are involved in various gastrointestinal inflammatory processes, but there is little information about their role in small intestinal mucosal damage induced by NSAIDs. We studied the effect of the oxygen radical scavengers superoxide dismutase (SOD), catalase (CAT), and allopurinol (ALLO) on indomethacin (INDO)-induced intestinal ulceration in the rat. Ulceration was produced by s.c. injection of 30 mg/kg of INDO 30 min after refeeding 24 h-fasted rats. Total ulcer area was measured 24 h after INDO administration. Study groups each consisted of eight animals which received either i.p. CAT, SOD, or both together, at a dosage of 5,000 U/kg each. All drugs were divided into five doses, given once an hour over a 4-h period, starting at the time of INDO injection. Another group received 100 mg/kg ALLO in two doses. Total ulcer area was reduced by SOD from 228 +/- 12 (sq mm, mean +/- SEM) to 153 +/- 12 (p < 0.001), by CAT to 179 +/- 13 (p < 0.01), and by both together to 95 +/- 5 (p < 0.0001). ALLO administration reduced the total ulcer area to 176 +/- 7 (p < 0.003). The protective effect of oxyradical scavengers supports the hypothesis that oxygen radicals are involved in the pathogenesis of INDO-induced small intestinal ulceration in the rat.

Total parenteral nutrition-associated cholestasis after selective damage to acinar zone 3 hepatocytes by bromobenzene in the rat.

Total parenteral nutrition is known to cause cholestasis, but the hepatic site of this effect has not been determined. The purpose of our study was to observe the effect of TPN on bile flow and bile salt secretion rate in rats after selective damage to acinar zone 3. Bromobenzene, 3.8 mmol/kg, was injected i.p., and the animals were studied 48 hours later. Experimental groups received either parenteral nutrition or saline for 2 hours. Bromobenzene caused selective damage to acinar zone 3 hepatocytes, and reduced baseline bile flow (23.99 +/- 1.09 vs 37.2 +/- 1.66, mean +/- SEM, microliter/min/kg, p < 0.001). Bromobenzene had no effect on bile salt secretion rate. Total parenteral nutrition decreased bile flow in the bromobenzene treated groups, despite the selective hepatic damage to acinar zone 3 (20.54 +/- 1.07 vs 23.28 +/- 1.63, mean +/- SEM, p < 0.001). Total parenteral nutrition reduced bile salt secretion rate in healthy animals, but this reduction was not seen in bromobenzene treated rats. Our results suggest that bile flow reduction in response to total parenteral nutrition is mediated through an effect on acinar zones 1 and 2, as this reduction is still observed after zone 3 destruction by bromobenzene. Zone 3 hepatocytes may be involved in the effect of parenteral nutrition on bile salt secretion, as the reduction in secretion rate seen in healthy animals was not observed in bromobenzene treated rats.