Hyperammonemia and orotic aciduria in portacaval-shunted rats

The effect of a portacaval shunt-induced alteration in liver function on nitrogen metabolism was studied in rats. Within a few days after surgery, portacaval-shunted rats grew with an average daily gain in body weight equal to sham-operated control rats. Within 1 week after surgery, portacaval-shunted rats excreted 20% more orotic acid in their urine compared to control rats. The difference increased to 37% after 3 weeks. Plasma ammonia levels were elevated by 78% in portacaval-shunted rats compared to control rats after 2 weeks. Portacaval-shunted rats injected with a challenging load of ammonium chloride (5 mmol/kg) excreted half as much orotic acid in their urine over a 24-hour period as similarly injected controls. The simultaneous injection of 1.5 mmol/kg of arginine prevented the ammonia-induced increase in orotic acid excretion in both shunted and control rats. However, feeding rats diets supplemented with 1% arginine did not prevent the chronic hyperammonemia and orotic aciduria produced by the construction of portacaval shunts. Similar experiments with diets supplemented with 1% sodium benzoate to induce alternative pathways for nitrogen excretion were also without effect. These results are in contrast to recent clinical studies reporting the effectiveness of sodium benzoate in treating hyperammonemia in patients with urea cycle enzyme defects.