REGULATION OF UREA AND CITRULLINE SYNTHESIS UNDER PHYSIOLOGICAL CONDITIONS

Information on the regulation of urea synthesis in vivo was obtained b y examining the relationship between ureagenesis in vivo, citrulline s ynthesis in vitro, and two factors currently hypothesized to exert sho rt-term regulation of this pathway: the liver mitochondrial content of N-acetylglutamate (NAG) and substrate availability. Rats meal-fed for 4 h every day (4-20 schedule) or for 8 h every other day (8-40 schedu le) were used. (1) The citrulline-synthesizing capacity of mitochondri a from livers of rats on the 8-40 schedule exceeded the corresponding velocity of urea synthesis in vivo at all time points studied. (2) Mit ochondrial NAG in these livers increased from 127 +/- 32 pmol/mg of pr otein at 0 h to 486 +/- 205 pmol/mg at 3 h after the start of a meal, and decreased thereafter, but the correlation between NAG content and the velocity of citrulline synthesis was not simple, suggesting that N AG is not the only determinant of the state of activation of carbamoyl phosphate synthase I. (3) In rats on the 4-20 schedule killed 1 h aft er the start of the meal, the fiver content of ornithine, citrulline, arginine, glutamate, alanine and urea increased 2.1-12-fold with respe ct to the values at 0 h; glutamine decreased by 39 %. (4) The combined findings indicate that in vivo, moment-to-moment control of the veloc ity of urea synthesis is exerted by substrate availability. (5) Digest ion limits the supply of substrate to the liver, and prevents its urea genic capacity from being overwhelmed following a protein-containing m eal.