EFFECTS OF GROWTH-HORMONE AND INSULIN-LIKE GROWTH-FACTOR-I SINGLY ANDIN COMBINATION ON IN-VIVO CAPACITY OF UREA SYNTHESIS, GENE-EXPRESSIONOF UREA CYCLE ENZYMES, AND ORGAN NITROGEN CONTENTS IN RATS

Improvement of nitrogen balance is desirable in patients with acute or chronic illness. Both growth hormone (GH) and insulin-like growth fac tor-I (IGF-I) are promising anabolic agents, and their combined admini stration has been shown to reverse catabolism more efficiently than ea ch of the peptides alone. This is believed to be mediated primarily th rough increased peripheral protein synthesis, whereas little attention has focused on a possible participation of amino acid metabolism in t he liver. Four groups of rats were given: 1) placebo; 2) GH (200 mu g/ d); 3) IGF-I (300 mu g/d); and 4) both GrH and IGF-I. After 3 days, th e maximum capacity of urea-nitrogen synthesis was determined by satura ting infusion of alanine (n = 8 in each group), together with measurem ents of liver messenger RNA (mRNA) levels for urea cycle enzymes (n = 5 in each group) and N-contents of muscles, heart, and kidney. Basal p lasma alpha-amino acid concentrations were similar in all groups. The capacity of urea-N synthesis [mu mol/(min x 100 g body weight)] was re duced in a stepwise manner (placebo: 8.25 +/- 1.2; GH treatment: 6.52 +/- 0.8; IGF-I treatment: 5.5 +/- 0.6; and GH/IGF-I: 4.22 +/- 1.6 [P < .001 by ANOVA]), each step being lower than the former. Serum IGF-I in creased stepwise from placebo (699 +/- 40 to 1,579 +/- 96 mu g/L in th e combined GH/GF-I group), and was correlated negatively with the capa city of urea-nitrogen synthesis (P < .01), mRNA levels for urea cycle enzymes in the liver decreased after GH and IGF-I treatment, and the e ffect was more pronounced after the combined treatment in which the ra te-limiting enzyme, arginosuccinate synthetase, was halved. Nitrogen c ontents of organs increased after both GH and IGF-I treatment, and eve n more so after the combination treatment, reaching an increase of 30% (P < .05). Data suggest that GH and IGF-I singly and, even more so in combination, additively inhibit urea synthesis. This is supposed to f avor protein buildup in organs. We speculate that this inhibitory effe ct on the capacity of urea synthesis is caused by a decreased translat ion rate of the urea cycle enzymes caused by GH and IGF-I's down-regul atory effect on urea cycle enzyme gene transcription. The findings may indicate a novel mechanism of the protein anabolic action of GH and I GF-I.