Effects of growth hormone and insulin-like growth factor-I singly and in combination on in vivo capacity of urea synthesis, gene expression of 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 factor-I (IGF-I) are promising anabolic agents, and their combined administration has been shown to reverse catabolism more efficiently than each of the peptides alone. This is believed to be mediated primarily through increased peripheral protein synthesis, whereas little attention has focused on a possible participation of amino acid metabolism in the liver. Four groups of rats were given: 1) placebo; 2) GH (200 micrograms/d); 3) IGF-I (300 micrograms/d); and 4) both GH and IGF-I. After 3 days, the maximum capacity of urea-nitrogen synthesis was determined by saturating infusion of alanine (n = 8 in each group), together with measurements of liver messenger RNA (mRNA) levels for urea cycle enzymes (n = 5 in each group) and N-contents of muscles, heart, and kidney. Basal plasma alpha-amino acid concentrations were similar in all groups. The capacity of urea-N synthesis [mumol/(min x 100 g body weight)] was reduced 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 increased stepwise from placebo (699 +/- 40 to 1,579 +/- 96 micrograms/L in the combined GH/IGF-I group), and was correlated negatively with the capacity of urea-nitrogen synthesis (P < .01). mRNA levels for urea cycle enzymes in the liver decreased after GH and IGF-I treatment, and the effect was more pronounced after the combined treatment in which the rate-limiting enzyme, argininosuccinate synthetase, was halved. Nitrogen contents of organs increased after both GH and IGF-I treatment, and even 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 favor protein buildup in organs. We speculate that this inhibitory effect on the capacity of urea synthesis is caused by a decreased translation rate of the urea cycle enzymes caused by GH and IGF-I's down-regulatory effect on urea cycle enzyme gene transcription. The findings may indicate a novel mechanism of the protein anabolic action of GH and IGF-I.
Grøfte
T
T
Department of Medicine V (Hepatology and Gastroenterology), Aarhus Kommunehospital, Denmark.
Wolthers
T
T
Jensen
S A
SA
Møller
N
N
Jørgensen
J O
JO
Tygstrup
N
N
Orskov
H
H
Vilstrup
H
H
D000818:Animals; D001124:Argininosuccinate Synthase / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014508:Urea / Q000378:metabolism*
D012333:RNA, Messenger; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D014508:Urea; D001124:Argininosuccinate Synthase; D009584:Nitrogen