Abstract
Objectives
Growth hormone (GH) reduces the catabolic side effects of steroid treatment via effects on the amino-nitrogen metabolism. Ipamorelin is a synthetic peptide with GH releasing properties. We wished to study the metabolic effects of Ipamorelin and GH on selected hepatic measures of α-amino-nitrogen conversion during steroid-induced catabolism.
Design
Five groups of rats were included: (1) free-fed controls (2) pair-fed controls (3) prednisolone (delcortol, 4 mg × kg−1 × day−1) (4) prednisolone and GH (1 mg × kg−1 × day−1) (5) prednisolone and Ipamorelin (0.5 mg × kg−1 × day−1). After seven days the hepatic capacity of urea-N synthesis (CUNS) was determined in parallel with measurements of liver mRNA levels of urea cycle enzymes, whole-body N-balance, and N-contents of various organs.
Results
Compared to pair-fed controls, prednisolone increased CUNS (p < 0.01) as well as the expression of urea cycle genes (p < 0.01), and decreased N-balance (p < 0.01) as well as organ N-contents (p < 0.05). Compared to prednisolone treated animals, co-administration of GH reduced CUNS by 33% (p < 0.01), normalized urea cycle gene expression, improved N-balance 2.5-fold, and normalized or improved organ N-contents. In prednisolone treated rats Ipamorelin reduced CUNS by 20% (p < 0.05), decreased the expression of urea cycle enzymes, neutralised N-balance, and normalized or improved organ N-contents.
Conclusion
Accelerated nitrogen wasting in the liver and other organs caused by prednisolone treatment was counteracted by treatment with either GH or its secretagogue Ipamorelin, though at the doses given less efficiently by the latter. This functional study of animals confirms that the GH secretagogue exerts GH related metabolic effects and may be useful in the treatment of steroid-induced catabolism.
Introduction
Glucocorticoid treatment, when used in various disease states, is a frequent cause of catabolism in humans. Catabolism is caused both by an increase in body protein breakdown and by an accelerated hepatic degradation of amino acid nitrogen into urea nitrogen [1], [2], [3].
Growth hormone may correct protein wasting during glucocorticoid treatment by increasing net tissue uptake of amino acid nitrogen as well as by reducing hepatic degradation of amino acid nitrogen into urea nitrogen [2], [4], [5], [6], [7].
Ipamorelin is a synthetic growth hormone (GH) secretagogue with specific GH releasing properties [8], [9]. In GH deficient and catabolic states, the use of secretagogues may be more clinically feasible than treatment with GH itself, since it is possible to administer some of these secretagogues orally [10], [11]. However, it remains to be documented that the secretagogues actually exert nitrogen preserving effects during catabolism similar to that of growth hormone.
We wanted to examine whether Ipamorelin exerts the same biological effects in rats as does GH, by counteracting both the increase in ability of urea synthesis and by reducing the parallel loss of organ nitrogen induced by glucocorticoid administration.
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Section snippets
Animals
Female Wistar rats (total N = 80, body weight 200–210 g) (Møllegaard Breeding Centre, Eiby, Denmark) were housed at 22 ± 2 °C, 55 ± 10% relative humidity. Air was changed 8–10 times per hour at a 12-h light, 12-h dark cycle (06.30–18.30 light). The animals had free or controlled access to standard chow (Altromin diet # 1324, Chr. Petersen Ltd., Slagelse, Denmark) and free access to tap water.
Each cage contained two rats, each rat was weighed daily during the study period. Food consumption was recorded
Food intake
Free-fed control rats ate 16 g daily on average. Prednisolone treated animals decreased their intake to 13 g daily. GH and Ipamorelin treated animals were pair-fed to prednisolone treated animals and thus received 13 g food daily.
Body weight
Initially, all groups had identical body weights, data not shown.
Basal blood amino-N concentration (Fig. 1)
Prednisolone decreased basal blood α-amino-N concentration by 30% compared to pair-fed controls (3.0 ± 0.5 mmol × l−1 vs. 4.2 ± 0.5 mmol × l−1, p < 0.05). Compared to steroid treated animals, the basal blood α-amino-N
Discussion
Our main findings are that Ipamorelin and GH both counteracted steroid-induced catabolism, although the latter more efficiently. Both substances reduced the prednisolone-induced up-regulation of the in vivo rate of urea synthesis (CUNS) and they reduced the increased gene expression of key urea cycle enzymes. Simultaneously, body weight, whole-body N-balance, and organ N-contents all improved.
The parallel changes in in vivo urea synthesis, urea enzyme gene expression, whole-body N-balance, and
Acknowledgements
The present study was supported by grants from Clinical Institute, Aarhus University; Danish Health Research Council; Novo Nordic Foundation for Growth and Regeneration; and “Savvæksejer Jeppe Juhl og hustru Ovita Juhls mindelegat”. Growth hormone and Ipamorelin were generously supplied by Novo Nordic, Gentofte, Denmark. The authors greatly appreciate the skilful technical assistance provided by Joan Didriksen, Lene Vestergård Jensen, Inger Schødt, Kirsten Nyborg, Kirsten Priisholm, and Bjørg
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Moreover, LOC101110727, LOC101110202, CYP3A24 were found in the steroid hormone biosynthesis pathway (P = 0.00055). An increase in vivo capacity of urea-N synthesis and increased mRNA levels of the rate- and flux-limiting urea cycle enzyme were observed in Wistar rats after administration of steroids (Aagaard et al., 2009). The genes LOC101110202, LOC101110727, and CYP3A24 were also found in the “retinol metabolism” (P=0.0092), “linoleic acid metabolism” (P = 0.0029), and “chemical carcinogenesis” (P = 0.013) pathways. View full text
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