Recombinant human growth hormone-binding protein fails to enhance the in vivo bioactivity of human growth hormone in normal rats.
GH circulates in the plasma partially bound with a GH-binding protein (GHBP), but the physiological significance of the GHBP and how it affects GH bioactivity in vivo is still unknown. In the present study, we took advantage of the known biological action of exogenous human (h) GH to inhibit endogenous rat (r) pulsatile GH release and examined the effect of combining hGH with recombinant hGHBP on this response in normal rats. Spontaneous 7-h plasma rGH and hGH profiles were obtained from four groups of free-moving adult male rats s.c. administered either: 1) 200 microg hGH alone; 2) a mixture of 200 microg hGH and 200 microg hGHBP preincubated for 30 min before injection; 3) 200 microg hGHBP alone; or 4) Tris buffer (vehicle) alone. Rats administered the vehicle or hGHBP separately exhibited the typical pulsatile pattern of rGH secretion. Injection of hGH alone resulted in a marked (P < 0.01) suppression of spontaneous rGH pulses for approximately 3.5 h after the injection compared with vehicle-injected controls; during the subsequent 3.5- to 7-h period, recovery of spontaneous rGH peaks was evident. Plasma levels of hGH in these animals reached a peak within 1 h after hGH injection and declined to near undetectable levels by the end of the sampling period. In contrast, the disappearance rate of hGH was markedly slower in rats administered the hGH + hGHBP complex; plasma hGH concentrations at 7 h after injection were 14-fold higher than those in animals administered hGH alone, and hGH was still readily detectable up to 24 h after injection. However, despite the markedly higher levels of hGH persisting throughout the sampling period in complex-injected rats, both the time course of hGH-induced inhibition of rGH and the recovery of spontaneous rGH pulses were similar to those of animals administered hGH alone. Moreover, there were no significant modifications of plasma insulin-like growth factor-1 levels for up to 24 h after injection of the hGH + hGHBP complex. Computer simulations revealed that most of the total hGH observed during the 3.5- to 7-h period was circulating in the bound form. These results demonstrate that, despite hGHBP's ability to markedly prolong the bioavailability of hGH, precomplexing hGH with hGHBP failed to enhance hGH's in vivo bioactivity in the inhibition of endogenous pulsatile rGH release. Our findings do not provide support for the concept that the GHBP enhances the bioactivity of GH in vivo, at least over the time course examined here.
Tzanela
M
M
Department of Pediatrics, McGill University-Montreal Children's Hospital Research Institute, Québec, Canada.
Wagner
C
C
Tannenbaum
G S
GS
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology*; D003198:Computer Simulation; D004338:Drug Combinations; D019382:Human Growth Hormone / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D012016:Reference Values
D002352:Carrier Proteins; D004338:Drug Combinations; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; C051815:somatotropin-binding protein