Study On The Effect And Mechanism Of Oral Arginine In Improving Linear Growth Of Long Bones

Objective:(1) To investigate and evaluate the effect of oral L-arginine on improving height growth in children with short stature. (2) To investigate the effect of oral L-arginine on linear growth of long bones and explore the action mechanism, focusing on the gene expressions related to the hypothalamus-pituitary growth axis and nitric oxide(NO)-cyclic guanosine monophosphate(cGMP) pathway through the experience in rats. (3) To observed the effect of oral arginine on histological structures and ultrastructures of the rat's vital organs and evaluate the safty of arginine for treatment.Methods:(1) In clinical study,45 children with short stature were given oral L-arginine. Before and after treatment, the height bone width(BW),bone mineral content(BMC) and bone mineral density(BMD) were measured. The data were analysed by paired-samples t test. (2) The rats were randomly divided into the control group and the intervention group. In the control group:physiological saline was applied for gastric perfusion, totally for 4 weeks. In the intervention group:L-arginine was applied for gastric perfusion, totally for 4 weeks. Bone histomorphometry analysis was used to measure growth plate width, mineral apposition rate of the tibia and trabecular bone volume fraction, osteoblast surface, osteoclast surface of the femur. Serum growth hormone(GH) concentration was determined by radioimmunoassay. Realtime-PCR was used to measure the gene expressions of neuronal nitric oxide synthase(nNOS), soluble guanylyl cyclaseα1(sGCα1), soluble guanylyl cyclase(sGCβ1), cGMP-dependent protein kinasell(PKGII), growth hormone-releasing hormone(GHRH), somatostatin (SS) in hypothalamus and GH in pituitary. Western blot was used to detect the protein levers of nNOS, sGCα1 and sGCβ1 in hypothalamus. The data were analysed by t test. (3) The rats were randomly divided into the control group and the intervention group. In the control group: physiological saline was applied for gastric perfusion, totally for 12 weeks. In the intervention group:L-arginine was applied for gastric perfusion, totally for 12 weeks. After treatment, the histological structures and ultrastructures of the cerebral cortex^ hypothalamus,pituitary,hear,liver and kidney were observed by light microscopy and transmission electron microscopy.Results:(1) After oral administration of arginine,the growth velocity,height SDS,bone mineral content and bone mineral density were increased(P<0.05). (2) After being intervened with oral arginine, the growth plate width of tibia and osteoblast surface of femur were increased(P<0.05), the serum GH concentration was elevated(P<0.05), the gene and protein expressions of nNOS, sGCal were up-regulated(P<0.05), the expression of SS mRNA was down-regulated(P<0.05) and the expression of GH mRNA was significantly up-regulated(P<0.01). (3) There was no significant difference in the histological structures and ultratructures of the cerebral cortex,hypothalamus,pituitary hear,liver and kidney between the control group and the intervention group.Conclusions:(1) Oral administration of arginine could speed up height growth and enhance bone mineral content and bone mineral density. There was no significant adverse reaction. (2) Oral arginine improved height growth in children with short stature and made bone metabolism in a positive balance. (3) Oral administration of arginine could improve linear growth of long bones by regulating the expressions of SS,GH mRNA and inducing GH secretion, possibly via nNOS-NO-sGC-cGMP signal transduction pathway. (4) The dose and treatment time of L-arginine in our study were saft. It had no harmful effects on the vital organs.