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Mechanisms Underlying Growth Hormone Effects in Augmenting Nitric Oxide Production and Protein Tyrosine Nitration during Endotoxin Challenge

Growth Biology Laboratory, United States Department of Agriculture, Agricultural Research Service (T.H.E., S.K., C.L.), Beltsville, Maryland 20705; Cancer Center, University of California San Diego (C.M., B.N.), La Jolla, California 92093; and Department of Anatomy, Physiology & Pharmacology (J.L.S.), Auburn University, Auburn, Alabama 36849

Address all correspondence and requests for reprints to: Dr. Ted H. Elsasser, United States Department of Agriculture, Agricultural Research Service, Growth Biology Laboratory, B-200, Room 201, Beltsville Agricultural Research Center-East, Beltsville, Maryland 20705. E-mail: elsasser{at}anri.barc.usda.gov.

The present study defined the effects of GH administration on components of the nitric oxide (NO)-generating cascade to account for observed increases in NO production and protein nitration after an immune challenge. Calves were assigned to groups with or without GH treatment (100 µg GH/kg body weight or placebo im, daily for 12 d) and with or without low-level endotoxin [lipopolysaccharide (LPS), 2.5 µg/kg, or placebo, iv]. Plasma was obtained for estimation of NO changes as [NO₂^– + NO₃^–] (NO_x). Transcutaneous liver biopsies were collected for measurement of protein tyrosine nitration, cationic amino acid transporter (CAT)-2 mRNA transporter, and constitutive NO synthase (cNOS), inducible NOS (iNOS), and arginase activity. Liver protein nitration increased more than 10-fold 24 h after LPS and an additional 2-fold in animals treated with GH before LPS. GH increased plasma NO_x after LPS to levels 27% greater than those measured in non-GH-treated calves. LPS increased CAT-2 mRNA after LPS; GH was associated with a 24% reduction in CAT-2 mRNA content at the peak time response. cNOS activity was 3-fold greater than iNOS after LPS. NOS activities were increased 140% (cNOS) at 3 h and 169% (iNOS) at 6 h, respectively, after LPS; GH treatment increased cNOS activity and the phosphorylation of endothelial NOS after LPS more than 2-fold over that measured in non-GH-treated calves. The data suggest that an increased production of nitrated protein develops in the liver during low-level, proinflammatory stress, and nitration is increased by GH administration through a direct effect on the competing activities of NOS and arginase, modulatable critical control points in the proinflammatory cascade.

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