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ORIGINAL RESEARCH ARTICLE

Plasma S-Nitrosothiol Status in Neonatal Calves: Ontogenetic Associations with Tissue-Specific S-Nitrosylation and Nitric Oxide Synthase

Stephan Christen^*, Isabelle Cattin, Iona Knight, Paul G. Winyard, Jürg W. Blum^,1 and Theodore H. Elsasser^,2

^* Institute for Infectious Diseases, University of Bern, CH-3010 Bern, Switzerland; Division of Nutrition and Physiology, Institute of Animal Genetics, Nutrition and Housing, University of Bern, CH-3012 Bern, Switzerland; Peninsula Medical School, Universities of Exeter and Plymouth, Exeter EX1 2LU, United Kingdom; and United States Department of Agriculture, Agricultural Research Service, Growth Biology Laboratory, Beltsville, Maryland 20705

To whom requests for reprints should be addressed at ² United States Department of Agriculture, Agricultural Research Service, Growth Biology Laboratory, Building 200, Room 201, B.A.R.C.-East, Beltsville, Maryland 20705. E-mail: elsasser{at}anri.barc.usda.gov

Neonatal cattle and in part neonates of other species have manyfold higher plasma concentrations of nitrite plus nitrate than mature cows and subjects of other species, suggesting an enhanced and needed activation of the nitric oxide (NO) axis at birth. While the biological half-life of NO is short (<1 sec), its functionality can be prolonged, and in many regards more discretely modulated, when it reacts with low-molecular-weight and protein-bound thiols to form S-nitrosothiols (RSNO), from which NO subsequently can be rereleased. We used the calf as a model to test the hypothesis that plasma concentrations of RSNO are elevated at birth in mammals, correlate with ascorbate and urate levels, are selectively generated in critical tissue beds, and are generated in a manner temporally coincident with changes in tissue levels of active NO synthases (NOS). Plasma concentrations of RSNO, ascorbate, and urate were highest immediately after birth (Day 0), dropped >50% on Day 1, and gradually decreased over time, reaching a nadir in mature cattle. Albumin and immunoglobulin G were identified as major plasma RSNO. The presence of S-nitrosocysteine (SNC, a validated marker for S-nitrosylated proteins), inducible NOS (iNOS), and activated endothelial NOS (eNOS phosphorylated at Ser1177) in different tissues was analyzed by immunohistochemistry in another group of similar-aged calves. SNC, iNOS, and phosphorylated eNOS were detected in liver and ileum at the earliest timepoint of sampling (4 hrs after birth), increased between 4 and 24 hrs, and then declined to near-nondetectable levels by 2 weeks of life. Our data show that the neonatal period in the bovine species is characterized by highly elevated and coordinated NO-generating and nitrosylation events, with the ontogenetic changes occurring in iNOS and eNOS contents in key tissues as well as RSNO products and associated antioxidant markers.

Key Words: reactive nitrogen oxides • ontogenesis • S-nitrosylation • nitric oxide synthase