A neurokinin-1 receptor antagonist that reduces intra-abdominal adhesion formation decreases oxidative stress in the peritoneum.
Oxidative stress has been implicated in intra-abdominal adhesion formation. Substance P, a neurokinin-1 receptor (NK-1R) ligand, facilitates leukocyte recruitment and reactive oxygen species (ROS) generation. We have shown in a rat model of adhesion formation that intraperitoneal administration of a NK-1R antagonist at the time of abdominal operation reduces postoperative adhesion formation. Thus we determined the effects of NK-1R antagonist administration on peritoneal leukocyte recruitment and oxidative stress within 24 h of surgery. Adhesions were induced in Wistar rats randomly assigned to receive the antagonist or vehicle intraperitoneally. Peritoneal tissue was isolated at 2, 4, 6, and 24 h after surgery for analysis of the oxidative stress biomarkers 8-isoprostane (8-IP), protein carbonyl, NADPH oxidase, myeloperoxidase (MPO), and ICAM-1 and VCAM-1 mRNAs. Total antioxidant capacity of peritoneal fluid was also determined. MPO, NADPH oxidase, 8-IP, and protein carbonyl were elevated (P < 0.05) by 6 h. ICAM-1 mRNA was elevated (P < 0.05) by 2 h, whereas VCAM-1 levels decreased (P < 0.05) at 24 h. The NK-1R antagonist delayed the MPO rise and reduced (P < 0.05) 8-IP levels by 6 h and ICAM-1 mRNA, VCAM-1 mRNA, and protein carbonyl at 2 h. The antagonist also increased (P < 0.05) the antioxidant capacity of peritoneal fluid at all time points. These data further support a role for oxidative stress in adhesion formation and suggest that the NK-1R antagonist may limit adhesions, in part, by reducing postoperative oxidative stress through an inhibition of neutrophil recruitment and an increase in peritoneal fluid antioxidant capacity.
Reed
Karen L
KL
Department of Surgery, Boston University School of Medicine, 88 East Newton Street, Boston, MA 02118, USA.
Heydrick
Stanley J
SJ
Aarons
Cary B
CB
Prushik
Scott
S
Gower
Adam C
AC
Stucchi
Arthur F
AF
Becker
James M
JM
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D005765:Gastrointestinal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007813:Laparotomy; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D020556:Neutrophil Infiltration / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D010532:Peritoneal Diseases / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D010537:Peritoneum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000601:surgery; D009195:Peroxidase / Q000378:metabolism; D050050:Protein Carbonylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D013997:Time Factors; D000267:Tissue Adhesions / Q000517:prevention & control; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
C480026:6-diphenylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-1-azabicyclo(2.2.2)octane-3-carboxylic acid; D000975:Antioxidants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005765:Gastrointestinal Agents; D064729:Neurokinin-1 Receptor Antagonists; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018040:Receptors, Neurokinin-1; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C075750:8-epi-prostaglandin F2alpha; D013373:Substance P; D015237:Dinoprost; D009195:Peroxidase; D019255:NADPH Oxidases