Beneficial effects of peroxynitrite decomposition catalyst in a rat model of splanchnic artery occlusion and reperfusion.
The aim of the present study was to investigate the protective effect of the peroxynitrite decomposition catalyst 5,10,15, 20-tetrakis(2,4,6-trimethyl-3,5-disulfonatophenyl)-porphyrinato iron (III) (FeTMPS) in a model of splanchnic artery occlusion shock (SAO). SAO shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamp (reperfusion). At 60 min after reperfusion, animals were killed for histological examination and biochemical studies. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine (a marker of peroxynitrite-induced oxidative processes) in the plasma of the SAO-shocked rats after reperfusion, but not during ischemia alone. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, an index of nitrogen species such as peroxynitrite, in the necrotic ileum in shocked rats. SAO-shocked rats developed a significant increase of tissue myeloperoxidase and malonaldehyde activity, and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival at 2 h after reperfusion). Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin localized mainly in the vascular endothelial cells. Ileum tissue sections obtained from SAO-shocked rats and stained with antibody to ICAM-1 showed a diffuse staining. Administration of FeTMPS significantly reduced ischemia/reperfusion injury in the bowel, and reduced lipid and the production of peroxynitrite during reperfusion. Treatment with PN catalyst also markedly reduced the intensity and degree of P-selectin and ICAM-1 staining in tissue sections from SAO-shocked rats and improved survival. Our results clearly demonstrate that peroxynitrite decomposition catalysts exert a protective effect in SAO and that this effect may be due to inhibition of the expression of adhesion molecules and the tissue damage associated with peroxynitrite-related pathways.
Cuzzocrea
S
S
Institute of Pharmacology and. Department of Biomorphology School of Medicine, University of Messina, Italy. USA. salvator@www.unime.it
Misko
T P
TP
Costantino
G
G
Mazzon
E
E
Micali
A
A
Caputi
A P
AP
Macarthur
H
H
Salvemini
D
D
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002384:Catalysis / Q000187:drug effects; D002445:Celiac Artery / Q000502:physiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005290:Ferric Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D007082:Ileum / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007958:Leukocyte Count / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology / Q000627:therapeutic use*; D009566:Nitrates / Q000097:blood / Q000378:metabolism*; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism; D009573:Nitrites / Q000097:blood / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019007:P-Selectin / Q000032:analysis; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D012235:Rhodamines / Q000097:blood / Q000378:metabolism; D013152:Splanchnic Circulation / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
C112917:5,10,15,20-tetrakis(2,4,6-trimethyl-3,3-disulfonatophenyl)porphyrinato iron(III); D005290:Ferric Compounds; D008665:Metalloporphyrins; D009566:Nitrates; D009573:Nitrites; D019007:P-Selectin; D012235:Rhodamines; C058319:dihydrorhodamine 123; D018799:Intercellular Adhesion Molecule-1; C039642:peroxynitric acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D009195:Peroxidase