Effects of a BLT receptor antagonist on local and remote reperfusion injuries after transient ischemia of the superior mesenteric artery in rats

• Published in: European journal of pharmacology 2000-09, Vol.403 (1), p.121-128
• Main Authors: Souza, Danielle G, Coutinho, Sibele F, Silveira, Micheline R, Cara, Denise C, Teixeira, Mauro M
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Benzopyrans - pharmacology; Biological and medical sciences; Capillary Permeability - drug effects; Carboxylic Acids - pharmacology; Cardiovascular system; CD18 Antigens - immunology; Disease Models, Animal; Dose-Response Relationship, Drug; Evans Blue - pharmacokinetics; Inflammation; Intestinal Mucosa - metabolism; Intestines - blood supply; Ischemia–reperfusion; Leukotriene Antagonists - pharmacology; Lung - blood supply; Lung - metabolism; Male; Medical sciences; Mesenteric artery; Mesenteric Artery, Superior - drug effects; Mesenteric Artery, Superior - metabolism; Mesenteric Artery, Superior - physiopathology; Mesentery - blood supply; Mesentery - metabolism; Miscellaneous; Neutrophil; Neutrophils - cytology; Neutrophils - drug effects; Oedema; Peroxidase - drug effects; Peroxidase - metabolism; Pharmacology. Drug treatments; Polysaccharides - pharmacology; Rats; Rats, Wistar; Receptors, Leukotriene B4 - antagonists & inhibitors; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; Reperfusion Injury - prevention & control; Tetrazoles - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(00)00574-4

Reperfusion of ischemic vascular beds may lead to recruitment and activation of leukocytes, release of mediators of the inflammatory process and further injury to the affected vascular bed and to remote sites. Neutrophils appear to play a major role in the pathophysiology of reperfusion injury. Amongst inflammatory mediators shown to activate neutrophils and induce their recruitment in vivo, much interest has been placed on the role of leukotriene (LT)B 4. Here, we have assessed the effects of the BLT receptor antagonist (+)-1-(3 S,4 R)-[3-(4-phenyl-benzyl)-4-hydroxy-chroman-7-yl]-cyclopentane carboxylic acid (CP 105,696) in a model of neutrophil-dependent ischemia and reperfusion injury in the rat. The superior mesenteric artery was isolated and ischemia was induced by its total occlusion for 30 min. After 30 min of reperfusion, injury was assessed by evaluating the extravasation of Evans blue, an index of vascular permeability, and the levels of myeloperoxidase, an index of neutrophil accumulation, in the intestine, mesentery and lung. The neutrophil-dependence of the local (intestine and mesentery) and remote (lung) injury was confirmed by using fucoidin, a selectin blocker, and WT-3, an anti-CD18 monoclonal antibody. Post-ischemic treatment with CP 105,696 dose-dependently inhibited vascular permeability and neutrophil accumulation in the intestine and mesentery. CP 105,696 also blocked the vascular permeability changes, but not neutrophil accumulation, in the lungs after reperfusion injury. Virtually identical results were obtained with another BLT receptor antagonist, 1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1 H-tetrazol-5-yl)-heptoxy)-phenyl)ethanone (LY255283). Our results suggest that post-ischemic treatment with BLT receptor antagonists may inhibit local and remote ischemia and reperfusion injury by blocking both the accumulation and/or activation of neutrophils.