Protective actions of a leukotriene B4 antagonist in splanchnic ischemia and reperfusion in rats.
Pentobarbital-anesthetized rats were subjected to occlusion of both the celiac and superior mesenteric arteries for 90 min followed by reperfusion for 2 h. All seven rats given only the vehicle died within 2 h of reperfusion, whereas rats treated with LY-255283 (3 or 10 mg/kg iv), a leukotriene B4 (LTB4) receptor antagonist given 10 min before reperfusion, exhibited significantly higher survival rates of 57% (4 out of 7) and 75% (6 out of 8), respectively, 2 h after reperfusion. Rats given 1 mg/kg of LY-255283 showed no significant improvement in survival. Splanchnic artery occlusion (SAO)-shock rats treated with LY-255283 (3 or 10 mg/kg) exhibited significantly attenuated accumulation of plasma free amino-nitrogenous compounds and of a myocardial depressant factor. Treatment with LY-255283 (10 mg/kg) markedly (P less than 0.01) ameliorated the deficits of endothelium-dependent relaxation of isolated superior mesenteric artery (SMA) rings in untreated SAO-shock rats. LY-255283 at 10 mg/kg significantly attenuated the increased myeloperoxidase activity in the intestinal tissue of SAO-shock rats. Moreover, LY-189444, a closely related compound having no LTB4 antagonist activity, did not protect rats in SAO shock, whereas a lipoxygenase inhibitor confirmed protection in SAO shock. These results suggest that LTB4 plays a pivotal role in endothelial dysfunction occurring in SAO-shock rats by chemoattraction and activation of neutrophils on the surface of vascular endothelial cells. Moreover, LY-255283 but not LY-189444 inhibited the adherence of rat neutrophils to isolated SMA endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)
Karasawa
A
A
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Guo
J P
JP
Ma
X L
XL
Tsao
P S
PS
Lefer
A M
AM
D000818:Animals; D001158:Arteries / Q000503:physiopathology; D001794:Blood Pressure; D002402:Cathepsin D / Q000097:blood; D003250:Constriction; D004730:Endothelium, Vascular / Q000503:physiopathology; D007082:Ileum / Q000201:enzymology; D007511:Ischemia / Q000517:prevention & control*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015424:Reperfusion; D013152:Splanchnic Circulation / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology*
D013777:Tetrazoles; D007975:Leukotriene B4; D009195:Peroxidase; D002402:Cathepsin D; C063823:LY 255283