Effects Of Losartan On Myocardial Ischemia And Reperfusion Injury In Rats

Objective To explore the effect of angiotensin II type 1 receptor antagonist losartan on the myocardial infarct size,the ultrastructure of myocardium,the production of tumor necrosis factor-a(TNF-α) and interleukin-6(IL-6),and the activation of NF-kB, and to investigate the possible molecular protective mechanism of losartan from myocardial ischemia and reperfusion(I/R) injury in rats.Methods Forty-two healthy male SD rats were randomly divided into four groups:(l)Control group(C group,n=6);(2)Ischemia-reperfusion group(I/R group,n=12): the left coronary artery was occluded for 30 min ischemia followed by 60 min reperfu-sion;(3)LOS1 group(n=12):losartan (5 mg·kg~-1) was injected intravenously at 15 min before ischemia;(4)LOS2 group(n=12):losartan (10mg·kg~-1) was injected intravenously at 15 min before ischemia.At the end of reperfusion,the blood sample was taken and the plasma concentrations of TNF-a and IL-6 were measured with enzyme-linked immunosorbent assay(ELISA) system.The heart was harvested for determination of myocardial infarct size (by-TTC) and ultrastructure examination (electron micro-scope),and activation of NF-kB (by ECL-western blot analysis).Results The infarct size in groups LOS 1(35 ±2)% and LOS2(22±4)% was significantly smaller than that in I/R group(45 ± 2)%(P<0.01).Myocardial ultrastructure in groups LOS1 and LOS2 was well-preserved,comparing with that in I/R heart.NF-KB activity in I/R group (42 ±2) was significantly increased compared to that in C group (21 ±5) (P<0.01).The NF-kB activity in LOS2 group was lower than that in LOS1 group(P<0.05).After 60min reperfusion,the plasma concentrations of TNF-a and IL-6 were significently higner than those in C group(P<0.01).Losartan significantly decreased the serum levels of TNF-a and IL-6.The mean concentrations of these two cytokines in LOS2 group were lower than those in LOS1 group(P<0.05).Conclusions Angiotensin II type I receptor antagonist losartan has cardioprotec-tive effect on ischemia and reperfusion myocardium in rats,the higher dose of losartan has better protective effect than the lower one.The mechanism may be involved in reducing the production of inflammatory cytokines(TNF-α IL-6) by inhibiting NF-kB activation during myocardial ischemia and reperfusion.