Delayed endothelial protective effects of monophosphoryl lipid A after myocardial ischemia and reperfusion in rats

Monophosphoryl lipid A (MLA) induces delayed (24 h) myocardial protection i n various animal models of ischemia/reperfusion injury, and thus mimics the second window of preconditioning against cardiac injury. However, the pote ntial endothelial protective effects of this drug have not been evaluated. The present study was designed to assess whether MLA exerts delayed protect ive effects against reperfusion-induced coronary endothelial dysfunction in rats, as well as the protective role of iNOS in this protection. Wistar ra ts received a single i.v. injection of MLA (450 mu g/kg) or solvent. Twenty -four hours later, they were anesthetized and subjected to 20 min ischemia with 60 min reperfusion, in the absence or the presence of the iNOS inhibit or aminoguanidine (300 mg/kg i.p.). At the end of reperfusion, 1.5-2 mm cor onary segments (average diameter 250 mu m) were removed distal to the site of occlusion and mounted in wire myographs. Endothelium-dependent relaxatio ns to acetylcholine were determined in arteries pre-contracted by serotonin , Ischemia/reperfusion induced a marked decrease in the coronary responses to acetylcholine (maximal relaxations: sham 64+/-8%, n=8; ischemia/reperfus ion: 41 +/- 9%, n = 8: P<0.05). This impaired response was partially restor ed by MLA (55 +/- 4%. n = 10: P<0.05 vs ischemia/reperfusion). The effect o f MLA was not affected by aminoguanidine (57 +/- 5%, n = 6). Thus. in addit ion to protecting myocytes, MLA induces a delayed protection against corona ry endothelial dysfunction. However, in contrast to its effects on myocytes , the endothelial protective effects do not appear to involve iNOS. (C) 199 9 Academic Press.