| Previous investigations have shown that a single dose of low-density lipoprotein (LDL) injection causes a marked decrease in endothelium-dependent relaxation, and that endothelial dysfunction aggravates myocardial injury due to ischemia-reperfusion in atherosclerotic animals. Monophosphoryl lipid A-induced delayedpreconditioning preverses the ischemic myocardium and endothelial cells. The objective of the present study was to examine the effect of monophosphoryl lipid A on endothelial function and ischemia-reperfusion-induced myocardial injury in the rats treated with LDL.Methods: Animal model of endothelium dysfunction: vascularendothelial injury was induced by a single injection of native LDL in the rats 48h before the experiment. After the rats were anesthetized sodium pentobarbital (60 mg·kg-1, i.p.), blood samples were collected from carotid artery. The serum concentration of ADMA (HPLC) was determined and endothelium dependent relaxation was tested. Animal model of cardiac injure induced by ischemic and reperfusion: theisolated rat hearts were perfused in a Langendorff model. All hearts, except those of the control group, were allowed an initial 20-min stabilization period before treatment with 30 min of global ischemia and 30 min of reperfusion. A water-filled latex balloon connected to a pressure transducer was inserted into the left ventricle via the mitral valve to record iso-volumic left ventricular pressure. Left ventricular pressure, the first derivative of left ventricular pressure (± dp/dtmax), and heart rate were continuously monitored. The activity of creatine kinase (CK) in coronary effluent was measured by timed collection of coronary effluent.Results: A single injection of native LDL (4 mg/kg, i.v.) causeda significant decrease in vasodilator responses to acetylcholine and an increase in the serum level of asymmetric dimethylarginine, the endogenous nitric oxide synthase inhibitor. Pretreatment with monophosphoryl lipid A (300 or 450 μg/kg, i.p.) significantly improved endothelium-dependent relaxation and decreased concentrations of asymmetric dimethylarginine, and the effects of monophosphoryl lipid A were attenuated by L-nitro-arginine-methyl ester, but not by aminoguanidine. LDL treatment only aggravated the decreased coronary flows but did not affect cardiac dysfunction due to ischemia-reperfusionin the rats treated with LDL. Pretreatment with monophosphoryl lipid A significantly improved cardiac dysfunction by ischemia-reperfusion in the rats treated with or without LDL, an effect that was abolished by aminoguanidine.Conclusion: The present study suggests that: (1) a single injection of native LDL causes a decrease in endothelium-dependent relaxation and aggravate the decrease of coronary flow due to ischemia-reperfusion, (2) pretreatment with monophosphoryl lipid A protects the myocardium against injury duo to ischemia-reperfusion in the rats treated with or without native LDL, and (3) the protective effect of monophosphoryl lipid A on endothelial cells is related to reduction of asymmetric dimethylarginine level.
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