EFFECTS OF MONOPHOSPHORYL LIPID-A ON MYOCARDIAL-ISCHEMIA REPERFUSION INJURY IN DOGS

We wished to determine if the previously observed cardioprotective eff ects of monophosphoryl lipid A (MLA, 65 mug/kg intravenously, i.v.), a n endotoxin derivative, were time related and mediated by an enhanceme nt of antioxidant defense mechanisms, i.e., myocardial catalase and su peroxide dismutase (SOD) activities and neutrophil infiltration as ass essed by myeloperoxidase (MPO) activity. We also wished to study the e ffect of pretreatment with MLA on vascular endothelial and smooth musc le function in vivo and in vitro. Barbital-anesthetized dogs were subj ected to 60-min left circumflex coronary artery (LCX) occlusion follow ed by 5-h reperfusion. Myocardial catalase, SOD, and MPO activities we re measured at the end of 5-h reperfusion. Pretreatment with MLA 24 h before ischemia produced a significant reduction in myocardial infarct size as measured by triphenyltetrazolium staining (15.3 +/- 4.4 vs. 3 0.9 +/- 5.2% in controls, p < 0.05), but 1-h pretreatment with MLA had no protective effect. MLA pretreatment for 24 h resulted in marked re duction (p < 0.05) in MPO activity in the border zone surrounding the infarct. Although a trend indicated an increase in catalase activity i n the 24-h pretreatment group, no significant changes were observed in either catalase or SOD activities among the three groups. The cardiop rotection produced by MLA was independent of differences in collateral blood flow to the ischemic region assessed by radioactive microsphere technique, systemic hemodynamics, myocardial oxygen demand, and ische mic bed size. Responses of the LCX bed to intracoronary acetylcholine (ACh) or nitroglycerin (NTG) in vivo and responses of isolated femoral artery rings to the endothelium-dependent vasodilators, ACh, A23187, bradykinin, or the nonendothelium-dependent vasodilator, sodium nitrop russide (SNP) in vitro were significantly decreased in the MLA 1-h pre treatment group but not in the 24-h pretreatment group. Incubation of the femoral artery rings from the MLA 1-h pretreatment group with 3 mM L-arginine for 1 h reversed the decreased endothelium-dependent respo nses to ACh and A23187, but not those to bradykinin. These results ind icate that (a) the MLA-induced myocardial infarct size reduction was p ronounced when MLA was administered for 24 h but was not evident at 1- h pretreatment; (b) a decrease in neutrophil infiltration into the sit e of ongoing tissue damage might be partially responsible for the prot ection; (c) vascular endothelial and/or smooth muscle function were tr ansiently decreased by MLA administration and returned to nearly norma l levels 24 h after treatment; and (d) the effect of MLA on endotheliu m-dependent responses might be mediated by the L-arginine/nitric oxide (NO) pathway.