Results of previous studies indicate that
monophosphoryl lipid A (MLA) reduces
myocardial infarct size when administered 24 but not 1 h before a prolonged period of regional
ischemia in dogs and rabbits. This cardioprotective effect of MLA could be reversed by the administration of the
adenosine triphosphate (
ATP)-sensitive potassium channel (K(
ATP)) blockers,
glibenclamide, or
5-hydroxydecanoate. MLA also was shown to attenuate
myocardial stunning in dogs; however, its mechanism in this model remains unknown. Therefore the major aim of our study was to determine the dose-related effect of MLA to enhance contractile function in
stunned myocardium and to determine the role of the K(
ATP) channel in mediating its cardioprotective effect. To produce
myocardial stunning,
barbital-anesthetized dogs were subjected to five cycles of 5 min of left anterior descending (LAD) coronary artery occlusion interspersed with 10 min of reperfusion and finally followed by 2 h of reperfusion. Regional segment shortening (%SS) was determined by sonomicrometers implanted in the subendocardium of the ischemic region. Single intravenous doses of MLA in the range of 10-35 microg/kg given 24 h before
ischemia resulted in an improvement in %SS over a 2-h reperfusion period. Similar to results obtained in the canine and rabbit
infarct models, cardioprotection against stunning with MLA appears to require activation of K(
ATP) channels during
ischemia, because
glibenclamide (50 microg/kg, 15 min before
ischemia) completely blocked the effect of MLA to improve regional %SS during reperfusion. Cardioprotective doses of MLA were without effect on systemic hemodynamics, blood
gases, and pH throughout the experiment. No treatment-related effects on regional myocardial blood flow were observed during
ischemia or reperfusion. These results suggest that MLA improves %SS at doses of 10-35 microg/kg by an
ATP-sensitive potassium channel-dependent process, and that MLA may mimic the antistunning effects observed during the second window of ischemic preconditioning.