Monophosphoryl lipid A (MLA), a derivative of the minimal substructure of
lipopolysaccharide (
lipid A) possesses immunomodulatory activity of the parent
lipid A yet enjoys reduced toxicity. It has previously been reported that pretreatment with MLA reduces
myocardial infarct size and stunning in dogs following
ischemia and reperfusion. The aim of this study was to evaluate the ability of
monophosphoryl lipid A (MLA) to preserve global cardiac function and peripheral hemodynamics in a rabbit model of prolonged regional
ischemia (90 min), and reperfusion (6 h). An evaluation of potential mechanisms by which MLA may preserve cardiac function was also undertaken. Single dose pretreatment with MLA (35 micrograms/kg i.v.) 24 h prior to
ischemia resulted in significant improvement in left ventricular developed pressure, dP/dt, rate-pressure product and mean arterial pressure during reperfusion (P < 0.05 v control). Although in this model of prolonged
ischemia MLA pretreatment did not reduce
infarct size (54.5 +/- 11.4% in control v 63.3 +/- 8.3% in MLA, P = N.S.), evaluation of myocardial adenylate and
adenosine catabolite pools at the end of
ischemia indicated a preservation of
ATP and
ADP and a decreased production of downstream
adenosine catabolites including
inosine,
xanthine and
uric acid.
Adenosine kinase, but not
5'-nucleotidase (5'-NTase) or
adenosine deaminase activity determined following reperfusion was 76% and 60% higher (P < 0.05) in non-risk and post-ischemic myocardium of MLA pretreated rabbits compared with controls. Although there was a trend toward lower tissue
myeloperoxidase activity in post-ischemic myocardium from treated rabbits, the results were not significantly different from control animals. These results suggest that a 24-h pretreatment with MLA, without further treatment during
ischemia or reperfusion was associated with: (1) preservation of global myocardial function during reperfusion; (2) preservation of myocardial high energy adenylates and reduced formation of
adenosine catabolites during
ischemia; (3) elevated myocardial
adenosine kinase activity. Increased recycling of
adenosine to phosphorylated
nucleotides may result from MLA's affect on
adenosine kinase, which could explain the drugs effect on adenylate and
adenosine metabolite pools.