CARDIAC FUNCTIONAL PRESERVATION BY MONOPHOSPHORYL LIPID A IN A RABBITMODEL OF PROLONGED REGIONAL CARDIAC ISCHEMIA AND REPERFUSION

A rabbit model of prolonged regional ischaemia is described which allo ws assessment of deteriorating global cardiac function following coron ary artery occlusion, such functional deterioration continuing through out a subsequent three-hour period of reperfusion. In comparison with baseline left ventricular developed pressure (LVDP) and rate pressure product (RPP), vehicle-treated control rabbits experienced more than a 40% loss of function following 90 min of ischaemia and 3h of reperfus ion. Rabbits intravenously administered monophosphoryl lipid A (MLA) 2 4h prior to undergoing regional cardiac ischaemia displayed significan t preservation across time of LVDP and RPP; at some MLA dose levels th e minimal loss (10%) of baseline global function was no worse than tha t observed in non-infarcted sham-operated rabbits. Preservation in LVD P and RPP observed in MLA-pretreated rabbits was not associated with a positive inotropic and/or chronotropic effect of the drug at the pre- ischaemic baseline. Increases in serum creatine phosphokinase concentr ations were restrained in MLA-treated rabbits as compared to control a nimals. MLA represents a novel pharmacologic class of cardiac ischaemi a reperfusion injury protective agents; namely immunomodulators which may have the ability to, for example, reduce post-ischaemic inflammato ry response, as has been previously reported.