MONOPHOSPHORYL LIPID-A INDUCES PHARMACOLOGICAL PRECONDITIONING IN RABBIT HEARTS WITHOUT CONCOMITANT EXPRESSION OF 70-KDA HEAT-SHOCK PROTEIN(VOL 156, PG 1, 1996)

The purpose of this study was to evaluate the protective effect of a n ew endotoxin analogue, monophosphoryl lipid A (MLA) in a rabbit model of myocardial ischemia/reperfusion and to show if this protection was mediated via synthesis of 70 kDa heat shock protein (HSP 70). Three gr oups of New Zealand White rabbits underwent 30 min coronary occlusion, followed by 4 hours reperfusion. First group of rabbits (n = 6) were treated with 0.35 ml vehicle (40% propylene glycol, 10% ethanol in wat er). The second and third group of rabbits (n = 6-8) were treated with MLA (35 mu g/kg, i.v.) 12 and 24 hours prior to ischemia and reperfus ion. MLA treatment either 12 or 24 h prior to ischemia/reperfusion dem onstrated significantly reduced infarct size (12.5 +/- 1.7 and 14.7 +/ - 2.1% for 12 and 24 h) when compared with vehicle control (40.4 +/- 8 .6%, mean +/- S.E.M, p < 0.05). No significant differences in the infa rct size was observed between the 12 and 24 h MLA treated groups. The area at risk was not significantly different between the three groups. Baseline values of heart rate, systolic and diastolic blood pressure were not significantly different between the control and MLA treated g roups. However, the systolic as well as diastolic blood pressure durin g reperfusion were significantly lower in rabbits treated with MLA. We stern blot analysis of the protein extracts of the hearts (n = 2/group ) demonstrated no increase in the expression of the inducible form of HSP 70 following treatment with MLA. We conclude that MLA has signific ant anti-infarct effect in rabbit which is not mediated by the cardiop rotective protein HSP 70. The anti-infarct effect of this drug is supe rior to the reported protective effects of delayed ischemic or heat st ress preconditioning. We hypothesize that the pharmacologic preconditi oning afforded by MLA is accomplished via a unique pathway that bypass es the usual intracellular signaling pathways which lead to the myocar dial protection with the expression of heat shock proteins.