Monophosphoryl lipid A induces delayed preconditioning against cardiac ischemia-reperfusion injury.

Monophosphoryl lipid A represents a novel agent capable of enhancing myocardial tolerance to ischemia/reperfusion injury. This cardioprotective activity of MLA manifests itself as a reduction in infarct size, myocardial stunning and dysrhythmias in multiple animal species. The drug appears to be efficacious in dogs and rabbits at doses of 10-35 micrograms/kg, with larger doses seemingly required in the rat. In the rabbit infarct model, protection appears 6 h following drug administration and lasts for 36 h. Although multifactorial mechanisms of ischemic tolerance may be induced by MLA, current evidence suggests that MLA's cardioprotective effects involve myocardial iNOS enzyme activation with nitric oxide coupled activation of myocardial KATP channels upon ischemic challenge. Monophosphoryl lipid A is presently being evaluated in Phase 2 clinical trials in patients undergoing cardiopulmonary bypass associated with coronary artery bypass engraftment or aortic valve replacement or reconstruction. Severity of lethal and reversible myocardial injury and dysrhythmia are study endpoints. Although further clinical testing will establish the utility of MLA as a cardioprotectant against ischemia/reperfusion injury in the human, presently this agent is proving very useful in expanding our understanding of mechanisms responsible for delayed cardiac preconditioning against ischemia/reperfusion injury.