Monophosphoryl Lipid A: A Novel Agent for Inducing Pharmacologic Myocardial Preconditioning.
Myocardial tissue appears to possess an endogenous protective mechanism whereby brief ischemic periods precondition cells to better withstand both reversible and irreversible injury associated with prolonged subsequent ischemic events. Protection develops within minutes of transient ischemia, dissipates within 1-2 hours, and then reappears 12-24 hours following the preconditioning ischemic event. This phenomena, known as ischemic preconditioning (IP), is associated with limitation of infarct size, contractile stunning, and ventricular arrhythmias in postischemic/reperfused hearts. Preconditioned myocardium displays reduced anerobic metabolism. ATPase function, and, hence, improved ATP preservation during ischemia, reduced cytosolic calcium concentrations during reperfusion, and preservation of ultrastructural and myofilament integrity. Efforts to dissect the intracellular signal transduction pathway operative in IP have met with some success. Ischemic preconditioning is associated w ith activation of myocyte Gi protein-coupled receptors such as adenosine and acetylcholine, activation of PKC, production of nitric oxide, and, eventually, opening of ATP-sensitive potassium (KATP) channels. Preconditioning can also be elicited by pharmacologic means using adenosine receptor agonists, activators of PKC, nitric oxide inducers, and KATP openers, among other strategies. Monophosphoryl lipid A (MLA), a nontoxic derivative of the endotoxin pharmacophore lipid A, has been evaluated for cardioprotective activity in numerous preclinical models of cardiac ischemia/reperfusion injury. MLA, when given as a single dose pretreatment in various canine and rabbit models 12-24 hours prior to ischemia, limits infarct size and reduces regional and global contractile dysfunction. Cardioprotection in various models is associated with preservation of ATP during ischemia, enhanced 5'-nucleotidase and adenosine kinase function during reperfusion, and in these aspects mimics ischemic pr econditioning. Priming of KATP channel for enhanced opening during ischemia may be a prerequisite for the cardioprotective activity of MLA and is another feature establishing a similarity between MLA and ischemia induced preconditioning. Efforts continue to further our understanding regarding how MLA may regulate KATP channel and thereby precondition myocardium. Ongoing studies include evaluation of a possible direct effect on the KATP channel, investigation of the ability of MLA to induce a secondary mediator of potassium channel modulation, and evaluation of MLA's ability to phosphorylate the KATP channel as a consequence of kinase activation. Pretreatment with MLA represents a novel method of pharmacologically preconditioning myocardium, displaying a time course for development similar to that of the second window of ischemic preconditioning. Prior clinical experience with MLA indicates that intravenous doses of up to at least 20 µg/kg may be given safely to humans. The drug is c urrently being evaluated in patients undergoing coronary artery bypass engraftment surgery and may prove to be a useful way to protect myocardium from anticipated ischemic events.
Elliott
GT
Division of Pharmaceutical Development, Ribi ImmunoChem Research, Inc., 553 Old Corvallis Road, Hamilton, MT 59840.