S.T. Rapundalo*, J.J. Edmunds and K.P. Gallagher Pages 483 - 506 ( 24 )
Ischemic preconditioning is a recently discovered phenomenon induced in the heart by a brief period of ischemia, which in tum makes the myocardium tolerant to a subsequent sustained and lethal ischemic epdisode. The discovery of this endogenous cytoprotective response has generated intense research interest towards identifying potential pharmacological therapies which could mimic ischemic preconditioning. The net effect of these agents would result in a reduction of infarct size and an enhancement in functional recovery of the postischemic myocardium. Various cellular and molecular mechanisms have been implicated in underlying the preconditioning response. Primary initiation seems to be through activation of Gi-protein coupled receptors, and in particular that of adenosine A1 and/or A3 subtypes. In addition, activation by muscarinic, o:-adrenergic, and vasoactive peptide (bradykinin, angiotensin II, and endothelin) receptor agonists has been shown to induce cardioprotection. Currently, the signal transduction pathways linking receptor activation with the protective effect are unclear, though they appear to be complex. Both phospholipase C and protein kinase C activation have been implicated in this regard. The final cellular effector of preconditioning has thus far remained elusive, though speculation has emerged that the target may be a phosphoprotein. As such, evidence that potassium channel openers can mimic preconditioning, have implicated the cardiac KATP channel as one such potential site for phosphorylation. Other possible effectors include stress proteins and anti-oxidant processes. This review will summarize the mechanisms involved in ischemic preconditioning, as well as the pharmacological approaches and agents that are currently available to exploit this unique cytoprotective phenomenon.