HARNESSING AN ENDOGENOUS CARDIOPROTECTIVE MECHANISM - CELLULAR SOURCES AND SITES OF ACTION OF ADENOSINE

Endogenous adenosine is produced by the heart during ischemia-reperfus ion as a natural cardioprotectant. The benefits of this local protecti ve mechanism can be harnessed by ischemic preconditioning and amplifie d by drugs such as acadesine, that augment extracellular adenosine lev els specifically during an ischemic event. Classically, adenosine prod uction by cardiomyocytes, and measured in the interstitial fluid, is c onsidered the relevant source of this mediator, In contrast, it is pro posed that there are two independent sites of adenosine formation in t he heart-the myocytes and the endothelial cells, that are differential ly regulated. Recent evidence implicates the vascular endothelium as a potentially important site of both adenosine formation and action tha t subserves the cardioprotective effects of the nucleoside, The mechan isms by which endogenous adenosine protects the heart from ischemia-re perfusion injury require clarification, and may involve different aden osine receptors (A1, A2, and A3) acting through various second messeng er systems that contribute to the overall response. Additional studies are required to define the source of adenosine, the mechanisms by whi ch its levels are regulated, and the effector pathways responsible for the myocardial protection observed.