Adenosine and preconditioning in the rat heart.

The report by Cave et al. [21] was a landmark paper which demonstrated that functional recovery protection by ischemic preconditioning (IPC) is not mediated by adenosine in the globally ischemic rat heart. This report raised several issues in the field of preconditioning. (1) It was enigmatic in that recent studies had demonstrated a predominant role of adenosine-receptors in preconditioning in the rabbit and dog so that the inability of adenosine to precondition in the rat implied that species differences might exist in the receptor pathways that lead to initiation of preconditioning. (2) Since rat cardiomyocyte metabolism preferentially relies upon exogenous glucose to support glycolysis, whereas the rabbit, dog, pig and man are more dependent upon endogenous glycogen, this report opened the possibility that species-dependent metabolic differences could also be involved in the mechanisms of IPC. (3) Since adenosine did not appear to precondition the rat, emphasis was placed on multiple G-protein coupled receptors that can induce preconditioning, e.g., α1-adrenergic-receptors in the rat [1], and on focused research on postreceptor, downstream events in the search for the ultimate mediators of protection. (4) Finally, the manuscript focused debate on the relationships between the mechanisms of preconditioning as assessed by functional recovery (stunning), reductions in arrythmias or ischemic cell death (infarction). Aortic flow during reperfusion is a sensitive end-point commonly used to assess postischemic functional recovery. Postischemic functional recovery is influenced by multiple parameters including: (1) degree of stunning during ischemia; (2) rate of anaerobic glycolysis; (3) ability to recover oxidative respiration, intracellular pH and ionic equilibrium; and (4) degree of diastolic contracture and vascular integrity at onset of reperfusion. Increased diastolic pressures subsequent to ischemic contracture reduce subendocardial perfusion such that zones of no-reflow may occur upon reperfusion. These subendocardial zones of no-reflow are a perfused heart artifact due …