OPTIMAL MYOCARDIAL PRECONDITIONING IN A HUMAN-MODEL OF ISCHEMIA AND REPERFUSION

Background-Adenosine (ADE) may mediate the protective effects of preco nditioning (PC). However, human data are lacking, and the optimal meth od of ADE administration and the mechanism of protection remain unreso lved. Methods and Results We have developed a model of simulated ''isc hemia'' (I) and ''reperfusion'' (R) in quiescent human ventricular car diomyocytes. Cellular injury and metabolic parameters were assessed af ter various interventions: Cells were preconditioned with anoxia (PC0) , hypoxia (PC16), anoxic supernatant (SUP0), or hypoxic supernatant (S UP16) with or without the ADE receptor antagonist (SPT) or ADE deamina se (ADA). ADE was applied before, during, or after I or continuously w ith and without SPT. Cells were treated with the PKC agonist PMA. PC c ells were incubated with the protein kinase-C (PKC) antagonist Calphos tin-C (Cal-C). PKC translocation and PKC activity were assessed. PCO w as most protective. Protection was transferable via SUP0, which produc ed the highest concentrations of ADE. Protection was lost with SPT or ADA. Intracellular ATP fell after PC and prolonged I and R. Exogenous ADE was most protective when administered before I at 50 mu mol. ADE d uring I was partially protective. No additional protection was provide d with continuous ADE treatment. ADE prevented ATP degradation but inc reased lactate immediately after its administration. SPT abolished the protective effects of ADE. PMA conferred protection, which was abolis hed with Cal-C. ADE stimulated PKC translocation and PKC activity in t he absence of SPT. Conclusions-Maximal I confers maximal PC. The degre e of I is reflected in supernatant ADE concentrations. The initial ATP fall with PC may account for a lack of ATP preservation after I and R . ADE reproduces the protective effects of PC, preserves ATP, and incr eases lactate production, perhaps by stimulating glycolysis. Clinical trials of ADE administered during cardiac surgery are necessary to fur ther define its beneficial effects in humans.