ADENOSINE PREVENTS PROTEIN-KINASE-C ACTIVATION DURING HYPOTHERMIC ISCHEMIA

Background The cardioprotective properties of exogenous and endogenous ly produced adenosine during ischemia have been shown previously. The models used to demonstrate the efficacy and mechanism of effect have b een primarily of normothermic ischemia where adenosine was given pre-i schemia in an effort to mimic the preconditioning phenomena. The propo sed mechanisms responsible for the protective effects of adenosine inc lude A(2)-receptor mediated vasodilation, A(1)-receptor mediated impro vement of glycolysis during ischemia and early reperfusion, and intera ction with protein kinase C (PKC) pre-ischemia. This study was designe d to assess the dose-dependent effects of adenosine on myocardial reco very after prolonged hypothermic ischemia. Methods and Results Using a n isolated Langendorff perfused rabbit heart model, we subjected heart s to 8 hours of hypothermic ischemia with crystalloid cardioplegia con taining adenosine 0, 0.01, 0.25, or 5 mmol/L followed by reperfusion. Pre-and postischemic (30 minutes of reperfusion) diastolic and develop ed pressure were compared among the groups. Translocation of PKC from cytosol to membrane, tissue levels of ATP, and total lactate productio n during ischemia were also determined. ATP levels at end-ischemia wer e higher in all adenosine-treated hearts, along with significantly enh anced anaerobic glycolysis as measured by total lactate production. Re covery of left ventricular diastolic pressure and developed pressure, however, were improved significantly only in hearts exposed to higher adenosine concentrations (0.25 and 5 mmol/L). The higher dose adenosin e cardioplegia also prevented translocation of PKC from cytosol to mem brane during ischemia. Conclusions We conclude that adenosine provides significant protection of the ischemic myocardium during prolonged hy pothermic ischemia and that 0.25 mmol/L adenosine was equally as prote ctive as 5 mmol/L. The mechanism of protection is most likely not rela ted to ATP preservation or enhanced glycolysis but may be caused by pr evention of PKC translocation during ischemia.