Adenosine prevents protein kinase C activation during hypothermic ischemia

The cardioprotective properties of exogenous and endogenously produced adenosine during ischemia have been shown previously. The models used to demonstrate the efficacy and mechanism of effect have been primarily of normothermic ischemia where adenosine was given pre-ischemia in an effort to mimic the preconditioning phenomena. The proposed mechanisms responsible for the protective effects of adenosine include A2-receptor mediated vasodilation, A1-receptor mediated improvement of glycolysis during ischemia and early reperfusion, and interaction with protein kinase C (PKC) pre-ischemia. This study was designed to assess the dose-dependent effects of adenosine on myocardial recovery after prolonged hypothermic ischemia.

Using an isolated Langendorff perfused rabbit heart model, we subjected hearts to 8 hours of hypothermic ischemia with crystalloid cardioplegia containing adenosine 0, 0.01, 0.25, or 5 mmol/L followed by reperfusion. Pre- and postischemic (30 minutes of reperfusion) diastolic and developed pressure were compared among the groups. Translocation of PKC from cytosol to membrane, tissue levels of ATP, and total lactate production during ischemia were also determined. ATP levels at end-ischemia were higher in all adenosine-treated hearts, along with significantly enhanced anaerobic glycolysis as measured by total lactate production. Recovery 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 adenosine cardioplegia also prevented translocation of PKC from cytosol to membrane during ischemia.

We conclude that adenosine provides significant protection of the ischemic myocardium during prolonged hypothermic ischemia and that 0.25 mmol/L adenosine was equally as protective as 5 mmol/L. The mechanism of protection is most likely not related to ATP preservation or enhanced glycolysis but may be caused by prevention of PKC translocation during ischemia.