The acute effects of AICAR on purine nucleotide metabolism and postischemic cardiac function.

The purine precursor AICAR (5-amino-4-imidazolecarboxamide) has been advocated as a substrate for myocardial adenine nucleotide repletion during postischemic reperfusion. The purpose of this study was to investigate the acute effects of this agent on adenine nucleotides, inosine monophosphate, and postischemic ventricular function in an isolated rat heart preparation. The hearts were perfused at constant flow, either continuously for 90 minutes or for a 30 minute period followed by 10 minutes of global normothermic (37 degrees C) ischemia. The ischemic hearts were then reperfused for 15, 30, and 60 minutes. Both groups were treated with AICAR in a concentration of 100 mumol/L throughout the perfusion protocols. In the nonischemic time control group there was no effect on the levels of adenosine nucleotides or developed pressure over 90 minutes of perfusion. In contrast, AICAR treatment increased tissue inosine monophosphate content four-fold and sevenfold at 60 and 90 minutes, respectively (p less than 0.05), but had no effect on tissue adenosine monophosphate levels. During ischemia, there was a 50% decrease in adenosine triphosphate content in the AICAR-treated hearts and a thirteen-fold increase in adenosine monophosphate levels (p less than 0.05). After 60 minutes of reperfusion, adenosine triphosphate and monophosphate levels in the AICAR-treated hearts recovered to only 52% and 59% of preischemic values, respectively. These findings were similar to those observed in the untreated ischemic hearts. In contrast, tissue inosine monophosphate content in the AICAR-treated hearts during reperfusion remained significantly elevated and was fivefold greater than the reperfusion values in the untreated group. Concurrently, AICAR failed to enhance the recovery of postischemic left ventricular developed pressure. These results suggest that inhibition of the conversion of inosine monophosphate to adenosine monophosphate limits the usefulness of the agent in evaluating the temporal relationships between postischemic adenosine triphosphate repletion and recovery of myocardial function in the acute setting.