Interventions such as
glycogen depletion, which limit myocardial anaerobic glycolysis and the associated
proton production, can reduce myocardial ischemic injury; thus it follows that inhibition of glycogenolysis should also be cardioprotective. Therefore, we examined whether the novel
glycogen phosphorylase inhibitor 5-Chloro-N-[(1S,2R)-3-[(3R,4S)-3,4-dihydroxy-1-pyrrolidinyl)]-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-
indole-2-carboxamide (
ingliforib; CP-368,296) could reduce
infarct size in both in vitro and in vivo rabbit models of
ischemia-reperfusion injury (30 min of regional
ischemia, followed by 120 min of reperfusion). In Langendorff-perfused hearts, constant perfusion of
ingliforib started 30 min before regional
ischemia and elicited a concentration-dependent reduction in
infarct size;
infarct size was reduced by 69% with 10 microM
ingliforib. No significant
drug-induced changes were observed in either cardiac function (heart rate, left ventricular developed pressure) or coronary flow. In open-chest anesthetized rabbits, a dose of
ingliforib (15 mg/kg loading dose; 23 mg.kg(-1).h(-1) infusion) selected to achieve a free plasma concentration equivalent to an estimated EC(50) in the isolated hearts (1.2 microM, 0.55 microg/ml) significantly reduced
infarct size by 52%, and reduced plasma
glucose and
lactate concentrations. Furthermore, myocardial
glycogen phosphorylase a and total
glycogen phosphorylase activity were reduced by 65% and 40%, respectively, and
glycogen stores were preserved in
ingliforib-treated hearts. No significant change was observed in mean arterial pressure or rate-pressure product in the
ingliforib group, although heart rate was modestly decreased postischemia. In conclusion,
glycogen phosphorylase inhibition with
ingliforib markedly reduces myocardial ischemic injury in vitro and in vivo; this may represent a viable approach for both achieving clinical cardioprotection and treating diabetic patients at increased risk of
cardiovascular disease.