Role of protein kinase C in the reduction of infarct size by N-methyl-1-deoxynojirimycin, an alpha-1,6-glucosidase inhibitor

1 Ploischaemic treatment with N-methyl-1-deoxynojirimycin (MOR-14), an alph a -1,6-glucosidase inhibitor, attenuates glycogenolysis and lactate accumul ation during ischaemia and markedly reduces infarct size in rabbit hearts. In the present study, we have investigated whether protein kinase C (PKC), a principal mediator of ischaemic preconditioning, is also involved in the cardioprotective effect of MOR-14. 2 To assess the effect of PKC inhibition on infarct size in MOR-13-treated hearts, 38 rabbits were subjected to 30 min of ischaemia followed by 48 h o f reperfusion. Infarct size, as a per cent of area at risk, was significant ly smaller in rabbits administered 100 mg kg(-1) of MOR-14 10 min before is chaemia (17 +/- 2%, n=10), than in a control group (46 +/- 5%, n=10). This beneficial effect of MOR-14 was abolished when 5 mg kg(-1) of chelerythrine , a PKC inhibitor, was given 10 min prior to MOR-14 injection (39 +/- 4%, n =10), although chelelythrine alone did not alter infarct size (43 +/- 4%, n =8). Further, chelerythrine had no effect on MOR-14-induced attenuation of glycogen breakdown and lactate accumulation in hearts excised at 30 min of ischaemia. 3 Immunoblot analysis of PKC in homogenates of Langendorff-perfused rabbit hearts revealed that MOR-14 significantly increased levels of PKC-e in the particulate fraction at 20 and 30 min of ischaemia and in the cytosolic fra ction at 30 min of ischaemia. 4 Taken as a whole, our data suggest that PKC acts downstream of the inhibi tion of glycogenolysis by MOR-14 to reduce infarct size. Thus, activation o f PKC is a more direct mediator of the cardioprotection afforded by MOR-14 than is inhibition of glycogenolysis.