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

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Abstract
Preischaemic treatment with N‐methyl‐1‐deoxynojirimycin (MOR‐14), an α‐1,6‐glucosidase inhibitor, attenuates glycogenolysis and lactate accumulation 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. To assess the effect of PKC inhibition on infarct size in MOR‐14‐treated hearts, 38 rabbits were subjected to 30 min of ischaemia followed by 48 h of reperfusion. Infarct size, as a per cent of area at risk, was significantly smaller in rabbits administered 100 mg kg−1 of MOR‐14 10 min before ischaemia (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 chelerythrine 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. Immunoblot analysis of PKC in homogenates of Langendorff‐perfused rabbit hearts revealed that MOR‐14 significantly increased levels of PKC‐ε in the particulate fraction at 20 and 30 min of ischaemia and in the cytosolic fraction at 30 min of ischaemia. Taken as a whole, our data suggest that PKC acts downstream of the inhibition of glycogenolysis by MOR‐14 to reduce infarct size. Thus, activation of PKC is a more direct mediator of the cardioprotection afforded by MOR‐14 than is inhibition of glycogenolysis. British Journal of Pharmacology (2001) 133, 635–642; doi:10.1038/sj.bjp.0704107

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