Role of protein kinase C in the reduction of infarct size by N-methyl-1-deoxynojirimycin, an alpha-1,6-glucosidase inhibitor.
Preischaemic treatment with N-methyl-1-deoxynojirimycin (MOR-14), an alpha-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-epsilon 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.
Arai
M
M
The 2nd Department of Medicine, Gifu University School of Medicine, Gifu, Japan.
Minatoguchi
S
S
Kumada
H
H
Uno
Y
Y
Nishida
Y
Y
Hashimoto
K
K
Wang
N
N
Takemura
G
G
Fujiwara
T
T
Higashioka
M
M
Kuwano
K
K
Fujiwara
H
H
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006003:Glycogen / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors; D007527:Isoenzymes / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D011817:Rabbits; D013997:Time Factors; D000520:alpha-Glucosidases / Q000378:metabolism
D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007527:Isoenzymes; D007773:Lactates; D017485:1-Deoxynojirimycin; D006003:Glycogen; D011493:Protein Kinase C; D000520:alpha-Glucosidases; C033424:N-methyldeoxynojirimycin