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(Circulation. 1998;97:1290-1297.)
© 1998 American Heart Association, Inc.

Basic Science Reports

N-Methyl-1-Deoxynojirimycin (MOR-14), an -Glucosidase Inhibitor, Markedly Reduced Infarct Size in Rabbit Hearts

Masazumi Arai, MD; Shinya Minatoguchi, MD; Genzou Takemura, MD; Yoshihiro Uno, MD; Tatsuya Kariya, MD; Hisato Takatsu, MD; Takako Fujiwara, MD; Masaya Higashioka, MS; Yoshiaki Yoshikuni, PhD; ; Hisayoshi Fujiwara, MD

From the 2nd Department of Internal Medicine, Gifu University School of Medicine; Kyoto Women's University (T.F.); and Nippon Shinyaku Co, Ltd (M.H., Y.Y.), Kyoto, Japan.

Correspondence to Hisayoshi Fujiwara, the 2nd Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-Machi, Gifu 500, Japan.

Background—N-methyl-1-deoxynojirimycin (MOR-14), an -glucosidase inhibitor, reduces the glycogenolytic rate by inhibiting the -1,6-glucosidase of glycogen-debranching enzyme in the liver, in addition to possessing an antihyperglycemic action by blocking -1,4-glucosidase in the intestine. Because the reduction of the glycogenolytic rate may be one of the mechanisms of myocardial protection in ischemic preconditioning, the compounds inhibiting myocardial -1,6-glucosidase may be protective against ischemic damage. Thus, we investigated whether MOR-14 could inhibit -1,6-glucosidase and reduce the infarct size in rabbit hearts without collateral circulation.

Methods and Results—MOR-14 dose-dependently decreased the -1,6-glucosidase activity in rabbit heart extract. A tracer study demonstrated the myocardial uptake of a considerable amount of MOR-14 sufficient to fully inhibit -1,6-glucosidase. To assess the infarct size–reducing effect of MOR-14, 54 rabbits were subjected to 30-minute coronary occlusion followed by 48-hour reperfusion. Preischemic treatment with 25, 50, and 100 mg/kg of MOR-14 dose-dependently reduced the infarct size (to 26±4%, 19±3%, and 14±2% of the area at risk, respectively), compared with the saline control (45±5%) without altering the blood pressure or heart rate. Another 40 rabbits given 100 mg of MOR-14 or saline 10 minutes before ischemia were euthanized at 10 or 30 minutes of ischemia for biochemical analysis. MOR-14 decreased the -1,6-glucosidase activity to 20% in vivo, reduced the glycogen breakdown, and attenuated the lactate accumulation at both 10 and 30 minutes of ischemia.

Conclusions—Preischemic treatment with MOR-14 preserved glycogen, attenuated the accumulation of lactate, and reduced the myocardial infarct size by 69%. This cardioprotective effect was independent of changes of blood pressure and heart rate or regional blood flow. It may be associated with -1,6-glucosidase inhibition, because MOR-14 markedly decreased the -1,6-glucosidase activity in the heart.

Key Words: glucose • ischemia • metabolism • myocardial infarction • pharmacology

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