N-methyl-1-deoxynojirimycin (MOR-14), an alpha-glucosidase inhibitor, markedly reduced infarct size in rabbit hearts.

Abstract

BACKGROUND:

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

METHODS AND RESULTS:

MOR-14 dose-dependently decreased the alpha-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 alpha-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 alpha-1,6-glucosidase activity to approximately 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 alpha-1,6-glucosidase inhibition, because MOR-14 markedly decreased the alpha-1,6-glucosidase activity in the heart.

• Authors: M Arai, S Minatoguchi, G Takemura, Y Uno, T Kariya, H Takatsu, T Fujiwara, M Higashioka, Y Yoshikuni, H Fujiwara
• Journal: Circulation (Circulation) Vol. 97 Issue 13 Pg. 1290-7 (Apr 07 1998) ISSN: 0009-7322 [Print] United States
• PMID: 9570200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Glycoside Hydrolase Inhibitors
• 1-Deoxynojirimycin
• Lactic Acid
• Glycogen
• N-methyldeoxynojirimycin

Topics

• 1-Deoxynojirimycin (analogs & derivatives, therapeutic use)
• Animals
• Collateral Circulation (drug effects)
• Enzyme Inhibitors (therapeutic use)
• Glycogen (metabolism)
• Glycoside Hydrolase Inhibitors
• Hemodynamics (drug effects)
• Lactic Acid (metabolism)
• Male
• Molecular Structure
• Myocardial Infarction (drug therapy)
• Rabbits
• Risk Factors