title: 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.
  
  
  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.affiliation: 2nd Department of Internal Medicine, Gifu University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Arai
authors.forename: S
authors.initials: S
authors.lastname: Minatoguchi
authors.forename: G
authors.initials: G
authors.lastname: Takemura
authors.forename: Y
authors.initials: Y
authors.lastname: Uno
authors.forename: T
authors.initials: T
authors.lastname: Kariya
authors.forename: H
authors.initials: H
authors.lastname: Takatsu
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.forename: M
authors.initials: M
authors.lastname: Higashioka
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshikuni
authors.forename: H
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D003097:Collateral Circulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006003:Glycogen / Q000378:metabolism*; D065089:Glycoside Hydrolase Inhibitors; D006439:Hemodynamics / Q000187:drug effects; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D009203:Myocardial Infarction / Q000188:drug therapy*; D011817:Rabbits; D012307:Risk Factors
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D017485:1-Deoxynojirimycin; D019344:Lactic Acid; D006003:Glycogen; C033424:N-methyldeoxynojirimycin