Diabetes increases the incidence of cardiovascular disease as well as the complications of myocardial infarction. Studies using animal models of diabetes have demonstrated that the metabolic alterations occurring at the myocyte level may contribute to the severity of ischemic injury in diabetic hearts. Of the several mechanisms being investigated to understand the pathogenesis of diabetic complications, the increased metabolism of glucose via the polyol pathway has received considerable attention. Deviant metabolic regulation due to increased flux through aldose reductase in diabetic hearts may influence the ability of the myocardium to withstand ischemia insult. To determine if aldose reductase inhibition improves tolerance to ischemia, hearts from acute type I diabetic and nondiabetic control rats were isolated and retrograde perfused. Each group was exposed to 1 μmol/l zopolrestat, a specific inhibitor of aldose reductase, for 10 min, followed by 20 min of global ischemia and 60 min of reperfusion in the absence of zopolrestat. Zopolrestat reduced sorbitol levels before ischemia in diabetic hearts. The cytosolic redox state (NADH/NAD+), as measured by lactate-topyruvate ratios, was significantly lowered under baseline, ischemic, and reperfusion conditions in diabetic hearts perfused with zopolrestat. In these diabetic hearts, ATP was significantly higher in zopolrestat hearts during ischemia, as were phosphocreatine and left ventricular–developed pressure on reperfusion. Zopolrestat provided similar metabolic and functional benefits in nondiabetic hearts. Creatine kinase release was reduced by ∼50% in both nondiabetic and diabetic hearts treated with zopolrestat. These data indicate that inhibition of aldose reductase activity preserves high-energy phosphates, maintains a lower cytosolic NADH/NAD+ ratio, and markedly protects both diabetic and nondiabetic hearts during ischemia and reperfusion.
Skip Nav Destination
Article navigation
Original Articles|
February 01 1997
Aldose Reductase Inhibition Protects Diabetic and Nondiabetic Rat Hearts from Ischemic Injury
Ravichandran Ramasamy;
Ravichandran Ramasamy
1
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California
Davis, California
Search for other works by this author on:
Peter J Oates;
Peter J Oates
2
Department of Metabolic Diseases, Central Research Division, Pfizer, Inc
Groton, Connecticut
Search for other works by this author on:
Saul Schaefer
Saul Schaefer
1
Department of Internal Medicine, Division of Cardiovascular Medicine, University of California
Davis, California
Search for other works by this author on:
Address correspondence and reprint requests to Dr. Ravichandran Ramasamy, Division of Cardiovascular Medicine, TB 172, Bioletti Way, University of California, Davis, CA 95616.
1
ANOVA, analysis of variance; C group, nondiabetic control group; CK, creatine kinase; DC group, diabetic control group; DZ, aldose reductase inhibitor–treated diabetic group; L/P ratio, lactate-to-pyruvate ratio; LVDP, left ventricular–developed pressure; LVEDP, left ventricular end-diastolic pressure; PCr, phosphocreatine; 31P NMR, 31P nuclear magnetic resonance; Z group, nondiabetic group.
Diabetes 1997;46(2):292–300
Article history
Received:
October 25 1995
Revision Received:
September 12 1996
Accepted:
September 12 1996
PubMed:
9000707
Citation
Ravichandran Ramasamy, Peter J Oates, Saul Schaefer; Aldose Reductase Inhibition Protects Diabetic and Nondiabetic Rat Hearts from Ischemic Injury. Diabetes 1 February 1997; 46 (2): 292–300. https://doi.org/10.2337/diab.46.2.292
Download citation file:
101
Views