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Myocardial ischemic injury in experimental diabetes

University of British Columbia

The nature and extent of myocardial ischemic injury (Mil) produced either by coronary artery ligation/reperfusion or by injection of isoproterenol (ISO) was studied in the 10-week alloxan-diabetic rabbit. Prior to the induction of ischemic injury, investigation of the left ventricles of the diabetic rabbit after 10-weeks revealed significant magnesium depletion and inhibition of myofibrillar and sarcoplasmic reticulum ATPase activities. In addition, the activity of the lysosomal enzyme, N-acetyl-β-glucosaminidase was significantly increased in diabetic left ventricular homogenates. Ultrastructural studies revealed significant lipid and glycogen accumulation, dilatation of the sarcoplasmic reticulum and damage to the mitochondria in left ventricles of the diabetic animals. Administration of ISO to both control and diabetic animals resulted in atrial tachycardias and ventricular fibrillation. The severity of the arrhythmias and the overall mortality was the same in both groups of animals. Serum analyses revealed significantly greater increases in blood glucose, free fatty acids, total cholesterol and creatine kinase activity in the ISO-treated diabetic animals relative to ISO-treated controls. ISO treatment of both control and diabetic animals produced similar increases in heart weight, left ventricular weight and myocardial water content. Analyses of various subcellular organelle marker enzyme activities indicated a significantly greater decrease in the K⁺ ,Ca²⁺ -stimulated sarcoplasmic reticulum ATPase of ISO-treated diabetic animal hearts. In addition, significantly greater increases in Ca and hydroxyproline and decreases in the levels of ATP were evident in the ISO-treated diabetic animal hearts. Ultra-structural studies revealed significant damage to the mitochondria in both ISO-treated control and diabetic hearts, the magnitude of the damage being greater in the diabetic animals. Mitochondria from both groups of animals showed swelling and fragmentation, myofibrils appeared as a homogeneous mass and did not show the characteristic Z-lines. Glycogen depletion and lipid accumulation was observed in both groups of animals. In addition, both groups of animals showed amorphous dense bodies in the mitochondria after ISO-treatment. After 40-minutes occlusion of the left circumflex coronary artery followed by 60-minutes of reperfusion, hemodynamic measurements revealed significant decreases in the left ventricular and systemic arterial pressures in the diabetic animals relative to controls. Analyses of subcellular organelle enzymes from the ischemic tissue revealed that sarcolemmal Na⁺ ,K⁺ -ATPase, mitochondrial ATPase and sarcoplasmic reticulum ATPase activities were decreased after coronary occlusion in both control and diabetic animals. However, upon reperfusion, unlike the control, no recovery of the mitochondrial ATPase was observed in the diabetic animals. In addition, a further depression of both the sarcolemmal and sarcoplasmic reticulum ATPase activities were seen in the diabetic animals compared to controls on reperfusion. Ion measurements revealed a significant accumulation of calcium in both control and diabetic animals, the magnitude of the increase being greater in the diabetic animals. Similarly, both tissue ATP levels and the ability of the mitochondria to generate ATP were depressed in the diabetic animals as compared to controls following coronary artery occlusion and reperfusion. Following coronary artery ligation and reperfusion, the diabetic animals showed a significantly higher incidence of ventricular fibrillation and cardiogenic shock as compared to controls. Ultrastructural studies revealed myocardial damage to both control and diabetic hearts following coronary artery ligation and reperfusion. However, the diabetic myocardium showed a higher incidence and frequency of hypercontraction bands, an increase in the amorphous dense bodies and slightly greater damage to the mitochondria. Coronary artery ligation in conscious control, 6 and 12 week-diabetic rats resulted in post-ligation arrhythmias (especially ventricular fibrillation), the incidence of which was much greater in the diabetic animals. The mortality rate of 12-week diabetic rats undergoing coronary ligation was 100% within 1-7 minutes following ligation. No differences in occluded or infarcted zones of the surviving 6-week diabetic and control rats were detected. Analyses of ionic composition revealed a significant magnesium deficiency in the diabetic hearts as compared to controls. These data indicate that the diabetic animals show a greater susceptibility of the myocardium to ischemic injury. Although numerous metabolic and chemical alterations are present in the diabetic myocardium, it is possible that magnesium deficiency may be a factor determining the higher incidence of arrhythmias and ischemic injury in diabetic animals.

Text

2010-06-11

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http://hdl.handle.net/2429/25562

Pharmaceutical Sciences

University of British Columbia

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