Sustained nonoxidative glucose utilization and depletion of glycogen in reperfused canine myocardium

Abstract

Ischemically injured reperfused myocardium is characterized by increased 18F-fluorodeoxyglucose uptake as demonstrated by positron emission tomography. To elucidate the metabolic fate of exogenous glucose entering reperfused myocardium, D-[6-14C] glucose and L-[U-13C] lactate were used to determine glucose uptake, glucose oxidation and the contribution of exogenous glucose to lactate production. The pathologic model under investigation consisted of a 3 h balloon occlusion of the left anterior descending coronary artery followed by 24 h of reperfusion in canine myocardium. The extent and severity of myocardial injury after the ischemia and reperfusion were assessed by histochemical evaluation (triphenyltetrazolium chloride and periodic acid-Schiff stains). Thirteen intervention and four control dogs were studied. The glucose uptake in the occluded/reperfused area was significantly enhanced compared with that in control dogs (0.40 +/- 0.14 versus 0.15 +/- 0.10 mumol/ml, respectively). In addition, a significantly greater portion of the glucose extracted immediately entered glycolysis in the intervention group (75%) than in the control dogs (33%). The activity of the nonoxidative glycolytic pathway was markedly increased in the ischemically injured reperfused area, as evidenced by the four times greater lactate release in this area compared with the control value. The dual carbon-labeled isotopes showed that 57% of the exogenous glucose entering glycolysis was being converted to lactate. Exogenous glucose contributed to greater than 90% of the observed lactate production. This finding was confirmed by the histochemical finding of sustained glycogen depletion in the occlusion/reperfusion area. The average area of glycogen depletion (37%) significantly exceeded the average area of necrosis (17%). These data demonstrate enhanced and sustained activity of the nonoxidative glycolytic pathway after a prolonged occlusion with reperfusion in canine myocardium. Because glycogen stores remain depleted, exogenous glucose becomes an important myocardial substrate under these pathologic conditions.

Persistent Changes in Myocardial Glucose Metabolism In Vivo During Reperfusion of a Limited-Duration Coronary Occlusion

“…This rate was chosen to raise the steady-state 13 C enrichments of plasma glucose and its myocardial intermediary metabolite pools to levels sufficient for precise measurement without raising plasma glucose concentration. As originally demonstrated by Lewandowski and others, 4,9 during continuous infusion of D- [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glucose, the myocardial pyruvate pool accumulates [3-13 C]pyruvate in proportion to that fraction of total glycolytic substrate contributed by circulating glucose relative to other carbon sources (eg, 12 C-glycogen). Myocardial concentrations of pyruvate are generally too low for its 13 C enrichment to be measured in small samples, but pyruvate is in equilibrium through transaminase reactions with the larger alanine pool.…”

“…Samples were then stored for 2 hours to allow complete decay of 13 N (t 1/2 ϭ10 minutes) and recounted for residual 18 F (t 1/2 ϭ110 minutes). 13 N counts per gram were …”

“…Total GS activity was defined as that observed at saturating (7.2 mmol/L) glucose-6-phosphate. Similarly, physiological (GP-a) and total GP activities were measured as the rates of incorporation of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]glucose-1-phosphate into glycogen in the absence and presence, respectively, of 5 mmol/L adenosine monophosphate. Activities are reported as the fraction of total activity present in the GS-i or GP-a forms.…”

“…Samples were counted immediately in a Beckmann gamma well counter to determine total radioactivity (ie, 13 N plus 18 F) per gram of myocardium. Correction factors were used to account for radioactive decay during counting.…”

Quantitative assessment of prolonged metabolic abnormalities in reperfused canine myocardium.

“…[4][5][6][7] The increase in glucose ; by an investigative group uptake in reperfused myocardium 24 hours after reperfusion reflects at least in part enhanced nonoxidative glucose utilization. 3 Qualitative evaluation of glucose utilization in chronically instrumented dogs demonstrated that glucose metabolism remained significantly higher in postischemic myocardium relative to remote normal myocardium 1 week after reperfusion.2 Quantitative measurements in chronically instrumented dogs demonstrated that relative enhancement of glucose metabolism in postischemic myo-cardium was observed only when glucose metabolism in normal myocardium was low. 1 Depressed oxygen consumption has also been demonstrated in reperfused myocardium, both acutely4,8-10 and 24 hours after reperfusion,4 although it should be noted that others have found normal'1 or even increased12 oxygen consumption in postischemic myocardium.…”