Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia.

Abstract

Myocardial regions perfused through a coronary stenosis may cease contracting, but remain viable. Clinical observations suggest that increased glucose utilization may be an adaptive mechanism in such "hibernating" regions. In this study, we used a combination of 13 C-NMR spectroscopy, GC-MS analysis, and tissue biochemical measurements to track glucose through intracellular metabolism in intact dogs infused with [1-13 C]glucose during a 3-4-h period of acute ischemic hibernation.During low-flow ischemia [3-13 C]alanine enrichment was higher, relative to plasma [1-13 C]glucose enrichment, in ischemic than in nonischemic regions of the heart, suggesting a greater contribution of exogenous glucose to glycolytic flux in the ischemic region ( ‫ف‬ 72 vs. ‫ف‬ 28%, P Ͻ 0.01). Both the fraction of glycogen synthase present in the physiologically active glucose-6-phosphate-independent form (46 Ϯ 10 vs. 9 Ϯ 6%, P Ͻ 0.01) and the rate of incorporation of circulating glucose into glycogen (94 Ϯ 25 vs. 20 Ϯ 15 nmol/ gram/min, P Ͻ 0.01) were also greater in ischemic regions. Measurement of steady state [4-13 C]glutamate/[3-13 C]alanine enrichment ratios demonstrated that glucose-derived pyruvate supported 26-36% of total tricarboxylic acid cycle flux in all regions, however, indicating no preference for glucose over fat as an oxidative substrate in the ischemic myocardium. Thus during sustained regional low-flow ischemia in vivo, the ischemic myocardium increases its utilization of exogenous glucose as a substrate. Upregulation is restricted to cytosolic utilization pathways, however (glycolysis and glycogen synthesis), and fat continues to be the major source of mitochondrial oxidative substrate. ( J. Clin. Invest. 1996. 98:62-69.)

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

“…7,8 After 40 minutes, hearts were excised and central portions of each region frozen in liquid nitrogen for measurement of tissue glycogen concentration, glycogen synthesis rates, and the activities of glycogen synthase (GS) and glycogen phosphorylase (GP) enzymes.…”

“…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.…”

“…7,8 Purified glycogen samples were then counted for 3 H and the results (dpm/g) divided by the average arterial plasma D- [3-3 H]glucose specific radioactivity (dpm/mol glucose) during each study to calculate regional glycogen synthesis rates (mol glucose ⅐ g Ϫ1 ⅐ min Ϫ1 ). 7,8 …”

“…7,8 For GS, the activity of the physiologically active (glucose-6-phosphate independent; GS-i) form of the enzyme was defined as the rate (mol/g/min) of incorporation of [U- 14 C]uridine diphosphoglucose into glycogen at physiological (0.17 mmol/L) concentration of the enzyme's activator, glucose-6-phosphate. Total GS activity was defined as that observed at saturating (7.2 mmol/L) glucose-6-phosphate.…”

“…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.…”