Glucose delivery is a major determinant of glucose utilisation in the ischemic myocardium with a residual coronary flow

doi:10.1016/S0008-6363(98)00100-X

Cardiovascular Research 1998 39(2):381-392; doi:10.1016/S0008-6363(98)00100-X
© 1998 by European Society of Cardiology

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Glucose delivery is a major determinant of glucose utilisation in the ischemic myocardium with a residual coronary flow

Linda M King^* and Lionel H Opie

MRC/UCT Ischemic Heart Disease Research Unit, UCT Medical School, Observatory, Cape Town, South Africa

^* Corresponding author. Tel.: +44 (1865) 275 275; Fax: +44 (1865) 275 259; E mail: linda@bioch.ox.ac.uk

Background: Experimental data from isolated rat hearts suggestthat glycolysis in severe myocardial ischemia is inhibited byaccumulation of glycolytic metabolites. In contrast, positronemission tomography (PET) in patients with myocardial ischemiarecords a ‘mismatch’ between the decreased coronaryflow in viable ischemic tissue and an increased fluorodeoxyglucose(¹⁸FDG) signal. To resolve this contradiction, we investigatedglucose uptake at very low coronary flows in the isolated ratheart model. Methods: Rates of glucose uptake were measuredin the isolated Langendorff-perfused Wistar rat heart, at control(12–15 ml/g wet wt/min) and low coronary flows (0.1, 0.2and 0.5 ml/g wet wt/min) and at a range of glucose concentrations(2.75, 5.5, 11 and 22 mM). Results: The steady-state rate ofglucose uptake versus glucose concentration could be describedby a double rectangular hyperbola at each coronary flow. Glucoseuptake fell to levels significantly below control at low coronaryflows. However, the extraction of glucose (glucose uptake as% of glucose delivered) rose sharply, from 1% at control coronaryflows, to 25–30% at low coronary flows. Crossover analysisof glycolytic intermediates in freeze-clamped tissue indicatedlittle inhibition at any specific site, although phosphofructokinaseactivity was restricted when glycolytic substrate availabilitywas high. Insulin and preconditioning both increased glucoseuptake with 11 mM glucose, possibly by increasing membrane transporterdensity and thus increasing glucose delivery to the cytosol.Conclusions: Despite the reduction in absolute glucose uptakeat low coronary flow-rates, the extraction of glucose was greatlyincreased, possibly following GLUT4 translocation. Deliveryof glucose to the glycolytic pathway appears to be a major controllingsite of glycolysis in low-flow ischemia. Downstream regulationis then distributed along the pathway with no one site exertinggreater inhibition than reduced glucose delivery.

KEYWORDS Glycolysis; Ischemia; Metabolic regulation; Preconditioning; Rat

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