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Impact of low-flow ischemia on substrate oxidation and glycolysis in the isolated perfused rat heart

¹Division of Cardiovascular Disease, Department of Medicine, ²Comprehensive Cancer Center, and ³Department of Physiology and Biophysics and Clinical Nutrition Research Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-0005

Submitted 20 October 2003 ; accepted in final form 25 February 2004

Interventions that stimulate carbohydrate oxidation appear to be beneficial in the setting of myocardial ischemia or infarction. However, the mechanisms underlying this protective effect have not been defined, in part because of our limited understanding of substrate utilization under ischemic conditions. Therefore, we used ¹H and ¹³C NMR spectroscopy to investigate substrate oxidation and glycolytic rates in a global low-flow model of myocardial ischemia. Isolated male Sprague-Dawley rat hearts were perfused for 30 min under conditions of normal flow (control) and low-flow ischemia (LFI, 0.3 ml/min) with insulin and ¹³C-labeled lactate, pyruvate, palmitate, and glucose at concentrations representative of the physiological fed state. Despite a 50-fold reduction in substrate delivery and oxygen consumption, oxidation of all exogenous substrates plus glycogen occurred during LFI. Oxidative metabolism accounted for 97% of total calculated ATP production in the control group and 30% in the LFI group. For controls, lactate oxidation was the major source of ATP; however, in LFI, this shifted to a combination of oxidative and nonoxidative glycogen metabolism. Interestingly, in the LFI group, anaplerosis relative to citrate synthase increased sevenfold compared with controls. These results demonstrate the importance of oxidative energy metabolism for ATP production, even during very-low-flow ischemia. We believe that the approach described here will be valuable for future investigations into the underlying mechanisms related to the protective effect of increasing cardiac carbohydrate utilization and may ultimately lead to identification of new therapeutic targets for treatment of myocardial ischemia.

nuclear magnetic resonance spectroscopy; energy metabolism; lactate; pyruvate; ATP

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