Stimulation of Carbohydrate Metabolism Reduces Hypothermia-induced Calcium Load in Fatty Acid-perfused Rat Hearts

In the present study we examined the impact of glycolysis and glucose oxidation on myocardial calcium control and mechanical function, of fatty acid-perfused rat hearts subjected to hypothermia and rewarming. One group (control) was given glucose (11.1 m ) and palmitate (1.2 m ) as energy substrates. In a second group glycolysis was inhibited by iodoacetate (IAA, 100μm) and replacement of glucose with pyruvate (5 m ), whereas in the third group glucose oxidation was stimulated by administration of dichloroacetate (DCA, 1 m ) and insulin (500μU/ml). All groups showed a rise in myocardial calcium ([Ca]total) in response to hypothermia (10°C). However, [Ca]totalwas significantly lower both in IAA- and DCA-treated hearts, as compared to controls (2.20±0.22 and 2.94±0.20v3.83±0.29 nmol/mg dry wt.,P<0.025). The reduced calcium load in the treated hearts was correlated with higher levels of high energy phosphates. Following rewarming, control and DCA-treated hearts still showed elevated [Ca]total, whereas IAA-treated hearts [Ca]totalwas not different from the pre-hypothermic value. All groups showed a reduction in cardiac output following rewarming. Furthermore, the control group, in contrast to both IAA- and DCA-treated hearts, showed a significant reduction in systolic pressure. These results show that hypothermia-induced calcium uptake in glucose and fatty acid-perfused rat hearts was reduced by two different metabolic approaches: (1) inhibition of glycolysis by IAA while simultaneously by-passing the glycolytic pathway by exogenous pyruvate; and (2) stimulation of glucose oxidation by DCA. Thus, glycolytic ATP is not an essential regulator of sarcolemmal calcium transport under the present experimental conditions. Instead, we suggest that a change in oxidative substrate utilization in favour of carbohydrates may improve myocardial calcium homeostasis during hypothermia and rewarming.