GLUCOSE-METABOLISM, H+ PRODUCTION AND NA+ H+-EXCHANGER MESSENGER-RNA LEVELS IN ISCHEMIC HEARTS FROM DIABETIC RATS/

Glycolysis uncoupled from glucose oxidation is a major reason for the intracellular acidosis that occurs during severe myocardial ischemia. The imbalance between glycolysis and glucose oxidation, and the result ant H+ produced from glycolytically derived ATP hydrolysis in the diab etic rat heart is the focus of this study. Isolated working hearts fro m 6 week streptozotocin diabetic rat hearts were perfused with 11 mM g lucose and 1.2 mM palmitate and subjected to a 25 min period of global ischemia. A second series of experiments were also performed in which hearts from control, diabetic, and islet-transplanted diabetic rats w ere subjected to a 30 min aerobic perfusion, followed by a 60 min peri od of low-flow ischemia (coronary flow = 0.5 ml/min) and 30 min of aer obic reperfusion. H+ production from glucose metabolism was measured t hroughout the two protocols by simultaneous measurement of glycolysis and glucose oxidation using perfusate labelled with [5-H-3/U-C-14]-glu cose. Rates of H+ production were calculated by measuring the differen ce between glycolysis and glucose oxidation. The H+ production through out the perfusion was generally lower in diabetic rat hearts compared to control hearts, while islet-transplantation of diabetic rats increa sed H+ production to rates similar to those seen in control hearts. Th is occurred primarily due to a dramatic increase in the rates of glyco lysis. Despite the difference in H+ production between control, diabet ic and islet-transplanted diabetic rat hearts, no difference in mRNA l evels of the cardiac Na+/H+-exchanger (NHE-1) was seen. This suggests that alterations in the source of protons (i.e. glucose metabolism) ar e as important as alterations in the fate of protons, when considering diabetes-induced changes in cellular pH. Furthermore, our data sugges ts that alterations in Na+/H+-exchange activity in the diabetic rat he art occur at a post-translational level, possibly due to direct altera tions in the sarcolemmal membranes.