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Am J Physiol Heart Circ Physiol 281: H515-H522, 2001;
0363-6135/01 $5.00
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Vol. 281, Issue 2, H515-H522, August 2001

Protection of ischemic myocardium in diabetics by inhibition of electroneutral Na+-K+-2Clminus cotransporter

Ravichandran Ramasamy1, John A. Payne2, John Whang1, Steven R. Bergmann1, and Saul Schaefer3

1 Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032; and 2 Department of Human Physiology and 3 Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis, California 95616

Diabetes increases both the incidence of cardiovascular disease and complications of myocardial infarction and heart failure. Studies using diabetic animals have shown that changes in myocardial sodium transporters result in alterations in intracellular sodium (Nai) homeostasis. Because the changes in sodium homeostasis can be due to increased entry of Na+ via the electroneutral Na+-K+-2Cl- cotransporter (NKCC), we conducted experiments in acute diabetic hearts to determine if 1) net inward cation flux via NKCC is increased, 2) this cotransporter contributes to a greater increase in Nai during ischemia, and 3) inhibition of NKCC limits injury and improves function after ischemia-reperfusion. These issues were investigated in perfused type I diabetic and nondiabetic rat hearts subjected to ischemia and 60 min of reperfusion. A group of diabetic and nondiabetic hearts was perfused with 5 µM of bumetanide, an inhibitor of NKCC. Flux via NKCC, Nai, and ATP was measured in each group with the use of radiotracer 86Rb, 23Na, and 31P nuclear magnetic resonance spectroscopy, respectively, whereas ischemic injury was assessed by measuring creatine kinase release on reperfusion. Cation flux via NKCC, as measured by 86Rb uptake, was significantly increased in diabetic hearts. Inhibition of NKCC significantly reduced ischemic injury in diabetic hearts, improved functional recovery on reperfusion, attenuated the ischemic rise in Nai, and conserved ATP during ischemia-reperfusion. Parallel studies in nondiabetic hearts showed that NKCC inhibition was not cardioprotective. These findings demonstrate that flux via NKCC is increased in type I diabetic hearts and that inhibition with bumetanide attenuates changes in Nai and ATP during ischemia and protects against ischemic injury. The data suggest a therapeutic role for pharmacological agents that inhibit flux via NKCC in diabetic patients with myocardial ischemia.

diabetes; ischemic injury; sodium transporters


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