Inhibition of Na+-H+ exchanger protects diabetic and non-diabetic hearts from ischemic injury: Insight into altered susceptibility of diabetic heartsto ischemic injury

It has been previously suggested that alterations in sodium homeostasis, le ading to calcium overload may play a part in the mediation of cardiac ische mic injury. It has been demonstrated that the Na+-H+ exchanger plays an imp ortant role with regard to the regulation of intracellular sodium during is chemia and reperfusion and that inhibition of the Na+-H+ exchanger during i schemia protects hearts from ischemic injury, Studies using chemically-indu ced diabetic animals have suggested that the cardiac Na+-H+ exchanger in th e diabetic heart is impaired and is responsible for limiting the increase i n sodium during ischemia. The extent to which the Na+-H+ exchanger contribu tes to increases in intracellular sodium during ischemia in diabetic hearts is unclear as direct measurements of exchanger activity have not been made in genetically diabetic hearts. Therefore, this paper aims to address the following issues: (a) is the Na+-H+ exchanger impaired in a genetically dia betic rat heart: (b):does this impairment result in lower [Na]i or [Ca]i du ring ischemia; and (c) does Na+-H+ exchanger inhibtion limit injury and fun ctional impairment in diabetic hearts during ischemia and reperfusion? Thes e issues were examined by inhibiting the Na+-H+ exchanger with ethylisoprop ylamiloride (BIPA) in isolated perfused hearts from both genetically diabet ic (BB/W) and non-diabetic rats. Levels of intracellular sodium, intracellu lar calcium, intracellular pH and high energy phosphates (using Na-23, F-19 , P-31 NMR spectroscopies, respectively) during global ischemia and reperfu sion were also measured. The impact of diabetes on Na+-H+ exchanger activit y was assessed by measuring pH recovery of these hearts after an acid load. Creatine kinase release during reperfusion was used as a measure of ischem ic injury. This study demonstrated that the Na+-H+ exchanger is impaired in diabetic hearts. Despite this impaired activity, inhibition of Na+-H+ exchanger protected di abetic hearts from ischemic injury and was associated with attenuation of t he rise in sodium and calcium, and limitation of acidosis and preservation of ATP during ischemia. The data presented here favor the use of Na+-H+ exc hanger inhibitors to protect ischemic myocardium in diabetics. Also, the da ta provides possible mechanisms for the altered susceptibility of diabetic hearts to ischemic injury. (C) 1999 Academic Press.