Inhibition of Na+-H+ exchanger protects diabetic and non-diabetic hearts from ischemic injury

Insight into altered susceptibility of diabetic hearts to ischemic injury

Ravichandran Ramasamy, Saul Schaefer

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

It has been previously suggested that alterations in sodium homeostasis, leading to calcium overload may play a part in the mediation of cardiac ischemic injury. It has been demonstrated that the Na+-H+ exchanger plays an important role with regard to the regulation of intracellular sodium during ischemia and reperfusion and that inhibition of the Na+-H+ exchanger during ischemia protects hearts from ischemic injury. Studies using chemically-induced diabetic animals have suggested that the cardiac Na+-H+ exchanger in the diabetic heart is impaired and is responsible for limiting the increase in sodium during ischemia. The extent to which the Na+-H+ exchanger contributes 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 diabetic rat heart: (b) does this impairment result in lower [Na](i) or [Ca](i) during ischemia: and (c) does Na+-H+ exchanger inhibtion limit injury and functional impairment in diabetic hearts during ischemia and reperfusion? These issues were examined by inhibiting the Na+-H+ exchanger with ethylisopropylamiloride (EIPA) in isolated perfused hearts from both genetically diabetic (BB/W) and non-diabetic rats. Levels of intracellular sodium, intracellular calcium, intracellular pH and high energy phosphates (using 23Na, 19F, 31P NMR spectroscopies, respectively) during global ischemia and reperfusion were also measured. The impact of diabetes on N+-H+-exchanger activity was assessed by measuring pH recovery of these hearts after an acid load. Creatine kinase release during reperfusion was used as a measure of ischemic injury. This study demonstrated that the Na+-H+-exchanger is impaired in diabetic hearts. Despite this impaired activity, inhibition of Na+-H+ exchanger protected diabetic hearts from ischemic injury and was associated with attenuation of the 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+ exchanger inhibitors to protect ischemic myocardium in diabetics. Also, the data provides possible mechanisms for the altered susceptibility of diabetic hearts to ischemic injury.

Original languageEnglish (US)
Pages (from-to)785-797
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume31
Issue number4
DOIs
StatePublished - Apr 1999

Fingerprint

Heart Injuries
Sodium-Hydrogen Antiporter
Ischemia
Wounds and Injuries
Sodium
Reperfusion
Calcium
Creatine Kinase
Acidosis
Myocardium
Homeostasis
Magnetic Resonance Spectroscopy
Adenosine Triphosphate
Phosphates

Keywords

  • Diabetes
  • Ischemia
  • Na-H exchanger
  • NMR

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Inhibition of Na+-H+ exchanger protects diabetic and non-diabetic hearts from ischemic injury: Insight into altered susceptibility of diabetic hearts to ischemic injury",
abstract = "It has been previously suggested that alterations in sodium homeostasis, leading to calcium overload may play a part in the mediation of cardiac ischemic injury. It has been demonstrated that the Na+-H+ exchanger plays an important role with regard to the regulation of intracellular sodium during ischemia and reperfusion and that inhibition of the Na+-H+ exchanger during ischemia protects hearts from ischemic injury. Studies using chemically-induced diabetic animals have suggested that the cardiac Na+-H+ exchanger in the diabetic heart is impaired and is responsible for limiting the increase in sodium during ischemia. The extent to which the Na+-H+ exchanger contributes 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 diabetic rat heart: (b) does this impairment result in lower [Na](i) or [Ca](i) during ischemia: and (c) does Na+-H+ exchanger inhibtion limit injury and functional impairment in diabetic hearts during ischemia and reperfusion? These issues were examined by inhibiting the Na+-H+ exchanger with ethylisopropylamiloride (EIPA) in isolated perfused hearts from both genetically diabetic (BB/W) and non-diabetic rats. Levels of intracellular sodium, intracellular calcium, intracellular pH and high energy phosphates (using 23Na, 19F, 31P NMR spectroscopies, respectively) during global ischemia and reperfusion were also measured. The impact of diabetes on N+-H+-exchanger activity was assessed by measuring pH recovery of these hearts after an acid load. Creatine kinase release during reperfusion was used as a measure of ischemic injury. This study demonstrated that the Na+-H+-exchanger is impaired in diabetic hearts. Despite this impaired activity, inhibition of Na+-H+ exchanger protected diabetic hearts from ischemic injury and was associated with attenuation of the 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+ exchanger inhibitors to protect ischemic myocardium in diabetics. Also, the data provides possible mechanisms for the altered susceptibility of diabetic hearts to ischemic injury.",
keywords = "Diabetes, Ischemia, Na-H exchanger, NMR",
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N2 - It has been previously suggested that alterations in sodium homeostasis, leading to calcium overload may play a part in the mediation of cardiac ischemic injury. It has been demonstrated that the Na+-H+ exchanger plays an important role with regard to the regulation of intracellular sodium during ischemia and reperfusion and that inhibition of the Na+-H+ exchanger during ischemia protects hearts from ischemic injury. Studies using chemically-induced diabetic animals have suggested that the cardiac Na+-H+ exchanger in the diabetic heart is impaired and is responsible for limiting the increase in sodium during ischemia. The extent to which the Na+-H+ exchanger contributes 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 diabetic rat heart: (b) does this impairment result in lower [Na](i) or [Ca](i) during ischemia: and (c) does Na+-H+ exchanger inhibtion limit injury and functional impairment in diabetic hearts during ischemia and reperfusion? These issues were examined by inhibiting the Na+-H+ exchanger with ethylisopropylamiloride (EIPA) in isolated perfused hearts from both genetically diabetic (BB/W) and non-diabetic rats. Levels of intracellular sodium, intracellular calcium, intracellular pH and high energy phosphates (using 23Na, 19F, 31P NMR spectroscopies, respectively) during global ischemia and reperfusion were also measured. The impact of diabetes on N+-H+-exchanger activity was assessed by measuring pH recovery of these hearts after an acid load. Creatine kinase release during reperfusion was used as a measure of ischemic injury. This study demonstrated that the Na+-H+-exchanger is impaired in diabetic hearts. Despite this impaired activity, inhibition of Na+-H+ exchanger protected diabetic hearts from ischemic injury and was associated with attenuation of the 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+ exchanger inhibitors to protect ischemic myocardium in diabetics. Also, the data provides possible mechanisms for the altered susceptibility of diabetic hearts to ischemic injury.

AB - It has been previously suggested that alterations in sodium homeostasis, leading to calcium overload may play a part in the mediation of cardiac ischemic injury. It has been demonstrated that the Na+-H+ exchanger plays an important role with regard to the regulation of intracellular sodium during ischemia and reperfusion and that inhibition of the Na+-H+ exchanger during ischemia protects hearts from ischemic injury. Studies using chemically-induced diabetic animals have suggested that the cardiac Na+-H+ exchanger in the diabetic heart is impaired and is responsible for limiting the increase in sodium during ischemia. The extent to which the Na+-H+ exchanger contributes 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 diabetic rat heart: (b) does this impairment result in lower [Na](i) or [Ca](i) during ischemia: and (c) does Na+-H+ exchanger inhibtion limit injury and functional impairment in diabetic hearts during ischemia and reperfusion? These issues were examined by inhibiting the Na+-H+ exchanger with ethylisopropylamiloride (EIPA) in isolated perfused hearts from both genetically diabetic (BB/W) and non-diabetic rats. Levels of intracellular sodium, intracellular calcium, intracellular pH and high energy phosphates (using 23Na, 19F, 31P NMR spectroscopies, respectively) during global ischemia and reperfusion were also measured. The impact of diabetes on N+-H+-exchanger activity was assessed by measuring pH recovery of these hearts after an acid load. Creatine kinase release during reperfusion was used as a measure of ischemic injury. This study demonstrated that the Na+-H+-exchanger is impaired in diabetic hearts. Despite this impaired activity, inhibition of Na+-H+ exchanger protected diabetic hearts from ischemic injury and was associated with attenuation of the 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+ exchanger inhibitors to protect ischemic myocardium in diabetics. Also, the data provides possible mechanisms for the altered susceptibility of diabetic hearts to ischemic injury.

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