Sodium ion/hydrogen ion exchange inhibition: A new pharmacologic approach to myocardial ischemia and reperfusion injury

Josh Levitsky, Daniel Gurell, William H. Frishman*

*Corresponding author for this work

Research output: Contribution to journalReview article

74 Citations (Scopus)

Abstract

Over the past few years, it has been shown that the cardiac myocyte plasma membrane sodium ion/hydrogen ion exchanger (NHE) plays an important role in the maintenance of intracellular pH, sodium, and calcium ion homeostasis. From the results of various experimental studies, it is clear that this ion exchanger is an important mediator of ischemic-reperfusion injury of the heart. During myocardial ischemia, intracellular acidosis develops quickly, activating the exchanger to extrude H+ into the extracellular environment and bring Na+ into the cell. With further progression of ischemia, the cell is unable to handle the overload of Na+, causing it to use its Na+/Ca2+ exchanger to unload intracellular Na+ into the extracellular space. At the same time, however, calcium is being transported into the cell. This can lead to detrimental cardiac injury, such as contracture and necrosis. During myocardial reperfusion, these events are magnified because the return of blood flow lowers the extracellular H+ concentration, stimulating the NHE to extrude more intracellular H+ ion. This leads to intracellular Na+ excess and eventually, intracellular Ca2+ overload and cardiac injury. In an effort to alter these pathophysiologic events, a number of investigators have studied the ability of various NHE inhibitors, such as amiloride, analogues of amiloride, and other drugs (HOE 694, HOE 642), to prevent cardiac ischemic-reperfusion damage. Preliminary results from studies in animal models have revealed that most of these agents are able to attenuate the development of myocardial contracture, infarction, and arrhythmias during both ischemia and reperfusion. Their efficacy and cardioprotective effects in human beings have yet to be determined. These agents appear to be promising not only in the prevention and treatment of ischemic heart disease, but also in avoiding cardiac damage in situations where low-flow states are followed by immediate recovery of flow, as in coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, thrombolytic therapy, and coronary arterial vasospasm. This article reviews the physiology of the NHE and analyzes the potential role of NHE inhibitors in the prevention of ischemic-reperfusion injury and other cardiac disease states.

Original languageEnglish (US)
Pages (from-to)887-897
Number of pages11
JournalJournal of Clinical Pharmacology
Volume38
Issue number10
DOIs
StatePublished - Jan 1 1998

Fingerprint

Myocardial Reperfusion Injury
Ion Exchange
Reperfusion Injury
Myocardial Ischemia
Protons
Sodium
Ions
Amiloride
Contracture
Ischemia
Coronary Vasospasm
Calcium
Myocardial Reperfusion
Coronary Balloon Angioplasty
Thrombolytic Therapy
Wounds and Injuries
Extracellular Space
Acidosis
Cardiac Myocytes
Coronary Artery Bypass

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

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title = "Sodium ion/hydrogen ion exchange inhibition: A new pharmacologic approach to myocardial ischemia and reperfusion injury",
abstract = "Over the past few years, it has been shown that the cardiac myocyte plasma membrane sodium ion/hydrogen ion exchanger (NHE) plays an important role in the maintenance of intracellular pH, sodium, and calcium ion homeostasis. From the results of various experimental studies, it is clear that this ion exchanger is an important mediator of ischemic-reperfusion injury of the heart. During myocardial ischemia, intracellular acidosis develops quickly, activating the exchanger to extrude H+ into the extracellular environment and bring Na+ into the cell. With further progression of ischemia, the cell is unable to handle the overload of Na+, causing it to use its Na+/Ca2+ exchanger to unload intracellular Na+ into the extracellular space. At the same time, however, calcium is being transported into the cell. This can lead to detrimental cardiac injury, such as contracture and necrosis. During myocardial reperfusion, these events are magnified because the return of blood flow lowers the extracellular H+ concentration, stimulating the NHE to extrude more intracellular H+ ion. This leads to intracellular Na+ excess and eventually, intracellular Ca2+ overload and cardiac injury. In an effort to alter these pathophysiologic events, a number of investigators have studied the ability of various NHE inhibitors, such as amiloride, analogues of amiloride, and other drugs (HOE 694, HOE 642), to prevent cardiac ischemic-reperfusion damage. Preliminary results from studies in animal models have revealed that most of these agents are able to attenuate the development of myocardial contracture, infarction, and arrhythmias during both ischemia and reperfusion. Their efficacy and cardioprotective effects in human beings have yet to be determined. These agents appear to be promising not only in the prevention and treatment of ischemic heart disease, but also in avoiding cardiac damage in situations where low-flow states are followed by immediate recovery of flow, as in coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, thrombolytic therapy, and coronary arterial vasospasm. This article reviews the physiology of the NHE and analyzes the potential role of NHE inhibitors in the prevention of ischemic-reperfusion injury and other cardiac disease states.",
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Sodium ion/hydrogen ion exchange inhibition : A new pharmacologic approach to myocardial ischemia and reperfusion injury. / Levitsky, Josh; Gurell, Daniel; Frishman, William H.

In: Journal of Clinical Pharmacology, Vol. 38, No. 10, 01.01.1998, p. 887-897.

Research output: Contribution to journalReview article

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