The rise of [Na(+)] (i) during ischemia and reperfusion in the rat heart-underlying mechanisms.

Abstract

Intracellular Na(+) concentration ([Na(+)](i)) rises in the heart during ischemia, and on reperfusion, there is a transient rise followed by a return toward control. These changes in [Na(+)](i) contribute to ischemic and reperfusion damage through their effects on Ca(2+) overload. Part of the rise of [Na(+)](i) during ischemia may be caused by increased activity of the cardiac Na(+)/H(+) exchanger (NHE1), activated by the ischemic rise in [H(+)](i). In support of this view, NHE1 inhibitors reduce the [Na(+)](i) rise during ischemia. Another possibility is that the rise of [Na(+)](i) during ischemia is caused by Na(+) influx through channels. We have reexamined these issues by use of two different NHE1 inhibitors, amiloride, and zoniporide, in addition to tetrodotoxin (TTX), which blocks voltage-sensitive Na(+) channels. All three drugs produced cardioprotection after ischemia, but amiloride (100 microM) and TTX (300 nM) prevented the rise in [Na(+)](i) during ischemia, whereas zoniporide (100 nM) did not. Both amiloride and zoniporide prevented the rise of [Na(+)](i) on reperfusion, whereas TTX was without effect. In an attempt to explain these differences, we measured the ability of the three drugs to block Na(+) currents. At the concentrations used, TTX reduced the transient Na(+) current (I (Na)) by 11 +/- 2% while amiloride and zoniporide were without effect. In contrast, TTX largely eliminated the persistent Na(+) current (I (Na,P)) and amiloride was equally effective, whereas zoniporide had a substantially smaller effect reducing I (Na,P) to 41 +/- 8%. These results suggest that part of the effect of NHE1 inhibitors on the [Na(+)](i) during ischemia is by blockade of I (Na,P). The fact that a low concentration of TTX eliminated the rise of [Na(+)](i) during ischemia suggests that I (Na,P) is a major source of Na(+) influx in this model of ischemia.

• Authors: Iwan A Williams, Xiao-hui Xiao, Yue-kun Ju, David G Allen
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 454 Issue 6 Pg. 903-12 (Sep 2007) ISSN: 0031-6768 [Print] Germany
• PMID: 17356886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics, Local
• Cardiotonic Agents
• Guanidines
• Pyrazoles
• Slc9a1 protein, rat
• Sodium Channel Blockers
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers
• Tetrodotoxin
• Amiloride
• zoniporide
• Sodium

Topics

• Amiloride (pharmacology)
• Anesthetics, Local (pharmacology)
• Animals
• Cardiotonic Agents
• Cell Separation
• Female
• Guanidines (pharmacology)
• In Vitro Techniques
• Intracellular Space (metabolism)
• Myocardium (metabolism)
• Patch-Clamp Techniques
• Pyrazoles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (metabolism)
• Sodium (metabolism)
• Sodium Channel Blockers (pharmacology)
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers (antagonists & inhibitors)
• Tetrodotoxin (pharmacology)