Na+ overload during ischemia and reperfusion in rat hearts: comparison of the Na+/H+ exchange blockers EIPA, cariporide and eniporide.

Abstract

Intracellular myocardial Na+ overload during ischemia is an important cause of reperfusion injury via reversed Na+/Ca2+ exchange. Prevention of this Na+ overload can be accomplished by blocking the different Na+ influx routes. In this study the effect of ischemic inhibition of the Na+/H+ exchanger (NHE) on [Na+]i, pH, and post-ischemic contractile recovery was tested, using three different NHE-blockers: EIPA, cariporide and eniporide. pHi and [Na+]i were measured using simultaneous 31P and 23Na NMR spectroscopy, respectively, in paced (5 Hz) isolated, Langendorff perfused rat hearts while contractility was assessed by an intraventricular balloon. NHE-blockers (3 microM) were administered during 5 min prior to 30 min of global ischemia followed by 30 min drug-free reperfusion. NHE blockade markedly reduced ischemic Na+ overload; after 30 min of ischemia [Na+]i had increased to 293 +/- 26, 212 +/- 6, 157 +/- 5 and 146 +/- 6% of baseline values in untreated and EIPA (p < 0.01 vs. untreated), cariporide (p < 0.01 vs. untreated) and eniporide (p < 0.01 vs. untreated) treated hearts, respectively. Ischemic acidosis did not differ significantly between groups. During reperfusion, however, recovery of pH, was significantly delayed in treated hearts. The rate pressure product recovered to 12.0 +/- 1.9, 12.1 +/- 2.1, 19.5 +/- 2.8 and 20.4 +/- 2.5 x 10(3) mmHg/min in untreated and EIPA, cariporide (p < 0.01 vs. untreated) and eniporide (p < 0.01 vs. untreated) treated hearts, respectively. In conclusion, blocking the NHE reduced ischemic Na+ overload and improved post-ischemic contractile recovery. EIPA, however, was less effective and exhibited more side effects than cariporide and eniporide in the concentrations used.

• Authors: Michiel ten Hove, Jan G van Emous, Cees J A van Echteld
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 250 Issue 1-2 Pg. 47-54 (Aug 2003) ISSN: 0300-8177 [Print] Netherlands
• PMID: 12962142 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Guanidines
• Phosphates
• Sodium-Hydrogen Exchangers
• Sulfones
• Amiloride
• cariporide
• eniporide
• Sodium
• Calcium
• ethylisopropylamiloride

Topics

• Amiloride (analogs & derivatives, pharmacology)
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Calcium (chemistry)
• Guanidines (pharmacology)
• Hydrogen-Ion Concentration
• Ischemia
• Magnetic Resonance Spectroscopy
• Male
• Myocardial Contraction (drug effects)
• Myocardium (metabolism)
• Perfusion
• Phosphates (chemistry)
• Rats
• Rats, Wistar
• Reperfusion Injury
• Sodium (chemistry, metabolism, pharmacology)
• Sodium-Hydrogen Exchangers (antagonists & inhibitors)
• Sulfones (pharmacology)
• Time Factors