Na+/Ca2+ Exchange Inhibition Protects the Rat Heart From Ischemia-Reperfusion Injury by Blocking Energy-Wasting Processes

Am J Physiol Heart Circ Physiol. 2005 Apr;288(4):H1699-707. doi: 10.1152/ajpheart.01033.2004. Epub 2004 Dec 30.

Abstract

We have recently reported that exposure of rat hearts to high Ca(2+) produces a Ca(2+) overload-induced contractile failure in rat hearts, which was associated with proteolysis of alpha-fodrin. We hypothesized that contractile failure after ischemia-reperfusion (I/R) is similar to that after high Ca(2+) infusion. To test this hypothesis, we investigated left ventricular (LV) mechanical work and energetics in the cross-circulated rat hearts, which were subjected to 15 min global ischemia and 60 min reperfusion. Sixty minutes after I/R, mean systolic pressure-volume area (PVA; a total mechanical energy per beat) at midrange LV volume (mLVV) (PVA(mLVV)) was significantly decreased from 5.89 +/- 1.55 to 3.83 +/- 1.16 mmHg.ml.beat(-1).g(-1) (n = 6). Mean myocardial oxygen consumption per beat (Vo(2)) intercept of (Vo(2)-PVA linear relation was significantly decreased from 0.21 +/- 0.05 to 0.15 +/- 0.03 microl O(2).beat(-1).g(-1) without change in its slope. Initial 30-min reperfusion with a Na(+)/Ca(2+) exchanger (NCX) inhibitor KB-R7943 (KBR; 10 micromol/l) significantly reduced the decrease in mean PVA(mLVV) and Vo(2) intercept (n = 6). Although Vo(2) for the Ca(2+) handling was finally decreased, it transiently but significantly increased from the control for 10-15 min after I/R. This increase in Vo(2) for the Ca(2+) handling was completely blocked by KBR, suggesting an inhibition of reverse-mode NCX by KBR. alpha-Fodrin proteolysis, which was significantly increased after I/R, was also significantly reduced by KBR. Our study shows that the contractile failure after I/R is similar to that after high Ca(2+) infusion, although the contribution of reverse-mode NCX to the contractile failure is different. An inhibition of reverse-mode NCX during initial reperfusion protects the heart against reperfusion injury.

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Blotting, Western
  • Calcium / metabolism
  • Cardiotonic Agents / pharmacology
  • Carrier Proteins / metabolism
  • Electrophoresis, Polyacrylamide Gel
  • Energy Metabolism / drug effects*
  • Energy Metabolism / physiology
  • Heart Ventricles / metabolism
  • Immunohistochemistry
  • Male
  • Microfilament Proteins / metabolism
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / metabolism*
  • Myocardium / metabolism
  • Oxygen Consumption / physiology
  • Rats
  • Rats, Wistar
  • Sodium-Calcium Exchanger / antagonists & inhibitors*
  • Sodium-Calcium Exchanger / metabolism
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology*
  • Ventricular Function, Left / drug effects
  • Ventricular Function, Left / physiology

Substances

  • 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
  • Anti-Arrhythmia Agents
  • Cardiotonic Agents
  • Carrier Proteins
  • Microfilament Proteins
  • Sodium-Calcium Exchanger
  • fodrin
  • Thiourea
  • Calcium