SEA0400, a novel Na+/Ca2+ exchanger inhibitor, reduces calcium overload induced by ischemia and reperfusion in mouse ventricular myocytes

Physiol Res. 2007;56(1):17-23. doi: 10.33549/physiolres.930894. Epub 2006 Feb 23.

Abstract

Given the potential clinical benefit of inhibiting Na+/Ca2+ exchanger (NCX) activity during myocardial ischemia reperfusion (I/R), pharmacological approaches have been pursued to both inhibit and clarify the importance of this exchanger. SEA0400 was reported to have a potent NCX selectivity. Thus, we examined the effect of SEA0400 on NCX currents and I/R induced intracellular Ca2+ overload in mouse ventricular myocytes using patch clamp techniques and fluorescence measurements. Ischemia significantly inhibited inward and outward NCX current (from -0.04+/-0.01 nA to 0 nA at -100 mV; from 0.23+/-0.08 nA to 0.11+/-0.03 nA at +50 mV, n=7), Subsequent reperfusion not only restored the current rapidly but enhanced the current amplitude obviously, especially the outward currents (from 0.23+/-0.08 nA to 0.49+/-0.12 nA at +50 mV, n=7). [Ca2+]i, expressed as the ratio of Fura-2 fluorescence intensity, increased to 138+/-7% (P<0.01) during ischemia and to 210+/-11% (P<0.01) after reperfusion. The change of NCX current and the increase of [Ca2+]i during I/R can be blocked by SEA0400 in a dose-dependent manner with an EC50 value of 31 nM and 28 nM for the inward and outward NCX current, respectively. The results suggested that SEA0400 is a potent NCX inhibitor, which can protect mouse cardiac myocytes from Ca2+ overload during I/R injuries.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology*
  • Animals
  • Calcium / antagonists & inhibitors*
  • Calcium / metabolism*
  • Cell Separation
  • Dose-Response Relationship, Drug
  • Fluorescent Dyes
  • Fura-2
  • Heart Ventricles / cytology
  • Heart Ventricles / drug effects
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism*
  • Patch-Clamp Techniques
  • Phenyl Ethers / pharmacology*
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / prevention & control*
  • Sodium-Calcium Exchanger / antagonists & inhibitors*
  • Ventricular Function

Substances

  • Aniline Compounds
  • Fluorescent Dyes
  • Phenyl Ethers
  • SEA 0400
  • Sodium-Calcium Exchanger
  • Calcium
  • Fura-2