Unique excitation–contraction characteristics of mouse myocardium as revealed by SEA0400, a specific inhibitor of Na+–Ca2+ exchanger

  • Hikaru Tanaka
  • Iyuki Namekata
  • Kentaro Takeda
  • Akihiro Kazama
  • Yoshiko Shimizu
  • Rina Moriwaki
  • Wataru Hirayama
  • Akira Sato
  • Toru Kawanishi
  • Koki Shigenobu
Original Article
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Accepted:

Abstract

The functional role of the sodium–calcium exchanger in mouse ventricular myocardium was evaluated with a newly developed specific inhibitor, SEA0400. Contractile force and action potential configuration were measured in isolated ventricular tissue preparations, and cell shortening and Ca2+ transients were measured in indo-1-loaded isolated ventricular cardiomyocytes. SEA0400 increased the contractile force, cell shortening and Ca2+ transient amplitude, and shortened the late plateau phase of the action potential. α-adrenergic stimulation by phenylephrine produced a sustained decrease in contractile force, cell shortening and Ca2+ transient amplitude, which were all inhibited by SEA0400. Increasing the contraction frequency resulted in a decrease in contractile force in the absence of drugs (negative staircase phenomenon). This frequency-dependent decrease was attenuated by SEA0400 and enhanced by phenylephrine. Phenylephrine increased the Ca2+ sensitivity of contractile proteins in isolated ventricular cardiomyocytes, while SEA0400 had no effect. These results provide the first pharmacological evidence in the mouse ventricular myocardium that inward current generated by Ca2+ extrusion through the sodium–calcium exchanger during the Ca2+ transient contributes to the action potential late plateau, that α-adrenoceptor-mediated negative inotropy is produced by enhanced Ca2+ extrusion through the sodium–calcium exchanger, and that the negative staircase phenomenon can be explained by increased Ca2+ extrusion through the sodium–calcium exchanger at higher contraction frequencies.

Keywords

Sodium–calcium exchanger Mouse Action potential α-Adrenoceptor Staircase SEA0400 
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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Hikaru Tanaka
    • 1
  • Iyuki Namekata
    • 1
  • Kentaro Takeda
    • 1
  • Akihiro Kazama
    • 1
  • Yoshiko Shimizu
    • 1
  • Rina Moriwaki
    • 1
  • Wataru Hirayama
    • 1
  • Akira Sato
    • 1
  • Toru Kawanishi
    • 2
  • Koki Shigenobu
    • 1
  1. 1.Department of PharmacologyToho University School of Pharmaceutical SciencesChibaJapan
  2. 2.Division of Biological Chemistry and BiologicalsNational Institute of Health SciencesTokyoJapan

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