KB-R7943 block of Ca2+ influx via Na+/Ca2+ exchange does not alter twitches or glycoside inotropy but prevents Ca2+ overload in rat ventricular myocytes

Hiroshi Satoh, Kenneth S Ginsburg, Ke Qing, Hajime Terada, Hideharu Hayashi, Donald M Bers

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

Background - The Na+/Ca2+ exchange (NCX) extrudes Ca2+ from cardiac myocytes, but it can also mediate Ca2+ influx, load the sarcoplasmic reticulum with Ca2+, and trigger Ca2+ release from the sarcoplasmic reticulum. In ischemia/reperfusion or digitalis toxicity, increased levels of intracellular [Na+] ([Na+](i)) may raise levels of intracellular [Ca2+] ([Ca2+](i)) via NCX, leading to cell injury and arrhythmia. Methods and Results - We used KB-R7943 (KBR) to selectively block Ca2+ influx via NCX to study the role of NCX-mediated Ca2+ influx in intact rat ventricular myocytes. Removing extracellular Na+ caused [Ca2+](i) to rise, due to Ca2+ influx via NCX, and this was blocked by 90% with 5 μmol/L KBR. However, KBR did not alter [Ca2+](i), decline due to NCX. Thus, we used 5 μmol/L KBR to selectively block Ca2+ entry but not efflux via NCX. Under control conditions, 5 μmol/L KBR did not alter steady-state twitches, Ca2+ transients, Ca2+ load in the sarcoplasmic reticulum, or rest potentiation, but it did prolong the late low plateau of the rat action potential. When Na+/K+ ATPase was inhibited by strophanthidin, KBR reduced diastolic [Ca2+](i) and abolished the spontaneous Ca2+ oscillations, but it did not prevent inotropy. Conclusions - In rat ventricular myocytes, Ca2+ influx via NCX is not important for normal excitation-contraction coupling. Furthermore, the inhibition of Ca2+ efflux alone (as [Na+](i) rises) may be sufficient to cause glycoside inotropy. In contrast, Ca2+ overload and spontaneous activity at high [Na+](i) was blocked by KBR, suggesting that net Ca2+ influx (not merely reduced efflux) via NCX is involved in potentially arrhythmogenic Ca2+ overload.

Original languageEnglish (US)
Pages (from-to)1441-1446
Number of pages6
JournalCirculation
Volume101
Issue number12
StatePublished - Mar 28 2000
Externally publishedYes

Keywords

  • Arrhythmia
  • Ion exchange
  • Myocytes
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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