The Na+/Ca2+ exchange blocker SEA0400 fails to enhance cytosolic Ca2+ transient and contractility in canine ventricular cardiomyocytes

Péter Birinyi, András Tóth, István Jóna, Károly Acsai, János Almássy, Norbert Nagy, János Prorok, Iuliana Gherasim, Zoltán Papp, Zita Hertelendi, Norbert Szentandrássy, Tamás Bányász, Ferenc Fülöp, Julius Gy Papp, András Varró, Péter P. Nánási, János Magyar

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Abstract

Aims: This study was designed to evaluate the effects of the Na +/Ca2+ exchange (NCX) inhibitor SEA0400 on Ca2+ handling in isolated canine ventricular myocytes. Methods and results: Intracellular Ca2+ ([Ca2+]i) transients, induced by either field stimulation or caffeine flush, were monitored using Ca2+ indicator dyes. [Ca2+]i-dependent modulation of the inhibitory effect of SEA0400 on NCX was characterized by the changes in Ni2+-sensitive current in voltage-clamped myocytes. Sarcoplasmic reticulum (SR) Ca2+ release and uptake were studied in SR membrane vesicles. Gating properties of single-ryanodine receptors were analysed in lipid bilayers. Ca2+ sensitivity of the contractile machinery was evaluated in chemically skinned myocytes. In myocytes paced at 1 Hz, neither diastolic [Ca2+]i nor the amplitude of [Ca2+]i transients was significantly altered by SEA0400 up to the concentration of 1 μM, which was shown to inhibit the exchange current. The blocking effect of SEA0400 on NCX decreased with increasing [Ca2+]i, and it was more pronounced in reverse than in forward mode operation at every [Ca2+]i examined. The rate of decay of the caffeine-induced [Ca2+]i transients was decreased significantly by 1 μM SEA0400; however, this effect was only a fraction of that observed with 10 mM NiCl2. Neither SR Ca 2+ release and uptake nor cell shortening and Ca2+ sensitivity of the contractile proteins were influenced by SEA0400. Conclusion: The lack of any major SEA0400-induced shift in Ca2+ transients or contractility of myocytes can well be explained by its limited inhibitory effect on NCX (further attenuated by elevated [Ca2+]i levels) and a concomitant reduction in Ca2+ influx due to the predominantly reverse mode blockade of NCX and suppression of L-type Ca2+ current.

Original languageEnglish
Pages (from-to)476-484
Number of pages9
JournalCardiovascular research
Volume78
Issue number3
DOIs
Publication statusPublished - Jun 1 2008

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Keywords

  • Calcium handling
  • Dog ventricular myocytes
  • NCX inhibitors
  • Na/Ca exchanger
  • SEA0400

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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