Cardiovascular Research Advance Access originally published online on February 5, 2008
Cardiovascular Research 2008 78(3):476-484; doi:10.1093/cvr/cvn031
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The Na+/Ca2+ exchange blocker SEA0400 fails to enhance cytosolic Ca2+ transient and contractility in canine ventricular cardiomyocytes
1 Department of Physiology, University of Debrecen, H-4012 Debrecen, PO Box 22, Hungary
2 Department of Pharmacology and Pharmacotherapy, University of Szeged, H-6701 Szeged, PO Box 427, Hungary
3 Division of Cardiovascular Pharmacology, Hungarian Academy of Sciences, H-6701 Szeged, PO Box 427, Hungary
4 Department of Cardiology, University of Debrecen, H-4012 Debrecen, PO Box 22, Hungary
5 Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, PO Box 121, Hungary
* Corresponding author. Tel: +36 52 416 634; fax: +36 52 432 289. E-mail address: nanasi{at}phys.dote.hu
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 Ca2+ 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.
KEYWORDS Na+/Ca2+ exchanger; Calcium handling; NCX inhibitors; SEA0400; Dog ventricular myocytes
Time for primary review: 26 days
These authors contributed equally to this work.
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