Pharmacological inhibition of Na/Ca exchange results in increased cellular Ca2+ load attributable to the predominance of forward mode block


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Ozdemir S., Bito V., Holemans P., Vinet L., Mercadier J., Varro A., ...More

CIRCULATION RESEARCH, vol.102, no.11, pp.1398-1405, 2008 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 102 Issue: 11
  • Publication Date: 2008
  • Doi Number: 10.1161/circresaha.108.173922
  • Journal Name: CIRCULATION RESEARCH
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.1398-1405
  • Keywords: cardiac myocytes, heart failure, Na/Ca exchange, sarcoplasmic reticulum, calcium overload, SODIUM-CALCIUM EXCHANGER, NA+/CA2+ EXCHANGE, VENTRICULAR MYOCYTES, NA+-CA2+ EXCHANGER, HEART-FAILURE, CANINE HEART, CONTRACTION, SEA0400, MOUSE, MYOCARDIUM
  • Akdeniz University Affiliated: Yes

Abstract

Block of Na/Ca exchange (NCX) has potential therapeutic applications, in particular, if a mode-selective block could be achieved, but also carries serious risks for disturbing the normal Ca2+ balance maintained by NCX. We have examined the effects of partial inhibition of NCX by SEA-0400 (1 or 0.3 mu mol/L) in left ventricular myocytes from healthy pigs or mice and from mice with heart failure (MLP-/-). During voltage clamp ramps with [Ca2+](i) buffering, block of reverse mode block was slightly larger than of forward mode ( by 25 +/- 5%, P < 0.05). In the absence of [Ca2+](i) buffering and with sarcoplasmic reticulum (SR) fluxes blocked, rate constants for Ca2+ influx and Ca2+ efflux were reduced to the same extent (to 36 +/- 6% and 32 +/- 4%, respectively). With normal SR function the reduction of inward NCX current (I-NCX) was 57 +/- 10% (n=10); during large caffeine-induced Ca2+ transients, it was larger (82 +/- 3%). [Ca2+](i) transients evoked during depolarizing steps increased (from 424 +/- 27 to 994 +/- 127 nmol/L at +10mV, P < 0.05), despite a reduction of I-CaL by 27%. Resting [Ca2+](i) increased; there was a small decrease in the rate of decline of [Ca2+](i). SR Ca2+ content increased more than 2-fold. Contraction amplitude of field-stimulated myocytes increased in healthy myocytes but not in myocytes from MLP-/- mice, in which SR Ca2+ content remained unchanged. These data provide proof-of-principle that even partial inhibition of NCX results in a net gain of Ca2+. Further development of NCX blockers, in particular, for heart failure, must balance potential benefits of I-NCX reduction against effects on Ca2+ handling by refining mode dependence and/or including additional targets.