Published online before print May 1, 2008, doi: 10.1161/CIRCRESAHA.108.173922
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Submitted on May 30, 2007
Revised on April 14, 2008
Accepted on April 23, 2008
Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca2+ Load Attributable to the Predominance of Forward Mode Block
Semir Ozdemir ;
From the Division of Experimental Cardiology (S.O., V.B., P.H., K.R.S.), University of Leuven, Belgium; Department of Biophysics (S.O.), Akdeniz University Faculty of Medicine, Antalya, Turkey; Department of Pharmacology and Pharmacotherapy (A.V.), University of Szeged, Hungary; and INSERM U698 (L.V., J.-J.M.), Groupe Hospitalier Bichat-Claude Bernard, Paris, France.
* To whom correspondence should be addressed. E-mail: Karin.Sipido{at}med.kuleuven.be.
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 µmol/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 (INCX) 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 ICaL 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 INCX reduction against effects on Ca2+ handling by refining mode dependence and/or including additional targets.
Key words: cardiac myocytes • heart failure • Na/Ca exchange • sarcoplasmic reticulum • calcium overload
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