Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca@@u2+@ Load Attributable to the Predominance of Forward Mode Block

Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca@@u2+@ Load Attributable to the Predominance of Forward Mode Block

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 Ca@@u2+@ balance maintained by NCX. We have examined the effects of partial inhibition of NCX by SEA-0400 (1 or 0...

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Veröffentlicht in:Circulation research 2008-06, Vol.102 (11), p.1398-1405
Hauptverfasser: Ozdemir, Semir, Bito, Virginie, Holemans, Patricia, Vinet, Laurent, Mercadier, Jean-Jacques, Varro, Andras, Sipido, Karin R
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container_end_page 1405
container_issue 11
container_start_page 1398
container_title Circulation research
container_volume 102
creator Ozdemir, Semir
Bito, Virginie
Holemans, Patricia
Vinet, Laurent
Mercadier, Jean-Jacques
Varro, Andras
Sipido, Karin R
description 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 Ca@@u2+@ balance maintained by NCX. We have examined the effects of partial inhibition of NCX by SEA-0400 (1 or 0.3 ^kmol/L) in left ventricular myocytes from healthy pigs or mice and from mice with heart failure (MLP@@u-/-@). During voltage clamp ramps with [Ca@@u2+@]@@di@ buffering, block of reverse mode block was slightly larger than of forward mode (by 25^c5%, P
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We have examined the effects of partial inhibition of NCX by SEA-0400 (1 or 0.3 ^kmol/L) in left ventricular myocytes from healthy pigs or mice and from mice with heart failure (MLP@@u-/-@). During voltage clamp ramps with [Ca@@u2+@]@@di@ buffering, block of reverse mode block was slightly larger than of forward mode (by 25^c5%, P&lt;0.05). In the absence of [Ca@@u2+@]@@di@ buffering and with sarcoplasmic reticulum (SR) fluxes blocked, rate constants for Ca@@u2+@ influx and Ca@@u2+@ efflux were reduced to the same extent (to 36^c6% and 32^c4%, respectively). With normal SR function the reduction of inward NCX current (I@@dNCX@) was 57^c10% (n=10); during large caffeine-induced Ca@@u2+@ transients, it was larger (82^c3%). [Ca@@u2+@]@@di@ transients evoked during depolarizing steps increased (from 424^c27 to 994^c127 nmol/L at +10mV, P&lt;0.05), despite a reduction of I@@dCaL@ by 27%. Resting [Ca@@u2+@]@@di@ increased; there was a small decrease in the rate of decline of [Ca@@u2+@]@@di@. SR Ca@@u2+@ content increased more than 2-fold. Contraction amplitude of field-stimulated myocytes increased in healthy myocytes but not in myocytes from MLP@@u-/-@ mice, in which SR Ca@@u2+@ content remained unchanged. These data provide proof-of-principle that even partial inhibition of NCX results in a net gain of Ca@@u2+@. 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Resting [Ca@@u2+@]@@di@ increased; there was a small decrease in the rate of decline of [Ca@@u2+@]@@di@. SR Ca@@u2+@ content increased more than 2-fold. Contraction amplitude of field-stimulated myocytes increased in healthy myocytes but not in myocytes from MLP@@u-/-@ mice, in which SR Ca@@u2+@ content remained unchanged. These data provide proof-of-principle that even partial inhibition of NCX results in a net gain of Ca@@u2+@. 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Resting [Ca@@u2+@]@@di@ increased; there was a small decrease in the rate of decline of [Ca@@u2+@]@@di@. SR Ca@@u2+@ content increased more than 2-fold. Contraction amplitude of field-stimulated myocytes increased in healthy myocytes but not in myocytes from MLP@@u-/-@ mice, in which SR Ca@@u2+@ content remained unchanged. These data provide proof-of-principle that even partial inhibition of NCX results in a net gain of Ca@@u2+@. Further development of NCX blockers, in particular, for heart failure, must balance potential benefits of I@@dNCX@ reduction against effects on Ca@@u2+@ handling by refining mode dependence and/or including additional targets.</abstract></addata></record>
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source American Heart Association Journals; EZB-FREE-00999 freely available EZB journals; Journals@Ovid Complete
title Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca@@u2+@ Load Attributable to the Predominance of Forward Mode Block
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