In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 102, No. 11 ( 2008-06-06), p. 1398-1405
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 Ca 2+ 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 [Ca 2+ ] i buffering, block of reverse mode block was slightly larger than of forward mode (by 25±5%, P 〈 0.05). In the absence of [Ca 2+ ] i buffering and with sarcoplasmic reticulum (SR) fluxes blocked, rate constants for Ca 2+ influx and Ca 2+ 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 Ca 2+ transients, it was larger (82±3%). [Ca 2+ ] 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 [Ca 2+ ] i increased; there was a small decrease in the rate of decline of [Ca 2+ ] i . SR Ca 2+ 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 Ca 2+ content remained unchanged. These data provide proof-of-principle that even partial inhibition of NCX results in a net gain of Ca 2+ . Further development of NCX blockers, in particular, for heart failure, must balance potential benefits of I NCX reduction against effects on Ca 2+ handling by refining mode dependence and/or including additional targets.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.108.173922
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2008
detail.hit.zdb_id:
1467838-X
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