Partial inhibition of Na/Ca exchange by SEA-0400 resulted in a net gain of cellular Ca2+, increasing [Ca2+]i transients from 424 to 994 nmol/L (P<0.05) in healthy myocytes.
Does partial inhibition of NCX by SEA-0400 alter cellular Ca2+ load and handling in healthy and failing ventricular myocytes?
Partial inhibition of NCX leads to a net gain of cellular Ca2+ due to predominant forward mode block, increasing contraction in healthy but not failing myocytes, highlighting the need to balance potential benefits against Ca2+ handling risks in heart failure drug development.
Absolute Event Rate: 994% vs 424%
p-value: p=<0.05
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 micromol/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 +10 mV, 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.
Özdemir et al. (Sun,) conducted a other in Heart failure. SEA-0400 vs. Baseline/Control was evaluated on [Ca2+](i) transients evoked during depolarizing steps at +10 mV (nmol/L) (p=<0.05). Partial inhibition of Na/Ca exchange by SEA-0400 resulted in a net gain of cellular Ca2+, increasing [Ca2+]i transients from 424 to 994 nmol/L (P<0.05) in healthy myocytes.