Linked Life Data

18451338

Source:http://linkedlifedata.com/resource/pubmed/id/18451338

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2008-6-6
pubmed:abstractText
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.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1524-4571
pubmed:author
pubmed:issnType
Electronic
pubmed:day
6
pubmed:volume
102
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1398-405
pubmed:meshHeading
pubmed-meshheading:18451338-Aniline Compounds, pubmed-meshheading:18451338-Animals, pubmed-meshheading:18451338-Calcium, pubmed-meshheading:18451338-Calcium Channel Blockers, pubmed-meshheading:18451338-Cardiotonic Agents, pubmed-meshheading:18451338-Cells, Cultured, pubmed-meshheading:18451338-Disease Models, Animal, pubmed-meshheading:18451338-Electric Stimulation, pubmed-meshheading:18451338-Female, pubmed-meshheading:18451338-Heart Failure, pubmed-meshheading:18451338-Male, pubmed-meshheading:18451338-Mice, pubmed-meshheading:18451338-Mice, Knockout, pubmed-meshheading:18451338-Myocardial Contraction, pubmed-meshheading:18451338-Myocytes, Cardiac, pubmed-meshheading:18451338-Patch-Clamp Techniques, pubmed-meshheading:18451338-Phenyl Ethers, pubmed-meshheading:18451338-Sarcoplasmic Reticulum, pubmed-meshheading:18451338-Sodium-Calcium Exchanger, pubmed-meshheading:18451338-Swine
pubmed:year
2008
pubmed:articleTitle
Pharmacological inhibition of na/ca exchange results in increased cellular Ca2+ load attributable to the predominance of forward mode block.
pubmed:affiliation
Division of Experimental Cardiology, University of Leuven, Belgium.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't