Inhibition of the cardiac electrogenic sodium bicarbonate cotransporter reduces ischemic injury.
OBJECTIVE
Although it is believed that sodium-driven acid-base transport plays a central role in the development of the reperfusion injury that follows cardiac ischemia, research to date has demonstrated only a role for Na(+)/H(+) exchange (NHE). However, Na(+)-driven HCO(-)(3) transport, which is quantitatively as important as NHE in cardiac cells, has not been examined.


RESULTS
Here the results show that a neutralizing antibody raised against the human heart electrogenic Na(+)/HCO(3)(-) cotransporter (hhNBC) blocked the recovery of pH after acidic pulse both in HEK-293 cells expressing hhNBC and in rat cardiac myocytes demonstrating the presence of an electrogenic NBC in rat cardiac myocytes similar to hhNBC. Administration of anti-NBC antibody to ischemic-reperfused rat hearts markedly protects systolic and diastolic functions of the heart during reperfusion. Furthermore, using a quantitative real-time RT-PCR (TaqMan) and Western blot analysis we demonstrated that in human cardiomyopathic hearts, mRNA and protein levels of hhNBC increase, whereas mRNA levels of the electroneutral Na(+)/HCO(3)(-) cotransporter (NBCn1) remain unchanged.


CONCLUSIONS
Our data provide evidence that inhibition of hhNBC, whose role in cardiac pathologies could be amplified by overexpression, represents a novel therapeutic approach for ischemic heart disease.
Khandoudi
N
N
GlaxoSmithKline Laboratoires Pharmaceutiques, 4 Rue du Chesnay-Beauregard, BP 96205, 35762 Cédex, Saint-Grégoire, France. nassirah_khandoudi@sbphrd.com
Albadine
J
J
Robert
P
P
Krief
S
S
Berrebi-Bertrand
I
I
Martin
X
X
Bevensee
M O
MO
Boron
W F
WF
Bril
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027982:Sodium-Bicarbonate Symporters / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D027982:Sodium-Bicarbonate Symporters; D017923:Sodium-Hydrogen Exchangers; D007770:L-Lactate Dehydrogenase