Mechanism of Na+/Ca2+ exchanger activation by hydrogen peroxide in guinea-pig ventricular myocytes.
Using the whole-cell voltage clamp, we examined the mechanism of activation of the Na(+)/Ca(2+) exchanger (NCX) by hydrogen peroxide (H(2)O(2)) in isolated guinea-pig cardiac ventricular myocytes. Exposure to H(2)O(2) increased the NCX current. The effect was inhibited by cariporide, an inhibitor of the Na(+)/H(+) exchanger (NHE), suggesting that there are NHE-dependent and -independent pathways in the effect of H(2)O(2) on NCX. In addition, both pathways were blocked by edaravone, a hydroxyl radical (*OH) scavenger; pertussis toxin, a Galpha(i/o) protein inhibitor; and U0126, an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK). On the other hand, wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited only the NHE-dependent pathway, while PP2, a Src family protein tyrosine kinase inhibitor, inhibited only the NHE-independent pathway. Taken together, our data suggest that H(2)O(2) increases the NCX current via two signal transduction pathways. The common pathway is the conversion of H(2)O(2) to *OH, which activates Galpha(i/o) protein and a mitogen-activated protein (MAP) kinase signaling pathway. Then, one pathway activates NHE with a PI3K-dependent mechanism and indirectly increases the NCX current. Another pathway involves activation of a Src family tyrosine kinase.
Hinata
Masamitsu
M
Department of Pharmacology, Fukushima Medical University, School of Medicine, Fukushima, Japan.
Matsuoka
Isao
I
Iwamoto
Takahiro
T
Watanabe
Yasuhide
Y
Kimura
Junko
J
D000818:Animals; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D016877:Oxidants / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
D016877:Oxidants; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D006861:Hydrogen Peroxide