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Blocking sodium current reduces the rise in intracellular calcium concentration during hypoxia in rat hippocampal neurons

W. Wu, Y. He, P.W. Gage, John Curtin School of Medical Research, The Australian National University, Canberra, Act, Australia

It is believed a marked rise in intracellular Ca2+ concentration ([Ca2+]i) is the leading cause of irreversible cell damage during hypoxia. There is increasing evidence that an increase in intracellular Na+ concentration ([Na+]i) is also involved. Whether there is a relationship between the rises in [Na+]i and [Ca2+]i remains controversial. We have studied this relationship in cultured hippocampal neurons (cells were obtained from rapidly decapitated newborn rats) by recording [Ca2+]i before and during hypoxia or exposure to ion channel blockers in cultured hippocampal neurons using the Ca2+ indicator fluo-3-AM. The fluorescence of fluo-3 was monitored within single cells before and during hypoxia to track changes in [Ca2+]i. It has been shown that low concentrations of the Na+ channel blockers TTX (1 nM) or lidocaine (10 nM) block persistent Na+ current but not the transient, inactivating Na+ current responsible for action potentials1. We found that these drugs effectively blocked the hypoxic rise in [Ca2+]i. In contrast, blocking Ca2+ channels with cadmium (100µM) did not prevent the hypoxic rise in [Ca2+]i. These results suggest that the persistent Na+ influx is making a major contribution to the [Ca2+]i rise during hypoxia. A rise in [Na+]i could influence [Ca2+]i by influencing removal of Ca2+ from cells by the Na+-Ca2+ exchanger. To test this hypothesis, we examined the effect of an Na+-Ca2+ exchanger inhibitor, KB-R7943 (5 ì M), and found that it reduced the hypoxic rise in [Ca2+]i. These results support the hypothesis that hypoxia causes an increase in [Ca2+]i by increasing persistent Na+ current and consequently [Na+]i and this then depresses removal of Ca2+ so that [Ca2+]i rises.

(1) 1. Hammarstrom AK and Gage PW. Inhibition of oxidative metabolism increases persistent sodium current in rat CA1 hippocampal neurons. J Physiol 510 ( Pt 3): 735-741, 1998.