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.