Mechanisms of Injury-Induced Calcium Entry into Peripheral Nerve Myelinated Axons: Role of Reverse Sodium-Calcium Exchange |
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Authors: | Ellen J Lehning Renu Doshi Norman Isaksson Peter K Stys Richard M LoPachin Jr |
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Institution: | Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, U.S.A., and; Loeb Neuroscience, Ottawa Civic Hospital, Ottawa, Ontario, Canada |
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Abstract: | Abstract: To investigate the route of axonal Ca2+ entry during anoxia, electron probe x-ray microanalysis was used to measure elemental composition of anoxic tibial nerve myelinated axons after in vitro experimental procedures that modify transaxolemmal Na+ and Ca2+ movements. Perfusion of nerve segments with zero-Na+/Li+-substituted medium and Na+ channel blockade by tetrodotoxin (1 µM) prevented anoxia-induced increases in Na and Ca concentrations of axoplasm and mitochondria. Incubation with a zero-Ca2+/EGTA perfusate impeded axonal and mitochondrial Ca accumulation during anoxia but did not affect characteristic Na and K responses. Inhibition of Na+-Ca2+ exchange with bepridil (50 µM) reduced significantly the Ca content of anoxic axons although mitochondrial Ca remained at anoxic levels. Nifedipine (10 µM), an L-type Ca2+ channel blocker, did not alter anoxia-induced changes in axonal Na, Ca, and K. Exposure of normoxic control nerves to tetrodotoxin, bepridil, or nifedipine did not affect axonal elemental composition, whereas both zero-Ca2+ and zero-Na+ solutions altered normal elemental content characteristically and significantly. The findings of this study suggest that during anoxia, Na+ enters axons via voltage-gated Na+ channels and that subsequent increases in axoplasmic Na+ are coupled functionally to extraaxonal Ca2+ import. Intracellular Na+-dependent, extraaxonal Ca2+ entry is consistent with reverse operation of the axolemmal Na+-Ca2+ exchanger, and we suggest that this mode of Ca2+ influx plays a general role in peripheral nerve axon injury. |
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Keywords: | Peripheral nerve Myelinated axons Anoxia Electron probe x-ray microanalysis Na+-Ca2+ exchanger Acrylamide |
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