The pathophysiology of anoxic injury in central nervous system white matter. White matter of the mammalian brain is susceptible to anoxic injury, but little is known about the pathophysiology of this process. We studied the mechanisms of anoxic injury in white matter using the isolated rat optic nerve, a typical central nervous system white-matter tract. Optic nerve function, measured as the area under the compound action potential, rapidly failed when exposed to anoxia. Postanoxic recovery was variable, depending on duration of the anoxic insult; after a standard 60-minute period of anoxia, the compound action potential recovered to 28.5% of control. Irreversible anoxic injury was critically dependent on extracellular Ca2+; maintaining the tissue in zero [Ca2+] solution throughout the anoxic period resulted in 100% compound action potential recovery. Increasing perfusate [Ca2+] during anoxia from zero to 4 mM resulted in progressively less recovery. Anoxic damage to the optic nerve appears to depend on the gradual accumulation (over tens of minutes) of Ca2+ in a cytoplasmic compartment. The inorganic Ca2+ channel blockers Mn2+ (1 mM), Co2+ (1 mM), or La3+ (0.1 mM) had no effect on recovery of the compound action potential after anoxia; only Mg2+ (10 mM) significantly improved recovery. Treatment with the dihydropyridine Ca2+ channel blockers nifedipine (1-10 microM) or nimodipine (1-40 microM) also had no effect on recovery from anoxia. Thus, Ca2+ influx during anoxia does not occur via conventional Ca2+ channels. Preliminary evidence suggests that this Ca2+ influx may occur via other cation channels that are imperfectly selective for Ca2+ or via the Na(+)-Ca2+ exchanger. 