VOLTAGE-GATED CALCIUM CHANNELS IN CNS WHITE-MATTER - ROLE IN ANOXIC INJURY

1. The effect of Ca2+ channel antagonists on the extent of anoxia-indu ced white matter injury was studied in the rat optic nerve, a white ma tter tract. Compound action potentials (CAPs) were recorded before and after a standard 60-min anoxic period to assess the extent of anoxic injury. 2. The L-type Ca2+ channel antagonists verapamil (90 mu M), di ltiazem (50 mu M), and nifedepine (2.5 mu M) significantly protected t he rat optic nerve from anoxic injury. Mean recovery of CAP area was 5 1.3 +/- 3.0% (mean +/- SE, n = 8, P < 0.01), 65.6 +/- 5.3% (n = 8, P < 0.01), and 54.3 +/- 6.1% (n = 8, P < 0.01), respectively. Mean CAP re covery under control conditions was 35.2 +/- 0.3 (n = 33). 3. Simultan eous block of L-type and N-type Ca2+ channels by coapplication of 50 m u M diltiazem and 1 mu M SNX-124 [synthetic omega-conotoxin (CgTx) GVI A], resulted in postanoxic CAP recovery of 73.6 +/- 6.0% (n = 12), sig nificantly larger than CAP recovery in diltiazem alone (P < 0.001). Bl ock of CgTx MVIIC-sensitive channels in addition to L-type and N-type channels by coapplication of 50 mu M diltiazem + 1 mu M SNX-230 + 1 mu M SNX-124 failed to produce any additional increase in CAP recovery ( 71.3 +/- 5.6%, n = 8). Application of 1 mu M SNX-124 alone did not sig nificantly protect against anoxic injury (CAP recovery, 36.3 +/- 2.9%, n = 10). 4. While N-type and L-type Ca2+ channels were involved in th e development of anoxic injury, perfusion with 50 mu M diltiazem or 1- 2 mu M SNX-124 had no effect on the normoxic CAP. Perfusion with 1 mu M SNX-230, however, produced a gradual increase in CAP area over 130 m in. CAP area reached an average of 114.2 +/- 5.8% of the initial value (n = 8), compared with a reduction of CAP area to 88.9 +/- 5.13% of t he initial value (n = 8) found after 130 min under control conditions (P < 0.005). 5. Concentrations of Co2+ and Cd2+ known to block Ca2+ ch annels irreversibly reduced CAP area. This effect of Cd2+ and Co2+ was potentiated by co-perfusion with 30 mM K+. Low concentrations of Cd2 (2 mu M) and Co2+ (200 mu M), which were below concentrations that re duced CAP area in 30 mM K+, had a protective action against anoxic inj ury but probably did not block the majority of Ca2+ channels. 6. We co nclude that L-type and N-type Ca2+ channels are involved in the develo pment of anoxic injury in CNS white matter. Ca2+ channels are therefor e involved in anoxic injury in both CNS gray matter and white matter, suggesting that strategies directed against Ca2+ influx via Ca2+ chann els may provide protection for a broad spectrum of CNS regions during stroke. In addition, we observed changes in the CAP following block of CgTx MVIIC-sensitive Ca2+ channels, indicating the presence of three pharmacologically distinct Ca2+ channels in CNS white matter.