Voltage-Gated Calcium Channels in CNS White Matter: Role in Anoxic Injury. Fern, Robert, Bruce R. Ransom, and Stephen G. Waxman. Department of Neurology, Yale University School of Medicine, New Haven, CT 06510 and Neuroscience Research Center, Department of Veterans Affairs Medical Center, West Haven, CT 16516.
APStracts 2:0024N, 1995.
SUMMARY AND CONCLUSIONS
1. The effect of calcium channel antagonists on the extent of anoxia-induced white matter injury was studied in the rat optic nerve, a white matter 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 calcium channel antagonists verapamil (90 [mu]M), diltiazem (50 [mu]M), and nifedepine (2.5 [mu]M) significantly protected the rat optic nerve from anoxic injury. Mean recovery of CAP area was 51.3 +/-3.0%, (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 recovery under control conditions was 35.2 +/-0.3 (n=33). 3. Simultaneous block of L-type and N-type Ca++ channels by co-application of 50 [mu]M diltiazem and 1[mu]M SNX-124 (synthetic w -conotoxin (CgTx) GVIA), resulted in post-anoxic CAP recovery of 73.6 +/-6.0% (n=12), significantly larger than CAP recovery in diltiazem alone (p<0.001). Block of CgTx MVIIC -sensitive channels in addition to L -type and N-type channels by co-application 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 significantly protect against anoxic injury (CAP recovery=36.3 +/-2.9%, n=10). 4. While N-type and L-type Ca++ channels were involved in the development of anoxic injury, perfusion with 50 [mu]M diltiazem or 1-2 [mu]M SNX-124 had no effect upon the normoxic CAP. Perfusion with 1 [mu]M SNX-230, however, produced a gradual increase in CAP area over 130 min. CAP area reached an average of 114.2 +/-5.8% of the initial value (n=8), compared to a reduction of CAP area to 88.9 +/-5.13% of the initial value (n=8) found after 130 min under control conditions (P<0.005). 5. Concentrations of Co++ and Cd++ known to block Ca++ channels irreversibly reduced CAP area. This effect of Cd++ and Co++ was potentiated by co-perfusion with 30 mM K+. Low concentrations of Cd++ (2[mu]M) and Co++ (200[mu]M), which were below concentrations that reduced CAP area in 30 mM K+, had a protective action against anoxic injury but probably did not block the majority of Ca++ channels. 6. We conclude that L-type and N-type Ca++ channels are involved in the development of anoxic injury in CNS white matter. Ca++ channels are therefore involved in anoxic injury in both CNS gray matter and white matter, suggesting that strategies directed against Ca++ influx via Ca++ channels 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 Ca++ channels, indicating the presence of three pharmacologically distinct Ca++ channels in CNS white matter. 

Received 17 January 1995; accepted in final form 16 March 1995.
APS Manuscript Number J37-5.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on  3 April 1995.