A comparison of Ca 2+ channel blocking mode between gabapentin and verapamil: implication for protection against hypoxic injury in rat cerebrocortical slices

The mode of Ca 2+ channel blocking by gabapentin [1‐(aminomethyl)cyclohexane acetic acid] was compared to those of other Ca 2+ channel blockers, and the potential role of Ca 2+ channel antagonists in providing protection against hypoxic injury was subsequently investigated in rat cerebrocortical slices. mRNA for the α 2 δ subunits of Ca 2+ channels was found in rat cerebral cortex. Nitric oxide (NO) synthesis estimated from cGMP formation was enhanced by KCl stimulation, which was mediated primarily by the activation of N‐ and P/Q‐type Ca 2+ channels. Gabapentin blocked both types of Ca 2+ channels, and preferentially reversed the response to 30 m M K + stimulation compared with 50 m M K + stimulation. In contrast, verapamil preferentially inhibited the response to depolarization by the higher concentration (50 m M ) of K + . Gabapentin inhibited KCl‐induced elevation of intracellular Ca 2+ in primary neuronal culture. Hypoxic injury was induced in cerebrocortical slices by oxygen deprivation in the absence (severe injury) or presence of 3 m M glucose (mild injury). Gabapentin preferentially inhibited mild injury, while verapamil suppressed only severe injury. ω ‐Conotoxin GVIA ( ω ‐CTX) and ω ‐agatoxin IVA ( ω ‐Aga) were effective in both models. NO synthesis was enhanced in a manner dependent on the severity of hypoxic insults. Gabapentin reversed the NO synthesis induced by mild insults, while verapamil inhibited that elicited by severe insults. ω ‐CTX and ω ‐Aga were effective in both the cases. Therefore, the data suggest that gabapentin and verapamil cause activity‐dependent Ca 2+ channel blocking by different mechanisms, which are associated with their cerebroprotective actions and are dependent on the severity of hypoxic insults.British Journal of Pharmacology (2003) 139 , 435–443. doi: 10.1038/sj.bjp.0705246