Article date: May 2003
By: Michiko Oka, Yoshinori Itoh, Miyuki Wada, Akira Yamamoto, Takuya Fujita in Volume 139, Issue 2, pages 435-443
The mode of Ca2+ channel blocking by gabapentin [1‐(aminomethyl)cyclohexane acetic acid] was compared to those of other Ca2+ channel blockers, and the potential role of Ca2+ channel antagonists in providing protection against hypoxic injury was subsequently investigated in rat cerebrocortical slices.
mRNA for the α2δ subunits of Ca2+ 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 Ca2+ channels. Gabapentin blocked both types of Ca2+ channels, and preferentially reversed the response to 30 mM K+ stimulation compared with 50 mM K+ stimulation. In contrast, verapamil preferentially inhibited the response to depolarization by the higher concentration (50 mM) of K+.
Gabapentin inhibited KCl‐induced elevation of intracellular Ca2+ in primary neuronal culture.
Hypoxic injury was induced in cerebrocortical slices by oxygen deprivation in the absence (severe injury) or presence of 3 mM 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 Ca2+ channel blocking by different mechanisms, which are associated with their cerebroprotective actions and are dependent on the severity of hypoxic insults.
The mode of Ca2+ channel blocking by gabapentin [1‐(aminomethyl)cyclohexane acetic acid] was compared to those of other Ca2+ channel blockers, and the potential role of Ca2+ channel antagonists in providing protection against hypoxic injury was subsequently investigated in rat cerebrocortical slices.
mRNA for the α2δ subunits of Ca2+ 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 Ca2+ channels. Gabapentin blocked both types of Ca2+ channels, and preferentially reversed the response to 30 mM K+ stimulation compared with 50 mM K+ stimulation. In contrast, verapamil preferentially inhibited the response to depolarization by the higher concentration (50 mM) of K+.
Gabapentin inhibited KCl‐induced elevation of intracellular Ca2+ in primary neuronal culture.
Hypoxic injury was induced in cerebrocortical slices by oxygen deprivation in the absence (severe injury) or presence of 3 mM 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 Ca2+ 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
DOI: 10.1038/sj.bjp.0705246
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