A comparison of Ca2+ channel blocking mode between gabapentin and verapamil: implication for protection against hypoxic injury in rat cerebrocortical slices.
1 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. 2 mRNA for the alpha(2)delta subunits of Ca(2+) channels was found in rat cerebral cortex. 3 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 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(+). 4 Gabapentin inhibited KCl-induced elevation of intracellular Ca(2+) in primary neuronal culture. 5 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. omega-Conotoxin GVIA (omega-CTX) and omega-agatoxin IVA (omega-Aga) were effective in both models. 6 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. omega-CTX and omega-Aga were effective in both the cases. 7 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.
Oka
Michiko
M
Department of Biochemical Pharmacology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
Itoh
Yoshinori
Y
Wada
Miyuki
M
Yamamoto
Akira
A
Fujita
Takuya
T
D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D000588:Amines; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020864:Calcium Channels, N-Type / Q000096:biosynthesis / Q000187:drug effects; D020865:Calcium Channels, P-Type / Q000096:biosynthesis / Q000187:drug effects; D020907:Calcium Channels, Q-Type / Q000096:biosynthesis / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003509:Cyclohexanecarboxylic Acids; D005333:Fetus; D000077206:Gabapentin; D002534:Hypoxia, Brain / Q000378:metabolism / Q000517:prevention & control*; D009569:Nitric Oxide / Q000096:biosynthesis; D011189:Potassium Chloride / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014700:Verapamil / Q000494:pharmacology* / Q000627:therapeutic use; D005680:gamma-Aminobutyric Acid; D020867:omega-Agatoxin IVA / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D000085:Acetates; D000588:Amines; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D003509:Cyclohexanecarboxylic Acids; D012333:RNA, Messenger; D020867:omega-Agatoxin IVA; D009569:Nitric Oxide; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D000077206:Gabapentin; D020866:omega-Conotoxin GVIA; D014700:Verapamil