A novel Na+/Ca2+ channel blocker, NS-7, suppresses hypoxic injury in rat cerebrocortical slices.
The substance 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7) has been developed recently as a cerebroprotective compound with Na+ and Ca2+ channel blocking action. In the present study, the effect of NS-7 in an in vitro model of hypoxic injury was examined and the possible involvement of Na+ and Ca2+ channels in the hypoxic injury subsequently determined. When slices of rat cerebral cortex were exposed to hypoxia/glucose deprivation followed by reoxygenation and restoration of the glucose supply, marked leakage of lactate dehydrogenase (LDH) occurred 3-6 h after reoxygenation. This hypoxia/reoxygenation-induced injury was blocked almost completely by the removal of extracellular Ca2+ or by chelating intracellular Ca2+ with 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA/AM). In addition, combined treatment with the N-type Ca2+ channel blocker omega-conotoxin GVIA and the P/Q-type Ca2+ channel blocker omega-agatoxin IVA significantly reduced LDH leakage, although neither of these Ca2+ channel blockers alone, nor nimodipine, an L-type Ca2+ channel blocker, was effective. On the other hand, several Na+ channel blockers, including tetrodotoxin, local anaesthetics and antiepileptics, significantly reduced the hypoxic injury. NS-7 (3-30 microM) concentration-dependently inhibited LDH leakage caused by hypoxia/reoxygenation, but had no influence on the reduction of tissue ATP content and energy charge during hypoxia and glucose deprivation. It is suggested that blockade of Na+ and Ca2+ channels is implicated in the cerebroprotective action of NS-7.
Tatsumi
S
S
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Itoh
Y
Y
Ukai
Y
Y
Kimura
K
K
D000255:Adenosine Triphosphate / Q000378:metabolism; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D000860:Hypoxia; D066298:In Vitro Techniques; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010100:Oxygen; D010101:Oxygen Consumption / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors
C106144:4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride; D000777:Anesthetics; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D000255:Adenosine Triphosphate; D005947:Glucose; D010100:Oxygen; D002118:Calcium