A NOVEL NA+ CA2+ CHANNEL BLOCKER, NS-7, SUPPRESSES HYPOXIC INJURY IN RAT CEREBROCORTICAL SLICES/

The substance 4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrim idine hydrochloride (NS-7) has been developed recently as a cerebropro tective compound with Na+ and Ca2+ channel blocking action. In the pre sent 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 cerebra l cortex were exposed to hypoxia/glucose deprivation followed by reoxy genation and restoration of the glucose supply, marked leakage of lact ate dehydrogenase (LDH) occurred 3-6 h after reoxygenation. This hypox ia/reoxygenation-induced injury was blocked almost completely by the r emoval of extracellular Ca2+ or by chelating intracellular Ca2+ with , 2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxyme thyl)ester (BAPTA/AM). In addition, combined treatment with the N-type Ca2+ channel blocker omega-conotoxin GVIA and the P/Q-type Ca2+ chann el blocker omega-agatoxin IVA significantly reduced LDH leakage, altho ugh 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, in eluding tetrodotoxin? local anaesthetics and antiepileptics, significantly reduced the hypoxic injury. NS-7 (3-30 m u M) concentration-dependently inhibited LDH leakage caused by hypoxia /reoxygenation, but had no influence on the reduction of tissue ATP co ntent 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.