Neuroprotective actions of calcium channel blockers in hippocampal slice preparations of stroke-prone spontaneously hypertensive rat

Stroke-prone spontaneously hypertensive rat (SHRSP) has been considered as an animal model of ischemic stroke in human. Transient ischemia causes neur onal damage in SHRSP but not in its mother strain, Wister Kyoto rat (WKY). Recently, S-312-d, a novel L-type Ca2+ channel blocker has been reported to suppress transient ischemia-induced neuronal damage in SHRSP. However, it is not known whether the neuroprotective action of S-312-d is mediated via its action on the neuronal or vascular system. In this study, we first demo nstrate that CA1 pyramidal neurons of SHRSP are more excitable and vulnerab le to short-term hypoxic and hypoglycemic ('ischemic') insult than those of WKY in hippocampal slice preparations. This vulnerability of hippocampal p yramidal neurons in the SHRSP strain did not depend on its hypertensive phe notype. Submicromolar concentration of Ca2+ channel blockers, S-312-d, its stereoisomer, S-312-l, and nimodipine suppressed spreading depression-like depolarization and protected CA1 pyramidal neurons against the neuronal dys function induced by 'ischemic' insult in SHRSP preparations. The rank order of effectiveness of the Ca2+ channel blockers as a neuroprotective agent i n our study was the same as that for L-type Ca2+ channel blocking action ex amined by in binding and pharmacological experiments. Thus, the neuroprotec tive effect is suggested to be exerted directly by blocking L-type Ca2+ cha nnels in hippocampal neurons.