Vulnerability of CA1 neurons in SHRSP hippocampal slices to ischemia, and its protection by Ca2+ channel blockers.
Vulnerability of CA1 pyramidal neurons to hypoxic and hypoglycemic insult was compared in hippocampal slices between the stroke-prone spontaneously hypertensive rat (SHRSP) and its mother strain, Wistar Kyoto rat (WKY). Stimulation of Schaffer collateral-commissural fibers induced D-2-amino-5-phosphonovalerate sensitive multi-component population spikes in slices from both strains when the external K+ concentration was elevated. The K+ concentration required for this phenomenon was significantly lower in SHRSP slice preparations than in those from WKY. The hypoxic and hypoglycemic insult in slice preparations is assumed to be equivalent to ischemic conditions in vivo. Although the short-term 'ischemic' insult caused a complete loss of population spikes in slices from both strains, a transient hyperexcitability, spreading depression-like depolarization, accumulation of extracellular K+ and reduction of extracellular Ca2+ occurred in SHRSP slices, but not in WKY. Time required for partial recovery of the population spike following the 'ischemic' insult was markedly increased in SHRSP slices compared with WKY. Thus, CA1 pyramidal neurons of SHRSP were more vulnerable to 'ischemic' insult than those of WKY. This vulnerability of pyramidal neurons in the SHRSP strain was independent of its hypertensive phenotype. A novel L-type Ca2+ channel blocker, S-312-d, its stereoisomer, S-312-1, and nimodipine protected the 'ischemic' insult-induced neuronal dysfunction at submicromolar concentrations. It is concluded that hippocampal neurons in SHRSP are innately vulnerable. This vulnerability is suggested to be due, at least in part, to some abnormality in K+ channel channels of hippocampal neurons.
Division of Pharmacology, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
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Yasui
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Kawasaki
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002561:Cerebrovascular Disorders / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004198:Disease Susceptibility; D005071:Evoked Potentials / Q000187:drug effects; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D010641:Phenotype; D011188:Potassium / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D002121:Calcium Channel Blockers; D011188:Potassium