Yasui M, Kawasaki K
Division of Pharmacology, Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Brain Res. 1994 Apr 11;642(1-2):146-52. doi: 10.1016/0006-8993(94)90916-4.
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.
在易中风自发性高血压大鼠（SHRSP）及其母系Wistar Kyoto大鼠（WKY）之间，比较了海马切片中CA1锥体神经元对缺氧和低血糖损伤的易感性。当细胞外K⁺浓度升高时，刺激Schaffer侧支-连合纤维在两种品系的切片中均诱发了D-2-氨基-5-磷酸戊酸敏感的多成分群体峰电位。SHRSP切片制备中出现这种现象所需的K⁺浓度明显低于WKY的切片。切片制备中的缺氧和低血糖损伤被认为等同于体内的缺血情况。尽管短期的“缺血”损伤导致两种品系切片中的群体峰电位完全丧失，但SHRSP切片中出现了短暂的兴奋性过高、类似扩散性抑制的去极化、细胞外K⁺积累和细胞外Ca²⁺减少，而WKY切片中未出现。与WKY相比，SHRSP切片中“缺血”损伤后群体峰电位部分恢复所需的时间明显延长。因此，SHRSP的CA1锥体神经元比WKY的更容易受到“缺血”损伤。SHRSP品系中锥体神经元的这种易感性与其高血压表型无关。一种新型L型Ca²⁺通道阻滞剂S-312-d、其立体异构体S-312-1和尼莫地平在亚微摩尔浓度下可保护“缺血”损伤诱导的神经元功能障碍。得出的结论是，SHRSP中的海马神经元天生就很脆弱。这种脆弱性至少部分归因于海马神经元K⁺通道的某些异常。
