Relationship between extracellular glutamate concentration and voltage-sensitive calcium channel function in focal...

Ischemic cell death occurs when extracellular glutamate levels increase, causing tissue depolarization and an excessive rise in intracellular calcium concentrations. The relative occurrence of the depolarization events and the changes in glutamate concentration in ischemia have not been studied. In a model of focal cerebral ischemia in the rat, three measurements were made simultaneously in vivo: cerebral blood flow (CBF) by the H2-clearance method, extracellular glutamate concentration by microdialysis, and activation of the voltage-sensitive calcium channel (VSCC) by its binding to [3H]nimodipine. Effects of probe implantation on these measurements were accounted for. The CBF to control ratio obtained during the experiments spanned the range of 1.08 to 0.07. Binding to [3H]nimodipine became significantly activated when CBF fell to approximately 0.49 of its control value while extracellular glutamate concentrations increased significantly only at a CBF ratio of < 0.33. Activation of the VSCC at this high CBF ratio may be due to ischemic depolarization, which has been shown to activate the binding to [3H]nimodipine. It may be useful to define a CBF threshold of 50% of normal in focal ischemia for opening of the VSCC. The same threshold has been linked to an overall depression of protein synthesis and to activation of a number of molecular responses.