Regulation of cerebral microvessels by glutamatergic mechanisms

This study examined the role of glutamate receptor activation in the regulation of microvascular tone in the hippocampus and neocortex of the rat. Microvascular and neuronal responses were simultaneously recorded in brain slices using videomicroscopic analysis in conjunction with electrophysiological recording. Glutamate and other glutamate receptor agonists, including NMDA, kainic acid, and ACPD elicited dose-dependent dilation in preconstricted hippocampal microvessels. The lower concentrations of NMDA elicited dilation with an increase in neuronal excitability while dilatory responses to other agonists were associated with substantial depolarization. NMDA-mediated dilation was inhibited completely with a sodium channel blocker (TTX), an NOS inhibitor (L-NNA), or a specific inhibitor of neuronal NOS (7-NI). Inhibition of the GABA(A) or the A2 adenosine receptor did not attenuate the NMDA-induced dilation. The role of spontaneous glutamate receptor activation by endogenous glutamate in the regulation of resting dilatory tone was also examined. Blocking AMPA or metabotropic glutamate receptors did not induce significant responses in resting hippocampal vessels. However, the NMDA receptor antagonist, APV, elicited a dose-dependent constriction. In surface vessels of the neocortex, NMDA elicited a comparable dose-dependent dilation, and APV elicited a significantly smaller dose-dependent constriction. A 60 min period of hypoxia elicited a significant dilation of preconstricted hippocampal microvessels. APV did not significantly influence this dilatory response indicating that hypoxia-induced dilation is not mediated by NMDA receptor activation. Taken together, these results indicate that glutamate contributes to the dilatory tone of cerebral microvessels under physiologic conditions and that this effect is mediated by NMDA receptors. Glutamatergic vasodilation is dependent on neuronal discharge activity and the neuronal production of NO. The tonic influence is more pronounced in hippocampal microvessels than in neocortical vessels suggesting that the contribution of NMDA receptor activation to resting dilatory tone is dependent on the location of vessels within the brain.