Mechanisms involved in the cerebrovascular dilator effects of N-methyl-d-aspartate in cerebral cortex

Abstract

Glutamate and its synthetic analogues N-methyl-d-aspartate (NMDA), kainate, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) are potent dilator agents in the cerebral circulation. The close linkage between neural activity-based release and actions of glutamate on neurons and the related decrease in cerebral vascular resistance is a classic example in support of the concept of tight coupling between increased neural activity and cerebral blood flow. However, mechanisms involved in promoting cerebral vasodilator responses to glutamatergic agents are controversial. Here we review the development and current status of this important field of research especially in respect to cerebrovascular responses to NMDA receptor activation.

Figure 1

Schematic illustration of likely mechanisms linking activation of neuronal NMDA receptors in the cerebral cortex to dilation of cerebral arteries and arterioles. NMDA or glutamate activates NMDA receptors on neurons, and following intercellular signaling to nNOS containing neurons, nitric oxide (NO) NO is produced which diffuses to arteries and arterioles and causes vasodilation. This intercellular transmission is blocked by tetrodotoxin (TTX), and the NMDA rceptors can be impaired by actions of reactive oxygen species (ROS). It seems likely that other dilator agents in addition to NO such as adenosine and P-450 monooxygenase products also are involved especially in some species. The role of carbon monoxide (CO) derived from astroglia remains controversial.