Glutamate-Induced Cerebral Vasodilation Is Mediated by Nitric Oxide Through N -Methyl- d -Aspartate Receptors

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Abstract
Background and Purpose It was found that glutamate, a major neurotransmitter, is vasoactive in the cerebral circulation. However, the mechanism is unclear. This study was designed to investigate the role of nitric oxide (NO) and N -methyl- d -aspartate (NMDA) receptors in cerebral arteriolar dilation to glutamate. Methods Newborn, chloralose-anesthetized pigs were equipped with a closed cranial window. The diameter of pial arterioles was measured by means of intravital microscopy, and NO synthase (NOS) activity in brain cortex was determined by the conversion assay of [ 14 C]arginine to [ 14 C]citrulline. Results Topical application of glutamate at 10 −7 , 10 −6 , and 10 −5 mol/L (n=5) increased the mean diameter by 12±3%, 13±2%, and 18±3% (±SEM), respectively (baseline, 91±10 μm; P <.05). Similarly, NMDA application at the above doses (n=5) dilated arterioles by 10±2%, 16±3%, and 18±6%, respectively (baseline, 97±4 μm; P <.05). Topical application of 10 −4 mol/L N G -nitro- l -arginine (L-NNA), which inhibited NOS activity by 93%, blocked the arteriolar dilation to glutamate or NMDA. Furthermore, administration of MK-801, a potent inhibitor of NMDA receptors, blocked glutamate-induced vasodilation completely in both topical application (10 −5 mol/L; n=6) and intravenous administration (5 to 10 mg/kg; n=5). In addition, neither L-NNA nor MK-801 attenuated the vasodilation to hypercapnia (P co 2 =40 to 68 mm Hg). Conclusions Glutamate-induced cerebral arteriolar dilation is mediated by NO through NMDA receptors, and NO does not play a major role in the cerebral arteriolar dilation to hypercapnia (P co 2 =40 to 68 mm Hg) in newborn pigs.