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Hyposerotonin-Induced Nitric Oxide Supersensitivity in the Cerebral Microcirculation


Address all correspondence to Dr. Anan Srikiatkhachorn, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.


Objective.–To investigate the relationship between hyposerotonin and cranial microvascular responses to nitric oxide (NO).

Background.–Although the mechanism underlying NO supersensitivity in migraine is still unclear, an alteration of the serotonin system is a possible explanation.

Methods.–Wistar rats were divided into control and hyposerotonin groups. Serotonin was depleted by intraperitoneal injection with 300 mg/kg of para-chlorophenylalanine (PCPA), a tryptophan hydroxylase inhibitor. Three days after PCPA pretreatment, the animals were prepared for assessment of their NO-induced vasomotor response using glyceryl trinitrate (GTN: 8 to 10 mg/kg, intravenously) as an NO donor. Pial circulation was visualized by the intravital fluorescein videomicroscopic technique. Images of vessels at 0, 5, 15, 30, and 60 minutes post GTN infusion were digitized and measured. At the end of monitoring, the rat brains were removed for ultrastructural study of the brain microvessels.

Results.–Infusion of GTN produced dose-dependent pial arteriolar dilatation. This vasodilator effect was significantly increased in the PCPA-treated groups, especially at 30 and 60 minutes. The percentage change from baseline diameter at 30 minutes after the 8-mg/kg GTN infusion was 42.6 ± 3.1 for the hyposerotonin group and 16.8 ± 2.9 for the control group (P<.001). Electron microscopic study revealed that exposure to the NO donor produced considerable changes in cerebral microvessels, characterized by focal ballooning of endothelial cells, increased microvillous formation, and increased endothelial pinocytosis. These anatomical changes were significantly more prominent in the hyposerotonin group.

Conclusions.–A hyposerotoninergic condition can facilitate the NO-induced physiological and pathological responses in meningeal and cerebral microvessels and, therefore, is a possible explanation for the supersensitivity to NO observed in patients with migraine.

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