Sumatriptan elicits both constriction and dilation in human and bovine brain intracortical arterioles

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Abstract
Little is known about serotonin (5-HT) receptors present on brain microvessels that are innervated by brainstem serotonergic neurons. Using 5-HT, sumatriptan and subtype selective 5-HT1 receptor agonists and/or the 5-HT1 receptor antagonist GR127935, we characterized the 5-HT receptors involved in regulating microvascular tone of pressurized intracortical arterioles (∼40 – 50 μm) isolated from human and bovine cerebral cortex. The role of nitric oxide (NO) on these responses was assessed with the Nω-nitro-L-arginine (L-NNA, 10−5 M), an inhibitor of NO synthesis. Bovine pial arteries were studied for comparative purposes. At spontaneous tone, 5-HT induced a dose-dependent constriction of human and bovine microarteries (respective pD2 values of 7.3±0.2 and 6.9±0.1); a response potently inhibited by GR127935 (pIC50 value of 8.5±0.1) in bovine microvessels. In both species, the 5-HT1 receptor agonist sumatriptan induced a biphasic response consisting of a small but significant dilation at low concentrations (1 and/or 10 nM) followed by a constriction at higher doses (pD2 for contraction of 6.9±0.1 and 6.6±0.2 in human and bovine vessels, respectively). Pre-incubation with L-NNA abolished the sumatriptan-induced dilation and significantly shifted the dose-response of the constriction curve to the left. In contrast, the selective 5-HT1D (PNU-109291) and 5-HT1F (LY344864) receptor agonists were devoid of any vasomotor effect. In bovine pial vessels, 5-HT and sumatriptan elicited potent constrictions (respective pD2 of 7.2±0.1 and 6.6±0.1), a weak dilation being occasionally observed at low sumatriptan concentrations. A significant negative correlation was observed between pial and intracortical vessels diameter and the extent of the dilatory response to 10−9 M sumatriptan. Together, these results indicate that sumatriptan, most likely via activation of distinctly localized microvascular 5-HT1B receptors, can induce a constriction and/or a dilation which is sensitive to inhibition of NO synthesis and dependent on the size and, possibly, the existing tone of the vessels.