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

1 Little is known about serotonin (5-HT) receptors present on brain microve ssels that are innervated by brainstem serotonergic neurons. Using 5-HT, su matriptan and subtype selective 5-HT1 receptor agonists and/or the 5-HT1 re ceptor antagonist GR127935, we characterized the 5-HT receptors involved in regulating microvascular tone of pressurized intracortical arterioles (sim ilar to 40-50 mum) isolated from human and bovine cerebral cortex. The role of nitric oxide (NO) on these responses was assessed with the N-omega-nitr o-L-arginine (L-NNA, 10(-5) M), an inhibitor of NO synthesis. Bovine pial a rteries were studied for comparative purposes. 2 At spontaneous tone, 5-HT induced a dose-dependent constriction of human and bovine microarteries (respective pot values of 7.3 +/- 0.2 and 6.9 +/- 0.1); a response potently inhibited by GR127935 (pIC(50) value of 8.5 +/- 0 .1) in bovine microvessels. 3 In both species, the 5-HT1 receptor agonist sumatriptan induced a biphasi c response consisting of a small but significant dilation at low concentrat ions (1 and/or 10 nM) followed by a constriction at higher doses (pD(2) for contraction of 6.9 +/- 0.1 and 6.6 +/- 0.2 in human and bovine vessels, re spectively). Pre-incubation with L-NNA abolished the sumatriptan-induced di lation and significantly shifted the dose-response of the constriction curv e to the left. In contrast, the selective 5-HT1D (PNU-109291) and 5-HT1F (L Y344864) receptor agonists were devoid of any vasomotor effect. 4 In bovine pial vessels, 5-HT and sumatriptan elicited potent constriction s (respective pot of 7.2 +/- 0.1 and 6.6 +/- 0.1), a weak dilation being oc casionally observed at low sumatriptan concentrations. 5 A significant negative correlation was observed between pial and intracor tical 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 o f NO synthesis and dependent on the size and, possibly, the existing tone o f the vessels.