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

Abstract

1. 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-HT(1) receptor agonists and/or the 5-HT(1) receptor antagonist GR127935, we characterized the 5-HT receptors involved in regulating microvascular tone of pressurized intracortical arterioles (approximately 40--50 microm) isolated from human and bovine cerebral cortex. The role of nitric oxide (NO) on these responses was assessed with the N(omega)-nitro-L-arginine (L-NNA, 10(-5) M), an inhibitor of NO synthesis. Bovine pial arteries were studied for comparative purposes. 2. At spontaneous tone, 5-HT induced a dose-dependent constriction of human and bovine microarteries (respective pD(2) 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-HT(1) 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 (pD(2) 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-HT(1D) (PNU-109291) and 5-HT(1F) (LY344864) receptor agonists were devoid of any vasomotor effect. 4. In bovine pial vessels, 5-HT and sumatriptan elicited potent constrictions (respective pD(2) of 7.2+/-0.1 and 6.6+/-0.1), a weak dilation being occasionally observed at low sumatriptan concentrations. 5. 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-HT(1B) 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.

Figure 1

Concentration-dependent vasomotor responses to 5-HT, and selective 5-HT₁ receptor agonists in human (A: n=3 – 8) and/or bovine (B: n=5 – 13) intracortical arterioles. (*P<0.05, ^**P<0.01 by paired t-test from control).

Figure 2

Repeated constriction upon application of 5-HT (10⁻⁶ M) to bovine intracortical arterioles in the absence (A), and presence (B) of graded concentrations of the 5-HT₁ receptor antagonist GR127935. Insert: inhibition concentration curve for GR127935 (n=5, ^**P<0.01, by ANOVA).

Figure 3

Effect of 10⁻⁵ M L-NNA on the sumatriptan-mediated vasomotor responses in (A), human (n=5 – 8, ^*P<0.05, ^***P<0.001, by ANOVA, B) and (B), bovine (n=5 – 12, ^*P<0.05, by paired t-test) intracortical arterioles.

Figure 4

Dose-response curves to 5-HT (n=9) and sumatriptan (n=6) in bovine pial vessels.

Figure 5

Correlation analysis between the vasomotor response to 10⁻⁹ M sumatriptan and the diameter of both pial (n=7) and intracortical (n=9) vessels (r=0.6, P<0.05).