It has been suggested that 5-HT_2B receptors may be involved in the initiation of migraine. 5-HT_2B receptor stimulation has been suggested to lead to relaxation of porcine pre-contracted cerebral artery via the release of nitric oxide (Schmuck et al., 1996). In addition, 5-HT receptor agonists have been shown to induce dural plasma protein extravasation in guinea pigs via nitric oxide release, an effect that was blocked by selective 5-HT_2B receptor antagonists (Johnson et al., 2003). The aim of the present study was to investigate the effect of 5-HT_2B activation on tone in human pre-contracted cerebral artery in vitro.

Samples of human middle, anterior, posterior and basilar cerebral artery (6 male and 5 female, ages 59-94,) were obtained post mortem (mean ( ± s.e.m.) delay of 6.4 ± 0.5 hours), with the informed consent of next of kin, and with the approval of local ethics committees. Intact rings of cerebral arteries, 2-3mm in length, (1-2mm i.d.) were mounted in organ baths containing oxygenated (95% O₂ / 5% CO₂) Krebs buffer containing glutathione (30mM) and ascorbic acid (100µM) at 37 °C. Tissues were placed under a tension equivalent to 5 mN (10mN for basilar artery) and left to equilibrate for a period of at least 60 min. Following equilibration, a cumulative concentration response curve to the thromboxane mimetic, U-46619, was constructed in all tissues. After washout, the selective 5-HT_1B/1D and 5-HT_2A/C antagonists, GR 127935 (1µM) and ketanserin (30nM), were added to the bathing solution, and left in contact with the tissues for 30 mins. An approximate EC₅₀ concentration of U-46619 was then added, and once a stable contraction had been obtained, the 5-HT₂ receptor selective agonist, -Me-5-HT (1µM), was applied, followed after at least 5 min by bradykinin (1µM). Changes in tone following administration of -Me-5-HT were compared with such changes over an equivalent time period prior to agonist administration. Statistical analysis was by ANOVA with post-hoc Bonferroni test (p<0.05).

Application of - Me-5-HT to pre-contracted human cerebral artery produced no statistically significant dilatation in any of the tissue types investigated (Table 1). All tissues showed dilator responses to bradykinin, showing that the arteries were capable of endothelium dependent relaxation.

Table 1: Responses (mN) are means±s.e.m. from three donors, + indicates contraction, - indicates vasodilatation

In conclusion, we have found no evidence to suggest that activation of 5-HT_2B receptors causes relaxation in human cerebral arteries in vitro.

Johnson et al., (2003). Cephalalgia, 23, 117-123.
Schmuck et al., (1996). Eur. J. Neurosci., 8(5), 959-967.