Contractile 5-HT(1B) receptors in human cerebral arteries: Pharmacological characterization and localization with immunocytochemistry

Abstract

1. The cerebrovascular receptor(s) that mediates 5-hydroxytryptamine (5-HT)-induced vasoconstriction in human cerebral arteries (HCA) has proven difficult to characterize, yet these are essential in migraine. We have examined 5-HT receptor subtype distribution in cerebral blood vessels by immunocytochemistry with antibodies selective for human 5-HT(1D) and human 5-HT(1D) receptors and also studied the contractile effects of a range of 5-HT receptor agonists and antagonists in HCA. 2. Immunocytochemistry of cerebral arteries showed dense 5-HT(1B) receptor immunoreactivity (but no 5-HT(1D) receptor immunoreactivity) within the smooth muscle wall of the HCA. The endothelial cell layer was well preserved and weak 5-HT(1B) receptor immunoreactivity was present. 3. Pharmacological experiments on HCA with intact endothelium showed that 5-carboxamidotryptamine was significantly more potent than α-methyl-5-HT, 2-methyl-5-HT and 5-HT in causing vasoconstriction. The 5-HT(1B/1D) receptor agonists naratriptan, sumatriptan, zolmitriptan and 181C91 (N-desmethyl zolmitriptan), all induced equally strong contractions and with similar potency as 5-HT. The maximum contractile response was significantly less for avitriptan and dihydroergotamine. There was a significant correlation between vasoconstrictor potency and 5-HT(1B)- and 5-HT(1D)-receptor affinity, but not with 5-HT(1A)-, 5-ht(1F) or 5-HT2- receptor affinity. 4. The 5-HT(1B/1D)-receptor antagonist GR 55562 (10-7-10-6 M) inhibited the contractile responses to sumatriptan and 5-CT in a competitive manner with a pK(B) value for GR 55562 of 7.4. Furthermore, ketanserin (10-7 M), prazosin (10-7 M), and sulpiride (10-7 M) were devoid of significant antagonistic activity of 5-HT-induced contraction in the HCA. 5. The results are compatible with the hypothesis that the 5-HT(1B) receptors play a major role in 5-HT-induced vasoconstriction in HCA.