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 di cult 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 1B and human 5-HT 1D receptors and also studied the contractile e ects 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 signi®cantly more potent than a-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 signi®cantly less for avitriptan and dihydroergotamine. There was a signi®cant correlation between vasoconstrictor potency and 5-HT 1B -and 5-HT 1D -receptor a nity, but not with 5-HT 1A -, 5-ht 1F or 5-HT 2 -receptor a nity. 4 The 5-HT 1B/1D -receptor antagonist GR 55562 (10 77 ± 10 76 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 77 M), prazosin (10 77 M), and sulpiride (10 77 M) were devoid of signi®cant 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.

Vascular plasticity in cerebrovascular disorders

“…To address the first part of this question, small samples of cortex arterioles were obtained in conjunction with neurosurgical tumor resections or operations to remove epileptic seizure areas. These vessels indeed express ET A and ET B receptors (Nilsson et al, 1997), AT 1 (Ahnstedt et al, 2011; Ansar et al, 2009), 5-HT 1B (Nilsson et al, 1999), and thromboxane A2 (Uski et al, 1983) receptors. Moreover, freshly obtained human cerebral arteries exhibit ET-1-induced responses that were found to be similar to the responses observed in fresh rat cerebral arteries; ET-1 elicited an ET A receptor-mediated contraction with E max 112% and pEC 50 9.2, whereas S6c elicited an ET B receptor-mediated dilatation on precontraction (Nilsson et al, 1997).…”

Molecular cloning, sequence analysis and pharmacological properties of the porcine 5‐HT1D receptor

“…These drugs also inhibit dural plasma protein extravasation and action potentials in trigeminal nucleus caudalis following stimulation of the trigeminal ganglion and superior sagittal sinus, respectively (Moskowitz, 1992;Edvinsson & Goadsby, 1998;Saxena & Tfelt-Hansen, 2000). Molecular and pharmacological studies have convincingly shown that the vasoconstrictor e ect of triptans is mediated via 5-HT 1B , but not 5-HT 1D or 5-ht 1F receptors (Bouchelet et al, 1996;De Vries et al, 1998;1999b;Verheggen et al, 1998;Cohen & Schenck, 1999;Nilsson et al, 1999). On the other hand, the trigeminal neural e ects of triptans seem to involve primarily the 5-HT 1D receptor, although 5-HT 1B and 5-ht 1F receptors have also been implicated Longmore et al, 1997;McCall, 1997;Wainscott et al, 1998;De Vries et al, 1999a;Hargreaves & Shepheard, 1999;Mitsikostas et al, 1999).…”

5-HT1F Receptor Agonists: A New Treatment Option for Migraine Attacks?

“…59 5-HT 1B , 5-HT 1F , and, to a smaller extent, 5-HT 1D receptor mRNAs have been identified in human cerebral arteries. 4 The 5-HT 1B receptor mRNA has also been found in human coronary arteries 7 and in peripheral blood vessels. 60,61 The 5-HT 1F mRNA receptor could only be detected in a very low amount in human coronary arteries.…”

“…However, 5-HT 1 receptors also participate to a smaller extent in cardiac vessel constriction, 10 mostly through activation of the 5-HT 1B receptor subtype. 7 Because the vasoconstrictive potency of the triptans is low in cardiac …”