No abstract

1 Continuous infusions of 5-hydroxytryptamine (5-HT) inhibit the tachycardiac responses to preganglionic (C 7 -T 1 ) sympathetic stimulation in pithed rats pretreated with desipramine. The present study identified the pharmacological profile of this inhibitory action of 5-HT. 2 The inhibition induced by intravenous (i.v.) continuous infusions of 5-HT (5.6 mg kg À1 min À1) on sympathetically induced tachycardiac responses remained unaltered after i.v. treatment with saline or the antagonists GR 127935 (5-HT 1B/1D ), the combination of WAY 100635 (5-HT 1A ) plus GR 127935, ritanserin (5-HT 2 ), tropisetron (5-HT 3/4 ), LY215840 (5-HT 7 ) or a cocktail of antagonists/inhibitors consisting of yohimbine (a 2 ), prazosin (a 1 ), ritanserin, GR 127935, WAY 100635 and indomethacin (cyclooxygenase), but was abolished by methiothepin (5-HT 1/2/6/7 and recombinant 5-ht 5A/5B ). These drugs, used in doses high enough to block their respective receptors/mechanisms, did not modify the sympathetically induced tachycardiac responses per se. 3 I.v. continuous infusions of the agonists 5-carboxamidotryptamine (5-CT; 5-HT 1/7 and recombinant 5-ht 5A/5B ), CP 93,129 (r5-HT 1B ), sumatriptan (5-HT 1B/1D ), PNU-142633 (5-HT 1D ) and ergotamine (5-HT 1B/1D and recombinant 5-ht 5A/5B ) mimicked the above sympatho-inhibition to 5-HT. In contrast, the agonists indorenate (5-HT 1A ) and LY344864 (5-ht 1F ) were inactive. Interestingly, 5-CT-induced cardiac sympatho-inhibition was abolished by methiothepin, the cocktail of antagonists/ inhibitors, GR 127935 or the combination of SB224289 (5-HT 1B ) plus BRL15572 (5-HT 1D ), but remained unchanged when SB224289 or BRL15572 were given separately. 4 Therefore, 5-HT-induced cardiac sympatho-inhibition, being unrelated to 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-ht 6 , 5-HT 7 receptors, a 1/2 -adrenoceptor or prostaglandin synthesis, seems to be primarily mediated by (i) 5-HT 1 (probably 5-HT 1B/1D ) receptors and (ii) a novel mechanism antagonized by methiothepin that, most likely, involves putative 5-ht 5A/5B receptors.

No abstract

1 It has been suggested that the inhibition of sympathetically-induced vasopressor responses produced by 5-hydroxytryptamine (5-HT) in pithed rats is mediated by 5-HT 1 -like receptors. The present study has re-analysed this suggestion with regard to the classi®cation schemes recently proposed by the NC-IUPHAR subcommittee on 5-HT receptors. Thus, after WAY 100635, the responses to 5-HT and indorenate, but not to 8-OH-DPAT, CP 93,129 and sumatriptan, were blocked. After cyanopindolol, the responses to 5-HT, indorenate and CP 93,129 were abolished, whilst those to 8-OH-DPAT and sumatriptan (except at the lowest frequency of stimulation) remained unaltered. In contrast, after GR 127935, the responses to 5-HT, CP 93,129 and sumatriptan, but not to 8-OH-DPAT and indorenate, were abolished. 4 In additional experiments, the inhibition induced by 5-HT was not modi®ed after 5-HT 7 receptor blocking doses of mesulergine. 5 The above results suggest that the 5-HT 1 -like receptors, which inhibit the sympathetic vasopressor out¯ow in pithed rats, display the pharmacological pro®le of the 5-HT 1A , 5-HT 1B and 5-HT 1D , but not that of 5-HT 7 , receptors.

1 The antimigraine drugs methysergide, ergotamine and dihydroergotamine (DHE) produce selective vasoconstriction in the external carotid bed of vagosympathectomized dogs anaesthetized with pentobarbital and arti®cially respired, but the receptors involved have not yet been completely characterized. Since the above drugs display anity for several binding sites, including aadrenoceptors and several 5-HT 1 and 5-HT 2 receptor subtypes, this study has analysed the mechanisms involved in the above responses. 2 Intracarotid (i.c.) infusions during 1 min of methysergide (31 ± 310 mg min 71 ), ergotamine (0.56 ± 5.6 mg min 71 ) or DHE (5.6 ± 31 mg min 71 ) dose-dependently reduced external carotid blood¯ow (ECBF) by up to 46+4, 37+4 and 49+5%, respectively. Blood pressure and heart rate remained unchanged. 3 The reductions in ECBF by methysergide were abolished and even reversed to increases in animals pre-treated with GR127935 (10 mg kg 71 , i.v.). 4 The reductions in ECBF by ergotamine and DHE remained unchanged in animals pre-treated (i.v.) with prazosin (300 mg kg 71), but were partly antagonized in animals pre-treated with either GR127935 (10 or 30 mg kg 71 ) or yohimbine (1000 mg kg 71 ). Pre-treatment with a combination of GR127935 (30 mg kg 71 ) and yohimbine (1000 mg kg 71 ) abolished the responses to both ergotamine and DHE. The above doses of antagonists were shown to produce selective antagonism at their respective receptors. 5 These results suggest that the external carotid vasoconstrictor responses to methysergide primarily involve 5-HT 1B/1D receptors, whereas those to ergotamine and DHE are mediated by 5-HT 1B/1D receptors as well as a 2 -adrenoceptors.