Serotonin-induced contraction in canine coronary artery and saphenous vein: Role of a 5-HT1D-like receptor
Abstract
The identity of the serotonin (5-HT) receptor(s) that mediate(s) contraction in canine coronary artery and saphenous vein remains controversial. Ring segments of endothelium-denuded coronary artery and helical strips of saphenous vein were suspended in organ chambers for measurement of isometric force. 5-HT, αMe-5-HT and sumatriptan contracted both coronary artery and saphenous vein and the non-selective 5-HT receptor antagonist 1-naphthylpiperazine (100nM) blocked 5-HT-and sumatriptan-induced contraction in both tissues. The agonist rank order potency for contraction (5-HT>sumatriptan>αMe5-HT>5-MeOT>5-MeT) was similar in both tissues and was consistent with that for a 5-HT1D receptor. Oligonucleotide primers specific for the 5-HT1D receptor sequence were designed for use in a polymerase chain reaction (PCR). cDNA derived from total RNA or mRNA from canine tissues was used in the PCR. PCR resulted in the amplification of a 632 base pair sequence in both canine coronary artery and saphenous vein; consistent with that expected for the 5-HT1D receptor. Southern blot analysis, with an oligonucleotide probe internal to the sequence amplified by the PCR primers, confirmed that the sequence amplified by PCR was the 5-HT1D receptor. Thus, the 5-HT1D receptor is expressed in canine coronary artery and saphenous vein and taken together with the pharmacological data, supports the possibility that a 5-HT1D-like receptor mediates contraction in these two tissues.
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Cited by (28)
Pharmacological characterization of almotriptan: An indolic 5-HT receptor agonist for the treatment of migraine
2000, European Journal of PharmacologyAlmotriptan (3-[2-(dimethylamino)ethyl]-5-(pyrrolidin-1-ylsulfonylmethyl)-1H-indole) has been studied in several models predictive of activity and selectivity at 5-HT receptors. Almotriptan showed low nanomolar affinity for the 5-HT1B and 5-HT1D receptors in several species, including the human, while affinity for 5-HT receptors other than 5-HT1B/1D was clearly less. Affinity for 5-HT7 and 5-HT1A receptors was approximately 40 and 60 times lower than that for 5-HT1B/1D receptors, respectively. Almotriptan did not exhibit significant affinity for several non-5-HT receptors studied up to 100 μM. Almotriptan inhibited forskolin-stimulated cyclic AMP accumulation in HeLa cells transfected with 5-HT1B or 5-HT1D human receptors. In this model, almotriptan had the same efficacy as serotonin and an affinity in the low nanomolar range. It induced vasoconstriction in several vessels in which it was compared with sumatriptan. In isolated dog saphenous veins, almotriptan elicited concentration-dependent contractions with an EC50 of 394 nM. In both these systems, almotriptan behaved as a full agonist. Infusion of almotriptan into the porcine meningeal vasculature induced vasoconstriction. In contrast, in the pig renal and rabbit mesenteric arteries, it had a very low maximal efficacy even at 100 μM, with similar results obtained in the rabbit renal artery. The results suggest that almotriptan is a potent and selective 5-HT1B/1D receptor agonist, with selectivity for the cranial vasculature as compared with peripheral vessels.
In vivo analysis of adrenergic and serotoninergic constrictions of the rabbit saphenous vein
2000, European Journal of PharmacologyWe aimed to develop a model to study in vivo the rabbit saphenous vein pharmacology and to investigate constrictions mediated by adrenoceptor and 5-HT receptor subtypes. We used the technique of high precision ultrasonic echo-tracking for direct measurement of saphenous vein diameters in pentobarbital anesthetized rabbits. Saphenous vein constrictions induced in rabbits by the α1-adrenoceptor agonist l-phenylephrine and the 5-HT1B receptor agonist sumatriptan were comparable with those induced in dogs but those induced by the 5-HT1B and 5-HT7 receptor agonist 5-carboxamidotryptamine failed to appear in dogs. Dose-related constrictions of rabbit veins were obtained with l-phenylephrine and the α2-adrenoceptor agonist dexmedetomidine. Frequency-related constrictions of rabbit veins induced by nerve stimulation were partially inhibited by an α1-adrenoceptor or a postsynaptic α2-adrenoceptor antagonist (prazosin and SKF 104,078) but not affected by the pre- and post-synaptic α2-adrenoceptor antagonists BRL 44408 or rauwolscine. Constrictions of rabbit veins to sumatriptan and 5-CT were inhibited by GR 127935 and those induced by quipazine, a 5-HT2 receptor agonist were prevented by ritanserin. The initial constrictions induced by 5-CT were followed by dilatations which were inhibited by the 5-HT7 receptor antagonist mesulergine. These data indicate that rabbit saphenous veins, in vivo and at rest, respond to activation of 5-HT1B and 5-HT2 receptors, α1- and α2-adrenoceptors and nerve stimulation; the dilator effect mediated by 5-HT7 receptor activation was also detected. The data validate a new animal model to study superficial vein reactivity and its pharmacological sensitivity.
Effects of alniditan on neurogenic oedema in the rat dura mater and on contraction of rat basilar artery
1999, European Journal of PharmacologyThe non-indole 5-HT receptor agonist, alniditan (R 91274), was tested and compared to sumatriptan in an in vivo model of neurogenic inflammation within the meninges of rats and in rat basilar artery in a Mulvany–Halpern chamber in vitro. Alniditan dose dependently attenuated the neurogenic inflammation and was more potent than sumatriptan. The alniditan response was blocked by the 5-HT1B/D receptor antagonist, GR 127935 (2′-methyl-4′-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide), but not by ketanserin, indicating that the effect is mediated through 5-HT1B/D receptors. Alniditan did not attenuate substance P-induced inflammation, suggesting that the mediating receptors are located prejunctionally. In vitro alniditan exhibited less vasoconstrictive effects on the rat basilar artery than did sumatriptan, although at a very high concentration (1 mM), alniditan caused intensive constriction, most likely through a mechanism independent from 5-HT receptor activation.
The selectivity of MDL 74,721 in models of neurogenic versus vascular components of migraine
1997, European Journal of PharmacologyMDL 74,721 (R)-2-(N1,N1-dipropylamino)-8-methylaminosulfonylmethyl-1,2,3,4-tetrahydronaphthalene, a sulfonamidotetralin, has been found to exhibit a 10,000-fold greater potency in neurogenic versus vascular models of migraine. Sumatriptan, a relatively pure 5-HT1D/5-HT1B receptor agonist, also showed higher potency versus neurogenic inflammation. However, for sumatriptan the potency difference (100-fold) in the two pathophysiological models was less pronounced than seen for MDL 74,721. The affinity profile of MDL 74,721 at 5-HT1 receptor subtypes may in part explain its ability to differentiate these two physiological responses. MDL 74,721 demonstrated nanomolar affinity for 5-HT1A (12.7±0.3 nM) and 5-HT1D (41.3±10.9 nM) but considerably lower affinity for 5-HT1B receptors (>1,000 nM). Serotonin-like activity was seen in in vitro functional assays including inhibition of forskolin-stimulated cAMP accumulation in human 5-HT1D receptor-transfected fibroblasts or eliciting vasoconstriction in isolated human pial arteries. The intrinsic activity (relative to 5−HTEAmax) and affinity (pD2) for the human cerebrovascular 5-HT receptors was: 5-HT (100%, 7.51±0.09), sumatriptan (94%, 6.85±0.1) and MDL 74,721 (66%, 5.70±0.23). In anaesthetised cats, treatment with MDL 74,721 resulted in a dose-related reduction in the percentage of carotid flow going through the arteriovenous anastomoses to the lungs, with an ED50 of 0.3 mg/kg i.v., the same as sumatriptan. However, in the guinea pig neurogenic model, MDL 74,721 inhibited plasma protein extravasation with an ED50 of 0.023 μg/kg compared to 2.5 μg/kg for sumatriptan. MDL 74,721 was also effective in this model (in rats) after oral administration. In conclusion, MDL 74,721 demonstrates a preclinical profile consistent with anti-migraine efficacy. Its marked preference for inhibiting neurogenic inflammation makes this compound a useful tool for assessing the relative contribution of this pathophysiological mechanism to the human disease state.
5-HT(1B/D) receptor antagonists
1997, General Pharmacology- 1.
1. 5-Hydroxytryptamine-1B (5-HT1B, formerly designated 5-HT1Dβ) and 5-hydroxy-tryptamine-1D (5-HT1D, formerly designated 5-HT1Dα) receptors are distinct molecular entities that mediate serotonergic neurotransmission. Both are G-protein-coupled receptors without introns in their coding region, negatively coupled to adenylate cyclase; their precise function in human beings remains to be defined. In brain, they are highly enriched in the globus pallidus and the substantia nigra.
- 2.
2. Presynaptic receptors take part in the control of the release not only of 5-HT itself, but also of other neurotransmitters—for example, acetylcholine, glutamate, dopamine, noradrenaline and γ-aminobutyric acid. Selective blockade of central autoreceptors should facilitate 5-HT neu-rotransmission and may offer a novel approach to antidepressant therapy. Other receptors are located postsynaptically; those receptors may be supersensitive in the pathophysiology of obsessive-compulsive disorder and may be a potential target for its treatment.
- 3.
3. Few if any ligands show selectivity for 5-HT1B or 5-HT1D receptors or both. Most pharmacological studies have been performed with nonselective antagonists—for example, metergoline, 1-naphthylpi, perazine, methiothepin, ketanserin and ritanserin. Recently, a novel series of benzanilides have been reported as the first examples of selective receptor antagonists. GR 127935, a representative compound of this series, displays mixed agonist-antagonist properties both in vitro and in vivo. It induces upon systemic administration in the guinea pig either an opposite (decrease) effect or a small increase (65%, 5 mg/kg) in the concentration of cortical extracellular 5-HT compared with fluoxetine (218%, 10 mg/kg). The importance of blockade of receptors in the raphé region, their possible interaction with 5-HT1A receptors, and consequent inhibition of 5-HT release in terminal receptor-containing regions are discussed.
- 4.
4. To find out whether the available so-called receptor antagonists are indeed antagonists and not partial agonists, efficacy was measured at recombinant human 5-HT1B and 5-HT1D receptor sites by using a [35S]-GTPγS binding assay to membrane preparations of stably transfected rat C6-glial cell lines. Metergoline and the selective receptor ligands GR 127935 as well as GR 125743 showed significant intrinsic activity (43% to 69%) at the 5-HT1D receptor subtype, whereas the nonselective ligand 1-naphthylpiperazine yielded less (15% to 19%) intrinsic activity at both receptor sub-types. In contrast, the nonselective ligands methiothepin, ketanserin and ritanserin are inverse agonists because they displayed negative efficacy (−14% to −28%). Differential blockade of receptors by neutral antagonists and inverse agonists is discussed in relation to the 5-HT tone on receptors.
- 5.
5. It can be concluded that receptor ligands modulate 5-HT neurotransmission through a terminal receptor. Future work should be directed toward the identification of selective 5-HT1B and 5-HT1D receptor ligands that display either neutral antagonist or inverse agonist properties to evaluate the therapeutic potential of receptor blockade.
- 1.
GR127935 is a potent antagonist of the 5-HT<inf>1</inf>-like receptor mediating contraction in the canine coronary artery
1996, European Journal of PharmacologyThe effects of the recently developed 5-HTid receptor antagonist, GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1,-biphenyl]-4-carboxamide), and those of the preferential human 5-HT1Da receptor antagonist, ketanserin, on the isometric contraction induced by 5-hydroxytryptamine (5-HT) and sumatriptan in endothelium-denuded ring segments of canine coronary artery were analyzed. Sumatriptan mimicked 5-HT with lower potency but similar efficacy. GR127935 (1, 3 and 10 nM) concentration dependently antagonized the contractions elicited by both agonists; only the 5-HT maximum was reduced. Ketanserin and mianserin (both at 1 μM) were inactive. These data strongly suggest that a 5-HTid receptor mediates contraction in the dog coronary artery. The possibility that this 5-HTid receptor resembles the cloned human 5-HTidβ subtype is discussed.
- 1
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