Characterization of flufylline, fluprofylline, ritanserin, butanserin and R 56413 with respect to in-vivo α1-, α2- and 5-HT2-receptor antagonism and in-vitro affinity for α1-, α2- and 5-HT2-receptors: comparison with ketanserin

Korstanje, C.; Sprenkels, R.; Doods, H. N.; Hugtenburg, J.G.; Boddeke, Erik; Batink, H. D.; Thoolen, Mjmc; Zwieten, P. A. van

doi:10.1111/j.2042-7158.1986.tb04590.x

Cited by 21 publications

(11 citation statements)

References 20 publications

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“…4B). Although it has been reported that high concentrations of ketanserin have an effect on ␣ 1 -adrenergic receptor activation, the concentration we used in this study (3 nM) should minimally affect the ␣ 1 -adrenergic receptor (ketanserin at 5-HT 2A receptor, K i ϭ 0.39 nM; Leysen et al, 1982; and ketanserin at ␣ 1 -adrenergic receptor, K i ϭ 72.4 nM; Korstanje et al, 1986). 5-HT 2C receptors, another receptor for which ketanserin has significant affinity, have never definitively been found in periphery (Barnes and Sharp, 1999).…”

Section: Discussionmentioning

confidence: 99%

(+)-Norfenfluramine-Induced Arterial Contraction Is Not Dependent on Endogenous 5-Hydroxytryptamine or 5-Hydroxytryptamine Transporter

Wilhelm

Bäder

et al. 2005

J Pharmacol Exp Ther

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The highly effective anorexigen (ϩ)-fenfluramine (Redux) was widely prescribed for the treatment of obesity until it was associated with primary pulmonary hypertension (Abenhaim et al., 1996) and aortic valvular disease (Connolly et al., 1997). We have reported previously that the hepatic deethylated metabolite of (ϩ)-fenfluramine, (ϩ)-norfenfluramine, is vasoactive. (ϩ)-Norfenfluramine causes contraction in isolated rat aorta, renal artery, and mesenteric resistance artery and increases blood pressure through activation of 5-hydroxytryptamine (5-HT) 2A receptor (Ni et al., 2004a).Recently, we found that 5-HT and a functional 5-HTT are present in rat peripheral arteries (Ni et al., 2004b). 5-HT is a vasoconstrictor and causes contraction in many arteries and veins, especially conduit vessels via 5-HT 2A receptors (Martin, 1994). (ϩ)-Fenfluramine and (ϩ)-norfenfluramine are 5-HTT substrates and potent 5-HT releasers (Garattini, 1995;Rothman and Baumann, 2002). Because the anorexic effect of (ϩ)-fenfluramine was considered to be due at least in part to 5-HT release (Fishman, 1999), we hypothesized that (ϩ)-norfenfluramine-induced vasoconstriction is dependent on release of endogenous 5-HT via 5-HTT with consequent 5-HT-induced activation of 5-HT 2A receptor-mediating contraction.We studied our hypothesis by using two different strains of mice. Aorta from tryptophan hydroxylase (TPH) 1-deficient

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Section: Discussionmentioning

confidence: 99%

(+)-Norfenfluramine-Induced Arterial Contraction Is Not Dependent on Endogenous 5-Hydroxytryptamine or 5-Hydroxytryptamine Transporter

Wilhelm

Bäder

et al. 2005

J Pharmacol Exp Ther

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“…2, B and C). In theory, this concentration of ketanserin has little effect on ␣ 1 -adrenergic receptor activation (ketanserin at 5-HT 2A receptor, K i ϭ 0.39 nmol, Leysen et al, 1982; and ketanserin at ␣ 1 -adrenergic receptor, K i ϭ 72.4 nmol; Korstanje et al, 1986). The 5-HT 2C receptor, another receptor for which ketanserin has significant affinity, has never definitively been found in periphery (Barnes and Sharp, 1999).…”

Section: Discussionmentioning

confidence: 99%

The Fenfluramine Metabolite (+)-Norfenfluramine Is Vasoactive

Li²,

Thakali³

et al. 2004

J Pharmacol Exp Ther

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The anorexigen (ϩ)-fenfluramine was used for treatment of obesity until the association of use with valvular heart disease and primary pulmonary hypertension. (ϩ)-Fenfluramine has been found in Chinese and Korean slimming pills. The hepatic metabolite of (ϩ)-fenfluramine, (ϩ)-norfenfluramine, has affinity for 5-hydroxytryptamine (5-HT) 2A and 5-HT 2B receptors. We tested the hypothesis that (ϩ)-norfenfluramine contracts arterial smooth muscle in a 5-HT receptor-dependent manner and acts as a pressor in the conscious rat. Isometric contraction experiments showed that (ϩ)-norfenfluramine (10 nM, 100 M) but not (ϩ)-fenfluramine nor the isomer (Ϫ)-norfenfluramine caused concentration-dependent contraction in arteries [Ϫlog EC 50 (moles per liter), thoracic aorta ϭ 5.77 Ϯ 0.09; renal artery ϭ 6.29 Ϯ 0.02; mesenteric resistance artery ϭ 5.70 Ϯ 0.06]. Contraction was dependent on the 5-HT 2A receptor because ketanserin (10 nM) rightward shifted (ϩ)-norfenfluramine response curves (aorta ϭ 16-fold, renal artery ϭ 26-fold, and resistance artery ϭ Ͼ100-fold). Dependence on activation of 5-HT 2A receptors and independence of (ϩ)-norfenfluramineinduced contraction from stimulation of ␣-adrenergic receptors and the sympathetic nervous system was validated by demonstrating 1) unchanged contraction to (ϩ)-norfenfluramine in arteries from chemically denervated rats; 2) a minimal effect of the ␣ 1 -adrenergic receptor antagonist prazosin (100 nM) on contraction; and 3) antagonism by [6-methyl-l-(1-methylethy)-ergoline-8␤-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate] LY53857 [6-methyl-1-(1-methylethy)-ergoline-8␤-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate], a 5-HT 2 receptor antagonist without ␣-receptor affinity. (ϩ)-Norfenfluramine (10 -300 g/kg i.v.) caused a dose-dependent increase in mean arterial blood pressure in conscious rats, the maximum of which could be virtually abolished by ketanserin (3 mg/kg i.v.) but not prazosin (0.2 mg/kg i.v.). Our findings demonstrate for the first time that (ϩ)-norfenfluramine is vasoactive and has the potential to increase blood pressure.

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“…age, slice thickness and/or rostrocaudal level). Alternatively, there may be non-selective effects of these drugs, since methysergide is an antagonist at some 5-HT receptors and a partial agonist at others, whereas ketanserin is a 5-HT 2 receptor antagonist and also has high affinity for α1-adrenoreceptors (Korstanje et al , 1986). Another possible explanation is that respiratory rhythm generation is less dependent on 5-HT in preparations containing more of the respiratory network.…”

Section: Neuromodulation Of Respiratory Outputmentioning

confidence: 99%

Contributions of 5-HT neurons to respiratory control: Neuromodulatory and trophic effects

Hodges¹,

Richerson²

2008

Respiratory Physiology & Neurobiology

124

111

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Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter produced by a small number of neurons in the midbrain, pons and medulla. These neurons project widely throughout the neuraxis, where they release 5-HT and co-localized neuropeptides such as substance P (SP) and thyrotropin-releasing hormone (TRH). Each of these chemicals produce effects largely through G protein-coupled receptors, second messenger systems and subsequent neuromodulatory effects on target neurons. Emerging evidence suggests that 5-HT has additional modes of action during development and in adult mammals, including trophic effects (neurogenesis, cell differentiation, proliferation, migration and maturation) and influences on synaptic plasticity. Here, we discuss some of the neuromodulatory and trophic roles of 5-HT in general and in the context of respiratory control, as well as the regulation of release of modulatory neurotransmitters from 5-HT neurons. Future directions of study are also discussed.

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Characterization of flufylline, fluprofylline, ritanserin, butanserin and R 56413 with respect to in-vivo α1-, α2- and 5-HT2-receptor antagonism and in-vitro affinity for α1-, α2- and 5-HT2-receptors: comparison with ketanserin

Cited by 21 publications

References 20 publications

(+)-Norfenfluramine-Induced Arterial Contraction Is Not Dependent on Endogenous 5-Hydroxytryptamine or 5-Hydroxytryptamine Transporter

(+)-Norfenfluramine-Induced Arterial Contraction Is Not Dependent on Endogenous 5-Hydroxytryptamine or 5-Hydroxytryptamine Transporter

The Fenfluramine Metabolite (+)-Norfenfluramine Is Vasoactive

Contributions of 5-HT neurons to respiratory control: Neuromodulatory and trophic effects

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