Characterization of 5‐HT receptors on human pulmonary artery and vein: functional and binding studies

Cortijo, Julio; Martı́-Cabrera, Miguel; Bernabeu, Eva; Domènech, Teresa; Bou, J.; Fernández, Andrés G.; Beleta, Jörge; Palacios, J.M.; Morcillo, Esteban J.

doi:10.1038/sj.bjp.0701509

Cited by 53 publications

(40 citation statements)

References 36 publications

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“…In previous studies on the reactivity of HPA to 5-HT, EC 50 values varied from 0.1 to 0.39 mM, which is consistent with the current results (EC 50 0.44 mM) [8,9,12]. It should be noted that, regarding CCRC to 5-HT in intrapulmonary arteries from male Wistar rats, EC 50 values varied from 0.8 to 7.4 mM [13], which is higher than the EC 50 values in HPAs.…”

Section: Effect Of 5-ht On Casupporting

confidence: 80%

“…In human pulmonary arteries (HPAs), while numerous studies have explored the role of 5-HT in vascular remodelling associated with smooth muscle hyperplasia [6,7], few studies have been performed on the contractile effect of 5-HT [8,9]. Nevertheless, 5-HT 1B , 5-HT 2A and 5-HT 2B receptors have been detected in HPA, and the contractile effect of 5-HT appeared to be mainly mediated by the 5-HT 1B receptors and also by the 5-HT 2A receptors [6,[8][9][10][11][12]. Despite the fact that pulmonary arterial vasoconstriction is an important early component of PAH, the current knowledge about transduction pathways involved in the 5-HTinduced vasoreactivity remains incomplete for HPAs.…”

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confidence: 99%

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Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Rodat-Despoix¹,

Aires²,

Ducret³

et al. 2009

Eur Respir J

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Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose plasma level is increased in pulmonary hypertensive patients. Thus, we explored the signalling pathways involved in the contractile response to 5-HT in human pulmonary arteries (HPAs).Intact and b-escin permeabilised rings from HPAs mounted in an organ bath system were used to assess both tension and myofilament Ca 2+ -sensitisation. KEYWORDS: Calcium, contraction, human pulmonary artery, myofilament calcium sensitivity, 5-HT S erotonin (5-hydroxytryptamine; 5-HT) is mainly stored in the platelets but is also locally released in the lung by pulmonary neuroendocrine cells, neuroepithelial bodies and pulmonary arterial endothelial cells [1][2][3]. 5-HT is a potent pulmonary vasoconstrictor whose high circulating concentration is clinically associated with pulmonary arterial hypertension (PAH), an often fatal disease. In animal models of PAH, 5-HT-induced hyperreactivity and mitogenic effects have been reported in pulmonary arteries [4,5]. In human pulmonary arteries (HPAs), while numerous studies have explored the role of 5-HT in vascular remodelling associated with smooth muscle hyperplasia [6,7], few studies have been performed on the contractile effect of 5-HT [8,9]. Nevertheless, 5-HT 1B , 5-HT 2A and 5-HT 2B receptors have been detected in HPA, and the contractile effect of 5-HT appeared to be mainly mediated by the 5-HT 1B receptors and also by the 5-HT 2A receptors [6,[8][9][10][11][12]. Despite the fact that pulmonary arterial vasoconstriction is an important early component of PAH, the current knowledge about transduction pathways involved in the 5-HTinduced vasoreactivity remains incomplete for HPAs.Owing to the low availability of human tissue, we previously studied the contractile response to 5-HT in rat intrapulmonary arteries and we demonstrated that there were regional differences in 5-HT-induced contraction [13]. Since calcium is essential for smooth muscle contraction, we addressed the relative contribution of calcium pools involved in the vasoreactivity to 5-HT. In small vessels, 5-HT activates voltage-independent calcium channels to a larger extent than it does voltage-dependent calcium channels (L-type calcium channels) [5,[13][14][15]. Calcium release from intracellular calcium stores (sarcoplasmic reticulum) also contributes to 5-HT-induced contraction in rat pulmonary arteries [13][14][15]. Studies from other groups have been performed on calcium signalling and ion channels in cultured human

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Section: Effect Of 5-ht On Casupporting

confidence: 80%

mentioning

confidence: 99%

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Rodat-Despoix¹,

Aires²,

Ducret³

et al. 2009

Eur Respir J

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“…drug doses were administered; correcting for probe recovery estimates, this value is increased to ϳ20 nM. Serotonin contracts human pulmonary arteries with EC 50 values that range from ap-proximately 100 nM (Morecroft et al, 1999) to the micromolar range (Cortijo et al, 1997). Thus, it would seem unlikely that fenfluramine and other SERT substrates could increase plasma 5-HT to a concentration that would directly contract pulmonary arteries.…”

Section: Discussionmentioning

confidence: 99%

Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Żółkowska¹,

Rothman²,

Baumann³

2006

J Pharmacol Exp Ther

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Elevations in plasma serotonin (5-HT) have been implicated in the pathogenesis of cardiac and pulmonary disease. Normally, plasma 5-HT concentrations are kept low by transporter-mediated uptake of 5-HT into platelets and by metabolism to 5-hydroxyindoleacetic acid (5-HIAA). Many abused drugs (e.g., substituted amphetamines) and prescribed medications (e.g., fluoxetine) target 5-HT transporters and could thereby influence circulating 5-HT. We evaluated the effects of amphetamines analogs [(Ϯ)-fenfluramine, (Ϯ)-3,4-methylenedioxymethamphetamine, (ϩ)-methamphetamine, (ϩ)-amphetamine, phentermine] on extracellular levels (i.e., plasma levels) of 5-HT and 5-HIAA in blood from catheterized rats. Effects of the 5-HT uptake blocker fluoxetine were examined for comparison. Drugs were tested in vivo and in vitro; plasma indoles were measured using a novel microdialysis method in whole blood. We found that baseline dialysate levels of 5-HT are ϳ0.22 nM, and amphetamine analogs evoke large dose-dependent increases in plasma 5-HT ranging from 4 to 20 nM. The ability of drugs to elevate plasma 5-HT is positively correlated with their potency as 5-HT transporter substrates. Fluoxetine produced small, but significant, increases in plasma 5-HT. Although the drug-evoked 5-HT concentrations are below the micromolar levels required for contraction of pulmonary arteries, they approach concentrations reported to stimulate mitogenesis in pulmonary artery smooth muscle cells. Additional studies are needed to determine the effects of chronic administration of amphetamines on circulating 5-HT.Serotonin (5-hydroxytryptamine, 5-HT) is an endogenous bioactive compound that is widely distributed in neurons, mast cells, enterochromaffin cells, and blood platelets (Cooper et al., 2003;Gershon, 2004). Under normal physiological conditions, plasma 5-HT levels are kept exquisitely low (i.e., Ͻ1 nM) due to transporter-mediated uptake of 5-HT into blood platelets and via metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) by monoamine oxidase (MAO). Included among the many physiological effects of 5-HT are mitogenesis and vasoconstriction. Accordingly, altered regulation of 5-HT levels in blood has been implicated in the pathogenesis of cardiac valvular heart disease (VHD) (Robiolio et al., 1995) and primary pulmonary hypertension (PPH) (MacLean et al., 2000). Many substituted amphetamine analogs (e.g., fenfluramine and aminorex) are substrates for 5-HT transporters (SERTs) and release 5-HT from neurons via reversal of SERT (Rothman et al., 1999). One hypothesis to explain the ability of these agents to increase the risk of developing PPH is that they increase plasma 5-HT by stimulating 5-HT release from platelets (i.e., "the 5-HT hypothesis" of PPH) (MacLean et al., 2000). Others have invoked the same mechanism to explain fenfluramine-induced VHD (Fishman, 1999), although a more likely mechanism in this case involves activation of 5-HT 2B receptors by the N-deethylated metabolite of fenfluramine, norfenfluramine (Rothman et al., 2000...

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“…Others noted in human coronary vessel strips with intact endothelium (obtained from transplanted hearts) a 5-HT-mediated vasoconstriction that was in part ketanserin-sensitive [116]. In isolated strips from human pulmonary veins or arteries, 5-HT led to vasoconstriction (regardless of the presence or absence of endothelium) and was interpreted to be mediated by 5-HT 2 -and 5-HT 1 -receptors while ligand-binding studies presented evidence for the expression of 5-HT 4 -, 5-HT 2A -, and 5-HT 1D -receptors in these tissues [117]. In summary, vasoconstriction can be mediated by 5-HT 2A -and 5-HT 1D -like receptors and the latter are more relevant for vasoconstriction [114,118].…”

Section: Effects Of 5-ht On Cardiac Vasculature Species Differencesmentioning

confidence: 96%

Production and Function of Serotonin in Cardiac Cells

Neumann¹,

Hofmann²,

Gergs³

2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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Serotonin [5-hydroxy-tryptamine (5-HT)] exerts a number of effects in the mammalian heart: increase in heart rate, increase in force of contraction, fibrosis of cardiac valves, coronary constriction, arrhythmias and thrombosis. These effects are, in part, mediated by 5-HT-receptors, in part, directly by 5-HT action on intracellular proteins. In the beginning, 5-HT was thought to be only produced in the gut and then transported into the heart via platelets, because platelets can take up 5-HT in the gut and enter the capillaries and thus the mammalian heart. 5-HT is to a large extent metabolized in the liver and excreted via the urine. Here, we will also overview data that argue for additional pathways, namely production and degradation of 5-HT in the cells of the heart itself.

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Characterization of 5‐HT receptors on human pulmonary artery and vein: functional and binding studies

Cited by 53 publications

References 36 publications

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Amphetamine Analogs Increase Plasma Serotonin: Implications for Cardiac and Pulmonary Disease

Production and Function of Serotonin in Cardiac Cells

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