Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts

Kirsty M Mair, Margaret R MacLean, Ian Morecroft, Yvonne Dempsie, Timothy M Palmer

Research output: Contribution to journalArticle

Abstract

Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive elevation in pulmonary arterial pressure and pulmonary vascular remodelling leading to right heart failure and death. Prognosis is poor and novel therapeutic approaches are needed. The serotonin hypothesis of PAH originated in the 1960s after an outbreak of the disease was reported among patients taking the anorexigenic drugs aminorex and fenfluramine. These are indirect serotinergic agonists and serotonin transporter substrates. Since then many advances have been made in our understanding of the role of serotonin in the pathobiology of PAH. The rate-limiting enzyme in the synthesis of serotonin is tryprophan hydroxylase (Tph). Serotonin is synthesized, through Tph1, in the endothelial cells of the pulmonary artery and can then act on underlying pulmonary arterial smooth muscle cells and pulmonary arterial fibroblasts in a paracrine fashion causing constriction and remodelling. These effects of serotonin can be mediated through both the serotonin transporter and serotonin receptors. This review will discuss our current understanding of ‘the serotonin hypothesis’ of PAH and highlight possible therapeutic targets within the serotonin system.
Original languageEnglish
Pages (from-to)606-16
Number of pages11
JournalBritish Journal of Pharmacology
Volume155
Issue number4
DOIs
Publication statusPublished - Oct 2008

Fingerprint

Receptor, Serotonin, 5-HT1B
rho-Associated Kinases
Serotonin
Fibroblasts
Lung
Pulmonary Hypertension
Serotonin Plasma Membrane Transport Proteins
Aminorex
Fenfluramine
Appetite Depressants
Serotonin Receptors
Mixed Function Oxygenases
Constriction
Pulmonary Artery
Smooth Muscle Myocytes
Disease Outbreaks
Arterial Pressure
Endothelial Cells
Heart Failure
Enzymes

Keywords

  • serotonin
  • pulmonary arterial hypertension
  • tryprophan hydroxylase
  • endothelial cells

Cite this

Mair, Kirsty M ; MacLean, Margaret R ; Morecroft, Ian ; Dempsie, Yvonne ; Palmer, Timothy M. / Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts. In: British Journal of Pharmacology. 2008 ; Vol. 155, No. 4. pp. 606-16.
@article{c1a946f5a4b5437494c7530d36923cc8,
title = "Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts",
abstract = "Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive elevation in pulmonary arterial pressure and pulmonary vascular remodelling leading to right heart failure and death. Prognosis is poor and novel therapeutic approaches are needed. The serotonin hypothesis of PAH originated in the 1960s after an outbreak of the disease was reported among patients taking the anorexigenic drugs aminorex and fenfluramine. These are indirect serotinergic agonists and serotonin transporter substrates. Since then many advances have been made in our understanding of the role of serotonin in the pathobiology of PAH. The rate-limiting enzyme in the synthesis of serotonin is tryprophan hydroxylase (Tph). Serotonin is synthesized, through Tph1, in the endothelial cells of the pulmonary artery and can then act on underlying pulmonary arterial smooth muscle cells and pulmonary arterial fibroblasts in a paracrine fashion causing constriction and remodelling. These effects of serotonin can be mediated through both the serotonin transporter and serotonin receptors. This review will discuss our current understanding of ‘the serotonin hypothesis’ of PAH and highlight possible therapeutic targets within the serotonin system.",
keywords = "serotonin, pulmonary arterial hypertension, tryprophan hydroxylase, endothelial cells",
author = "Mair, {Kirsty M} and MacLean, {Margaret R} and Ian Morecroft and Yvonne Dempsie and Palmer, {Timothy M}",
year = "2008",
month = "10",
doi = "10.1038/bjp.2008.310",
language = "English",
volume = "155",
pages = "606--16",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "4",

}

Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts. / Mair, Kirsty M; MacLean, Margaret R; Morecroft, Ian; Dempsie, Yvonne; Palmer, Timothy M.

In: British Journal of Pharmacology, Vol. 155, No. 4, 10.2008, p. 606-16.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel interactions between the 5-HT transporter, 5-HT1B receptors and Rho kinase in vivo and in pulmonary fibroblasts

AU - Mair, Kirsty M

AU - MacLean, Margaret R

AU - Morecroft, Ian

AU - Dempsie, Yvonne

AU - Palmer, Timothy M

PY - 2008/10

Y1 - 2008/10

N2 - Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive elevation in pulmonary arterial pressure and pulmonary vascular remodelling leading to right heart failure and death. Prognosis is poor and novel therapeutic approaches are needed. The serotonin hypothesis of PAH originated in the 1960s after an outbreak of the disease was reported among patients taking the anorexigenic drugs aminorex and fenfluramine. These are indirect serotinergic agonists and serotonin transporter substrates. Since then many advances have been made in our understanding of the role of serotonin in the pathobiology of PAH. The rate-limiting enzyme in the synthesis of serotonin is tryprophan hydroxylase (Tph). Serotonin is synthesized, through Tph1, in the endothelial cells of the pulmonary artery and can then act on underlying pulmonary arterial smooth muscle cells and pulmonary arterial fibroblasts in a paracrine fashion causing constriction and remodelling. These effects of serotonin can be mediated through both the serotonin transporter and serotonin receptors. This review will discuss our current understanding of ‘the serotonin hypothesis’ of PAH and highlight possible therapeutic targets within the serotonin system.

AB - Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive elevation in pulmonary arterial pressure and pulmonary vascular remodelling leading to right heart failure and death. Prognosis is poor and novel therapeutic approaches are needed. The serotonin hypothesis of PAH originated in the 1960s after an outbreak of the disease was reported among patients taking the anorexigenic drugs aminorex and fenfluramine. These are indirect serotinergic agonists and serotonin transporter substrates. Since then many advances have been made in our understanding of the role of serotonin in the pathobiology of PAH. The rate-limiting enzyme in the synthesis of serotonin is tryprophan hydroxylase (Tph). Serotonin is synthesized, through Tph1, in the endothelial cells of the pulmonary artery and can then act on underlying pulmonary arterial smooth muscle cells and pulmonary arterial fibroblasts in a paracrine fashion causing constriction and remodelling. These effects of serotonin can be mediated through both the serotonin transporter and serotonin receptors. This review will discuss our current understanding of ‘the serotonin hypothesis’ of PAH and highlight possible therapeutic targets within the serotonin system.

KW - serotonin

KW - pulmonary arterial hypertension

KW - tryprophan hydroxylase

KW - endothelial cells

U2 - 10.1038/bjp.2008.310

DO - 10.1038/bjp.2008.310

M3 - Article

VL - 155

SP - 606

EP - 616

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 4

ER -