In vivo effects of a combined 5-HT1B receptor/SERT antagonist in experimental pulmonary hypertension

Morecroft, I., Pang, L., Baranowska, M., Nilsen, M., Loughlin, L., Dempsie, Y., Millet, C. and MacLean, M. R. (2010) In vivo effects of a combined 5-HT1B receptor/SERT antagonist in experimental pulmonary hypertension. Cardiovascular Research, 85(3), pp. 593-603. (doi: 10.1093/cvr/cvp306) (PMID:19736308)

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Publisher's URL: http://dx.doi.org/10.1093/cvr/cvp306

Abstract

<b>Aims</b> A mechanism for co-operation between the serotonin (5-hydroxytryptamine, 5-HT) transporter and 5-HT<sub>1B</sub> receptor in mediating pulmonary artery vasoconstriction and proliferation of pulmonary artery smooth muscle cells has been demonstrated <i>in vitro</i>. Here we determine, for the first time, the <i>in vivo</i> effects of a combined 5-HT<sub>1B</sub> receptor/serotonin transporter antagonist (LY393558) with respect to the development of pulmonary arterial hypertension (PAH) and its <i>in vitro</i> effects in human pulmonary artery smooth muscle cells (hPASMCs) derived from idiopathic PAH (IPAH) patients.<p></p> <b>Methods and results</b> We determined the effects of LY393558 as well as a selective serotonin transporter inhibitor, citalopram, on right ventricular pressure, right ventricular hypertrophy, and pulmonary vascular remodelling in wildtype mice and mice over-expressing serotonin transporter (SERT+ mice) before and after hypoxic exposure. We also compared their effectiveness at reversing PAH in SERT+ mice and hypoxic mice. Further, we examined the proliferative response to serotonin in IPAH hPASMCs. We also clarified the pharmacology of serotonin-induced vasoconstriction and 5-HT<sub>1B</sub> receptor/serotonin transporter interactions in mouse isolated pulmonary artery. Citalopram had a moderate effect at preventing and reversing experimental PAH <i>in vivo</i> whereas LY393558 was more effective. LY393558 was more effective than citalopram at reversing serotonin-induced proliferation in IPAH hPASMCs. There is synergy between 5-HT<sub>1B</sub> receptor and serotonin transporter inhibitors against serotonin-induced vasoconstriction in mouse pulmonary arteries.<p></p> <b>Conclusion</b> 5-HT<sub>1B</sub> receptor and serotonin transporter inhibition are effective at preventing and reversing experimental PAH and serotonin-induced proliferation of PASMCs derived from IPAH patients. Targeting both the serotonin transporter and 5-HT<sub>1B</sub> receptor may be a novel therapeutic approach to PAH.<p></p>

Item Type:Articles
Keywords:Pulmonary hypertension, Serotonin, Hypoxia, Serotonin transporter, 5HT1B
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Dempsie, Dr Yvonne and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret and Millet, Dr Caroline and Pang, Miss Louise and Morecroft, Dr Ian
Authors: Morecroft, I., Pang, L., Baranowska, M., Nilsen, M., Loughlin, L., Dempsie, Y., Millet, C., and MacLean, M. R.
Subjects:Q Science > QH Natural history > QH345 Biochemistry
Q Science > QH Natural history > QH301 Biology
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Cardiovascular Research
Journal Abbr.:Cardiovasc Res
Publisher:Oxford University Press
ISSN:0008-6363
ISSN (Online):1755-3245
Published Online:25 September 2009
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