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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Abstract

Aims A mechanism for co-operation between the serotonin (5-hydroxytryptamine, 5-HT) transporter and 5-HT1B receptor in mediating pulmonary artery vasoconstriction and proliferation of pulmonary artery smooth muscle cells has been demonstrated in vitro. Here we determine, for the first time, the in vivo effects of a combined 5-HT1B receptor/serotonin transporter antagonist (LY393558) with respect to the development of pulmonary arterial hypertension (PAH) and its in vitro effects in human pulmonary artery smooth muscle cells (hPASMCs) derived from idiopathic PAH (IPAH) patients. Methods and results 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-HT1B receptor/serotonin transporter interactions in mouse isolated pulmonary artery. Citalopram had a moderate effect at preventing and reversing experimental PAH in vivo whereas LY393558 was more effective. LY393558 was more effective than citalopram at reversing serotonin-induced proliferation in IPAH hPASMCs. There is synergy between 5-HT1B receptor and serotonin transporter inhibitors against serotonin-induced vasoconstriction in mouse pulmonary arteries. Conclusion 5-HT1B 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-HT1B receptor may be a novel therapeutic approach to PAH.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MacLean, Professor Margaret and Millet, Dr Caroline and Dempsie, Dr Yvonne and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret and Morecroft, Dr Ian
Authors: Morecroft, I., Pang, L., Baranowska, M., Nilsen, M., Loughlin, L., Dempsie, Y., Millet, C., and MacLean, M. R.
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
Publisher:Oxford University Press
ISSN:0008-6363
ISSN (Online):1755-3245
Published Online:07 September 2009

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
467691Interactions between serotonin and BMPR-II in the pulmonary circulation: effect on the development of pulmonary hypertensionMargaret MacLeanBritish Heart Foundation (BHF)PG/08/037/24921Institute of Cardiovascular and Medical Sciences
411571Interactions between mts 1 and serotonin in vascular remodellingMargaret MacLeanBiotechnology and Biological Sciences Research Council (BBSRC)BB/D007623/1Institute of Cardiovascular and Medical Sciences
460941The role of endothelial tryptophan hydroxylase in pulmonary vascular remodelling: an integrated approachMargaret MacLeanBiotechnology and Biological Sciences Research Council (BBSRC)BB/F005423/1Institute of Cardiovascular and Medical Sciences