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. ISSN 0008-6363 (doi:10.1093/cvr/cvp306)
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Publisher's URL: http://dx.doi.org/10.1093/cvr/cvp306
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.
|Glasgow Author(s):||MacLean, Prof Margaret and Dempsie, Dr Yvonne and Loughlin, Mrs Lynn and Nilsen, Mrs Margaret and Millet, Dr Caroline 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 > Institute of Cardiovascular and Medical Sciences|
College of Medical Veterinary and Life Sciences
|Journal Name:||Cardiovascular Research|
|Published Online:||7 September 2009|