RGD Reference Report - In vivo effects of a combined 5-HT1B receptor/SERT antagonist in experimental pulmonary hypertension. - Rat Genome Database

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

Authors: Morecroft, I  Pang, L  Baranowska, M  Nilsen, M  Loughlin, L  Dempsie, Y  Millet, C  MacLean, MR 
Citation: Morecroft I, etal., Cardiovasc Res. 2010 Feb 1;85(3):593-603. Epub 2009 Sep 7.
RGD ID: 4889432
Pubmed: PMID:19736308   (View Abstract at PubMed)
DOI: DOI:10.1093/cvr/cvp306   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SLC6A4Humanpulmonary hypertension  ISOSlc6a4 (Mus musculus)associated with AnoxiaRGD 
SLC6A4Humanpulmonary hypertension  IMP  RGD 
Slc6a4Ratpulmonary hypertension  ISOSlc6a4 (Mus musculus)associated with AnoxiaRGD 
Slc6a4Ratpulmonary hypertension  ISOSLC6A4 (Homo sapiens) RGD 
Slc6a4Mousepulmonary hypertension  ISOSLC6A4 (Homo sapiens) RGD 
Slc6a4Mousepulmonary hypertension  IMP associated with AnoxiaRGD 

Objects Annotated

Genes (Rattus norvegicus)
Slc6a4  (solute carrier family 6 member 4)

Genes (Mus musculus)
Slc6a4  (solute carrier family 6 (neurotransmitter transporter, serotonin), member 4)

Genes (Homo sapiens)
SLC6A4  (solute carrier family 6 member 4)


Additional Information