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

AbstractAIMS:
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.
AuthorsIan Morecroft, Louisa Pang, Marta Baranowska, Margaret Nilsen, Lynn Loughlin, Yvonne Dempsie, Caroline Millet, Margaret R MacLean
JournalCardiovascular research (Cardiovasc Res) Vol. 85 Issue 3 Pg. 593-603 (Feb 1 2010) ISSN: 1755-3245 [Electronic] England
PMID19736308 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cyclic S-Oxides
  • LY 393558
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Uptake Inhibitors
  • Thiadiazines
  • Citalopram
Topics
  • Animals
  • Cell Proliferation (drug effects)
  • Citalopram (administration & dosage)
  • Cyclic S-Oxides (administration & dosage)
  • Female
  • Hypertension, Pulmonary (drug therapy, pathology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Serotonin 5-HT1 Receptor Antagonists
  • Serotonin Uptake Inhibitors (administration & dosage)
  • Thiadiazines (administration & dosage)
  • Vasoconstriction (drug effects)

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