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


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.


CONCLUSIONS
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.
Morecroft
Ian
I
FBLS, University of Glasgow, Glasgow G12 8QQ, UK.
Pang
Louisa
L
Baranowska
Marta
M
Nilsen
Margaret
M
Loughlin
Lynn
L
Dempsie
Yvonne
Y
Millet
Caroline
C
MacLean
Margaret R
MR
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015283:Citalopram / Q000008:administration & dosage*; D003499:Cyclic S-Oxides / Q000008:administration & dosage*; D005260:Female; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage*; D013829:Thiadiazines / Q000008:administration & dosage*; D014661:Vasoconstriction / Q000187:drug effects
D015283:Citalopram; D003499:Cyclic S-Oxides; D058829:Serotonin 5-HT1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013829:Thiadiazines; C446282:LY 393558