Dexfenfluramine (Dfen) is an appetite suppressant associated with an increased risk of pulmonary arterial hypertension (PAH), a disease characterised by vasoconstriction and remodelling of pulmonary resistance arteries (PRAs). Dfen is a 5-HT reuptake inhibitor and substrate for the 5-HT transporter (5-HTT). Increased expression of the 5-HTT is implicated in the pathogenesis of PAH (Eddahibi et al. 2000, MacLean et al. 2004). Heterozygous loss of function mutations in the bone morphogenetic protein receptor II (BMPR-II) were found to occur at a high frequency in pulmonary hypertensive patients (Thomson et al. 2000). Recent evidence has indicated an interaction between 5-HT and reduced BMPR-II signalling showing that 5-HT can uncover a pulmonary hypertensive phenotype in mice deficient in BMPR-II (BMPR-II +/- mice) (Long et al. 2006). We assessed the ability of dfen to contract PRAs in the mouse and whether this is affected by overexpression of 5-HTT and/or deficiency in BMPR-II. We employed three transgenic mouse models, one overexpressing the human form of 5-HTT (5-HTT +), another BMPR-II +/- and one both 5-HTT + and BMPR-II +/- (all mice were age 5-6 months and 25-40g weight). Vasoconstriction was assessed by wire myography. Under halothane (1%; inhalation) anaesthesia, we also analysed the pulmonary haemodynamics of the 5-HTT + and 5-HTT + /BMPR-II +/- mouse using transdiaphragmatic cardiac puncture to measure systolic right ventricular pressure (sRVP). Statistical comparisons were made by one-way ANOVA followed by Tukey’s multiple comparison test. Dfen induced contraction of PRAs only at high concentrations (> 1 μM). It was significantly more potent in 5-HTT + (pEC50, 5.33 ± 0.12, n=6) and 5-HTT + /BMPR-II +/- (pEC50, 5.55 ± 0.12, n=9) mice than in wild type (pEC50, 3.97 ± 0.12, n=6) and BMPR-II +/- (pEC50, 3.72 ± 0.10, n=4) mice (p<0.001). The Emax values were not significantly different. Wild type mice had a sRVP of 12.5 ± 1.1 mmHg, n=12 and this was significantly lower (p<0.001) than in 5-HTT + mice (31.1 ± 4.1 mmHg, n=10). 5-HTT + /BMPR-II +/- mice had a pressure of 19.0 ± 0.10 mmHg, n=11. Interestingly this was significantly lower than 5-HTT + mice (p<0.01). Dfen-induced vasoconstriction was increased in mice that overexpress the 5-HTT both in mice with intact and deficient BMPR-II signalling. Dfen may increase extracellular 5-HT by preventing 5-HT uptake or may exert intracellular responses similar or perhaps greater than 5-HT by acting as a 5-HTT substrate. Overexpression of the 5-HTT caused an increase in sRVP in our mouse model. This effect was reduced by a deficiency in BMPR-II. The reason for this protective effect is unclear. BMPR-II interacts with several intracellular signalling pathways including 5-HT and elucidating these will allow a better understanding of the observed phenotype.