Click to download
Dexfenfluramine reduces right ventricular pressure in chronic hypoxic mice over-expressing the 5-HT transporter Familial pulmonary arterial hypertension (fPAH) can be associated with increased activity/expression of the 5-HT transporter (5-HTT; Eddahibi et al., 2001). PAH often occurs secondary to chronic hypoxia; and the appetite suppressant dexfenfluramine (Dfen) has been associated with an increase in the risk of developing PAH in a sub-population of patients. Therefore increased expression of 5-HTT may pre-dispose patients to Dfen-induced PAH. Indeed, we have shown that normoxic mice over-expressing the human 5-HTT gene (5-HTT+ mice) are predisposed to Dfen-induced pulmonary vascular remodelling (Dempsie et al., P097 this meeting). Here we investigate the effects of Dfen administration in these mice and their wildtype (WT) controls, under hypoxic conditions. Female 5-HTT+ and WT mice (C57BL/6 x CBA, 5-6 months, 20-30g; received, Dfen (5mg/kg once per day, orally) for 28 days. After 14 days of Dfen administration, mice were subjected to 14 days of either hypoxia (10% O2) or normoxia. Control groups received administration vehicle (distilled water). Under halothane (1% in a mixture of 6:1oxygen:nitrous oxide) anaesthesia, systolic right ventricular pressure (sRVP) was obtained by direct, transdiaphragmatic, right ventricular cannulation. Pulmonary arteries (PAs) (~250μm internal diameter (i.d)) were mounted (Krebs, 370C) on wire myographs and cumulative concentration responses to 5-HT (1nM-0.1mM) constructed. Pulmonary vascular remodelling was assessed by calculating the percentage of pulmonary arteries <80μm i.d with double elastic laminae (MacLean et al., 2004) Statistical comparisons were made by one-way ANOVA with a Newman-Keuls post-test. Data are expressed as mean ± s.e.mean. Hypoxia, and Dfen treatment, increased systolic RVP (sRVP) in WT mice from 19.9 ± 0.9mmHg (n=10) to 36.6 ± 5.3mmHg (n=6; P<0.05) and 40.1± 3.6mmHg, (n = 12, P<0.01) respectively. As previously observed under normoxia (MacLean et al., 2004), 5-HTT+ mice have elevated sRVP (39.0 ± 5.6mmHg, n=10, P<0.01 vs WT) but hypoxia did not increase this further (sRVP = 43.8 ± 6.0mmHg, n = 5). When administered to hypoxic mice, Dfen reduced sRVP in 5-HTT+ mice (27.8 ± 2.3mmHg, n=8, P<0.05), but not in WT mice (sRVP = 32.0 ± 3.8mmHg, n = 6) nor in normoxic 5-HTT+ mice (sRVP = 42.0 ± 4.4mmHg n = 10). Dfen also reduced remodelling in 5-HTT+ mice (16.8 ± 2.0% vs vehicle: 25.4 ± 1.2% n=4, P<0.01), but not in WT mice (17.0 ± 1.4% vs vehicle: 15.3 ± 1.2% n=4) under hypoxia. Under hypoxia, Dfen did not affect the contractile response of PAs to 5-HT in either WT (pEC 50 values: vehicle: 6.9 ± 0.1, n=11 vs Dfen: 6.7 ± 0.1, n=4) or 5-HTT+ ( p EC 50 values: vehicle: 6.1 ± 0.2, n = 7 vs Dfen: 6.1± 0.1, n = 7) mice. Dfen increases sRVP in normoxic WT mice, but reduces chronic hypoxia-induced PAH in mice over-expressing the 5-HTT. A similar protective effect of Dfen against PAH has been reported by others (Eddahibi et al., 1998). These effects are not associated with changes in pulmonary vascular reactivity to 5-HT.
Eddahibi, S et al., (2001) J. Clin. Invest., 108 :1141-1150. |
|
