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Effects of dexfenfluramine on development of pulmonary hypertension in mice over-expressing the 5HT transporter Familial pulmonary arterial hypertension (fPAH) can be associated with increased activity/expression of the 5HT transporter (5HTT; Eddahibi et al., 2001). PAH can also develop after ingestion of the anorexigen dexfenfluramine (Dfen; Simonneau et al., 1998). However, not all patients taking Dfen develop PAH. Therefore, increased expression of 5HTT may pre-dispose patients to Dfen-induced PAH. This possibility was investigated by examining the effects of Dfen administration in mice over-expressing the human 5HTT gene (5HTT+ mice) and their wildtype (WT) controls. Female mice (C57BL/6 x CBA, WT and 5HTT+, 5 to 6 months, 20-30g) received Dfen, at a dose of 5mg/kg per day, orally, for 28 days. Aged-matched control groups received the administration vehicle, distilled H2O. Anaesthesia was induced and maintained with 2-4% and 1-1.5% halothane respectively and a mixture of nitrous oxide and oxygen (1:6). Systemic arterial pressure (SAP) was obtained via a cannula (Portex, 0.75mm OD) inserted into the carotid artery. Right ventricular pressure (RVP) was obtained via a 25-gauge needle inserted directly into the right ventricle using a transdiaphragmatic approach. Pulmonary vascular remodelling was assessed by calculating the percentage of remodelled pulmonary arteries (PAs) <80 μm i.d. contractile responses to 5HT (10-9M-10-4M) were examined in isolated PAs (~250 m m i.d.) set up on wire myographs. Statistical analysis was by one-way analysis of variance with Newman-Keuls post-test. Data are expressed as mean ± S.E.M. Dfen treatment increased systolic RVP (sRVP) in WT mice from 19.9 ± 0.9mmHg (n=10) to 40.1 ± 3.6mmHg (n=12; P<0.01). As previously observed (MacLean et al., 2004), 5-HTT+ mice demonstrate elevated sRVP (39.0 ± 5.6mmHg in vehicle treated 5-HTT+ mice, n=10, P<0.01 vs WT) but Dfen did not increase this further (sRVP in Dfen treated 5-HTT+ mice: 42.0 ± 4.4mmHg, n=10). Dfen had no effect on SAP which was (mmHg): WT-vehicle: 82.1 ± 1.4, 5-HTT+-vehicle: 76.8 ± 2.1, WT-Dfen: 72.7 ± 6.4, 5HTT+-Dfen: 76.4 ± 2.2. Remodelling of pulmonary vessels was increased by Dfen in both WT (5.6 ± 0.4%, n=4 to 8.1 ± 0.6%, n=4, P<0.05) and 5-HTT+ mice (8.1 ± 0.5, n=4 to 12.0 ± 0.8, n=4, P<0.001) with 5-HTT+ mice showing significantly (P<0.01) more Dfen-induced remodelling than WT mice.Dfen did not affect the 5HT contractile response in vessels from either WT (pEC50 values: vehicle: 7.0 ± 0.9, n=15, Dfen: 6.9 ± 0.1, n=16) or 5-HTT+ mice (pEC50 values: vehicle: 5.0 ± 0.1, n=10; Dfen: 5.4 ± 0.1, n=9). Dfen induces PAH in WT mice, and pre-disposes 5-HTT+ mice to Dfen-induced remodelling. These effects are not associated with changes in pulmonary vascular reactivity to 5HT.
Eddahibi et al., (2001) J. Clin. Invest., 108 , 1141-1150. |
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