Key result
Treatment with Ambrisentan led to significantly greater PGIS mRNA expression compared to Bosentan (18% vs 7%, p=0.003), although this had no beneficial effect on pulmonary haemodynamics.
Why the study?
Does ambrisentan increase prostacyclin synthase I (PGIS) expression compared to bosentan in rats with monocrotaline-induced pulmonary hypertension?
Does ambrisentan increase prostacyclin synthase I (PGIS) expression compared to bosentan in rats with monocrotaline-induced pulmonary hypertension?
In a rat model of pulmonary hypertension, ambrisentan led to greater PGIS expression than bosentan, but this did not translate into beneficial effects on pulmonary hemodynamics at 4 weeks.
Answers are grounded in this paper and cite their sources.
Ambrisentan increased PGIS expression without hemodynamic benefit in this rat model; hypothesis-generating for differential ERA effects, should not yet change practice.
OBJECTIVE: Compared to the unselective endothelin (ET) receptor antagonist (Bosentan), superior effects of selective ET-A-receptor blockage (Ambrisentan) for the treatment of pulmonary hypertension (PH) are expected due to ET-B-receptor mediated beneficial effects. Our hypothesis was that treatment with Ambrisentan leads to an increase in prostacyclin synthase I (PGIS) expression compared to Bosentan. MATERIAL AND METHODS: To test this hypothesis, rats were treated with either monocrotaline (MCT) only, MCT+Ambrisentan or MCT+Bosentan. After 4 weeks, right ventricular systolic pressure (RVSP), pulmonary vascular remodelling and right ventricular hypertrophy (RV/(LV+S)) were measured. RESULTS: In MCT only treated animals, significantly greater expression of PGIS mRNA was found in the lungs compared to control animals, and this was confirmed by immunohistochemical analysis indicating increased staining of PGIS in the very small pulmonary arteries (17 % greater expression of PGIS mRNA in MCT versus control, p = 0.002; Remmele score (RS): 51 versus 102, p = 0.009). Treatment with Bosentan resulted in a significantly lower expression of PGIS mRNA compared to Ambrisentan and MCT only (7 % versus 18 %, p = 0.003 and 7 % versus 17 %, p = 0.004). This observation was also confirmed by immunohistochemical analysis (RS very small arteries: 45 versus 81, p = 0.003; RS small arteries: 45 versus 108, p = 0.014). No difference was observed in RVSP, RV/(LV+S) or pulmonary vascular remodelling between the two treatment groups (RVSP: 28 versus 39 mmHg, p = 0.189; RV/(LV+S) 0.46 versus 0.48, p = 0.818; medial area: 78.3 % versus 75.2 %, p = 0.823). CONCLUSIONS: Treatment with Bosentan leads to lower PGIS expression in pulmonary arteries compared to Ambrisentan, although the greater PGIS expression by Ambrisentan treatment had no benefical effect on pulmonary haemodynamics.
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Schroll et al. (2008) studied Experimental pulmonary hypertension. Ambrisentan vs. Bosentan was evaluated on Prostacyclin synthase I (PGIS) mRNA expression (p=0.003). Treatment with Ambrisentan led to significantly greater PGIS mRNA expression compared to Bosentan (18% vs 7%, p=0.003), although this had no beneficial effect on pulmonary haemodynamics.
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