Effectiveness of a nonselective ETA/B and a selective ETA antagonist in rats with monocrotaline-induced pulmonary hypertension

Background-Both nonselective ETA/B receptor and selective ETA receptor anta gonists can reduce pulmonary hypertension (PH) and right ventricular hypert rophy (RVH) in various animal models. Depending on their net effects after blockade of endothelial and smooth muscle ETB receptors, nonselective ETA/B antagonists could be more or less effective than selective ETA antagonists . Methods and Results-Two weeks after injection of saline or 60 mg/kg monocro taline (MCT), rats received 50 mg.kg(-1).d(-1) of a selective (LU135252) or nonselective (BSF420627) antagonist for 3 weeks. This resulted in 4 groups : control (n=15), MCT (n=60), MCT+ETA (n=39), and MCT+ETA/B (n=40), Five-we ek survival was 35% in the MCT group; this was increased to 56% in the MCTETA group (P=0.10) and to 67% in the MCT+ETA/B group (P=0.0015). Drug admin istration was stopped 48 hours before hemodynamic measurements to evaluate the chronic effects of therapy: PH in the MCT group (RV systolic pressure 8 7+/-1 mm Hg) was improved similarly in both MCT+ETA and MCT+ETA/B groups (7 2+/-3 and 70+/-3 mm Hg, respectively, P<0.05), Severe RVH in the MCT group (RV/left ventricle + septum weight ratio 73+/-1%) was not affected by the s elective antagonist (70+/-2%) but was reduced to 54+/-2% in the MCT+ETA/B g roup (P<0.01). Pulmonary resistive proper-ties, assessed from isolated lung pressure-flow relationships, were improved similarly in survivors from bot h treated groups. Conclusions-Both the nonselective ETA/B antagonist BSF420627 and the select ive ETA antagonist LU135252 are effective in this model of PH. Similar dire ct comparative studies in other models of PH and with various dosage regime ns are warranted to define the optimal pharmacological approach of PH when ET receptor antagonists are used.