(Circulation. 2001;103:314.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Effectiveness of a Nonselective ETA/B and a Selective ETA Antagonist in Rats With Monocrotaline-Induced Pulmonary Hypertension
From the Department of Medicine, Montreal Heart Institute and the Royal Victoria Hospital, Montreal, Quebec, Canada.
Correspondence to Dr Jocelyn Dupuis, Research Center, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec H1T 1C8, Canada. E-mail dupuisj{at}icm.umontreal.ca
Background—Both nonselective ETA/B receptor and selective ETA receptor antagonists can reduce pulmonary hypertension (PH) and right ventricular hypertrophy (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 monocrotaline (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-week survival was 35% in the MCT group; this was increased to 56% in the MCT+ETA group (P=0.10) and to 67% in the MCT+ETA/B group (P=0.0015). Drug administration was stopped 48 hours before hemodynamic measurements to evaluate the chronic effects of therapy: PH in the MCT group (RV systolic pressure 87±1 mm Hg) was improved similarly in both MCT+ETA and MCT+ETA/B groups (72±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 selective antagonist (70±2%) but was reduced to 54±2% in the MCT+ETA/B group (P<0.01). Pulmonary resistive properties, assessed from isolated lung pressure-flow relationships, were improved similarly in survivors from both treated groups.
Conclusions—Both the nonselective ETA/B antagonist BSF420627 and the selective ETA antagonist LU135252 are effective in this model of PH. Similar direct comparative studies in other models of PH and with various dosage regimens are warranted to define the optimal pharmacological approach of PH when ET receptor antagonists are used.
Key Words: receptors • hypertension, pulmonary • pulmonary heart disease • endothelium-derived factors
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