ObjectiveTo examine the chronic effects of a newly synthesized, potent and selective endothelin (ET) ETAreceptor antagonist, J-105859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to conFIrm the potential of this compound as an ETAantagonist.MethodsVehicle and J-105859 were administered to saltloaded DS rats for 12 weeks. Throughout the experimental period, blood pressure was measured continuously using a telemetry system and the survival rate was determined. The surviving animals were subsequently sacrificed and autopsy was performed. Binding and functional assays were also carried out to characterize J-105859.ResultsThe Kivalues of J-105859 for cloned human ETAand ETBwere 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions in rabbit iliac artery (pA2= 10.08) and BQ-3020 (ETBagonist)-induced contractions in pulmonary artery (pA2= 7.63). The pressor response to intravenous (i.v.) ET-1 (0.5 nmol/kg) was significantly inhibited by J-105859 at a dose of 0.03 mg/kg i.v. Chronic treatment with J-105859 [0.1 and 1 mg/kg per day orally (p.o.)] from the prehypertensive stage decreased the mortality of salt-loaded DS rats and markedly inhibited the development of brain lesions. The survival rates in the control and J-105859 (0.1 and 1 mg/kg per day) groups were 34, 80 and 100%, respectively. Development of hypertension was markedly inhibited at a dose of 1 mg/kg per day.ConclusionJ-105859 is a selective, potent, orally active ETA-selective antagonist. ETAantagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.