Marked reduction of mortality in salt-loaded Dahl salt-sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859

Objective To examine the chronic effects of a newly synthesized, potent and selective endothelin (ET) ETA receptor antagonist, J-105859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to confirm the potential o f this compound as an ETA antagonist. Methods Vehicle and J-105859 were administered to salt-loaded DS rats for 1 2 weeks. Throughout the experimental period, blood pressure was measured co ntinuously using a telemetry system and the survival rate was determined. T he surviving animals were subsequently sacrificed and autopsy was performed . Binding and functional assays were also carried out to characterize J-105 859. Results The K-i values of J-105859 for cloned human ETA and ETB were 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions i n rabbit iliac artery (pA(2) = 10.08) and BQ-3020 (ETB agonist)-induced con tractions in pulmonary artery (pA(2) = 7.63). The presser response to intra venous (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 mortal ity 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 pe r day) groups were 34, 80 and 100%, respectively. Development of hypertensi on was markedly inhibited at a dose of 1 mg/kg per day. Conclusion J-105859 is a selective, potent, orally active ETA-selective ant agonist ETA antagonists may reduce morbidity as well as mortality in salt-s ensitive hypertension. (C) 2000 Lippincott Williams & Wilkins.