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-1 05859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to confirm the potential of this compound as an ETA antagonist


METHODS
Vehicle and J-105859 were administered to salt-loaded 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-1 05859.


RESULTS
The Ki values of J-1 05859 for cloned human ETA and ETB were 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions in rabbit iliac artery (pA2 = 10.08) and BQ-3020 (ETB agonist)-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-1 05859 at a dose of 0.03 mg/kg i.v. Chronic treatment with J-1 05859 [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-1 05859 (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.


CONCLUSIONS
J-105859 is a selective, potent, orally active ETA-selective antagonist ETA antagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.
Okada
M
M
Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd, Ibaraki, Japan.
Nishino
M
M
Saito
M
M
Ikeda
T
T
Uehara
S
S
Okada
H
H
Niiyama
K
K
Ohtake
N
N
Hayama
T
T
Nishikibe
M
M
D000473:Alkanes / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007083:Iliac Artery / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D012965:Sodium Chloride / Q000008:administration & dosage; D014661:Vasoconstriction / Q000187:drug effects
D000473:Alkanes; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; C422782:J-105859; D010446:Peptide Fragments; D011725:Pyridines; D044022:Receptor, Endothelin A; C075771:BQ 3020; D012965:Sodium Chloride