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

Abstract

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.

CONCLUSION:

J-105859 is a selective, potent, orally active ETA-selective antagonist ETA antagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.

• Authors: M Okada, M Nishino, M Saito, T Ikeda, S Uehara, H Okada, K Niiyama, N Ohtake, T Hayama, M Nishikibe
• Journal: Journal of hypertension (J Hypertens) Vol. 18 Issue 12 Pg. 1815-23 (Dec 2000) ISSN: 0263-6352 [Print] England
• PMID: 11132606 (Publication Type: Journal Article)

Chemical References

• Alkanes
• Endothelin Receptor Antagonists
• Endothelins
• J-105859
• Peptide Fragments
• Pyridines
• Receptor, Endothelin A
• BQ 3020
• Sodium Chloride

Topics

• Alkanes (pharmacology)
• Animals
• Blood Pressure (drug effects)
• Endothelin Receptor Antagonists
• Endothelins (pharmacology)
• Humans
• Hypertension (etiology, physiopathology, prevention & control)
• Iliac Artery (drug effects)
• In Vitro Techniques
• Male
• Peptide Fragments (pharmacology)
• Pulmonary Artery (drug effects)
• Pyridines (pharmacology)
• Rabbits
• Rats
• Rats, Inbred Dahl
• Rats, Sprague-Dawley
• Receptor, Endothelin A
• Sodium Chloride (administration & dosage)
• Vasoconstriction (drug effects)