Inhibition of endothelin-1 and hypoxia-induced pulmonary pressor responses in the rat by a novel selective endothelin-A receptor antagonist, di-n-butylaminocarbamyl-L-leucyl-D-tryptophanyl-D-4-chloro-Phe.

Abstract

Pulmonary hypertension is a kind of disease associated with a very high rate of mortality, and there are not many effective drugs for the treatment. Today, endothelin (ET)-1 receptor antagonists were proved to be effective in the treatment of pulmonary hypertension. Aiming at developing new endothelin-A receptor (ETA) antagonist for treatment of pulmonary hypertension, di-n-butylaminocarbamyl-L-leucyl-D-tryptophanyl-D-4-chloro-Phe, named GF063, was synthesized at base of selective ETA receptor antagonist BQ485 and selected for the further pharmacological characterization. The preliminary pharmacodynamics of GF063 was evaluated by radioligand receptor binding assay and test of antivasoconstriction effects in vitro and in vivo. The integrative pharmacodynamics was evaluated in hypoxia-induced rat pulmonary hypertension. In vitro, GF063 bound to ETA receptor with 100,000-fold higher affinity than to ETB receptor. GF063 concentration dependently inhibited contraction of isolated rat aortic ring induced by ET-1 and shifted the cumulative concentration-contraction response curve to right with no change in the maximal response. In vivo, GF063 inhibited the increase of mean systemic arterial pressure induced by ET-1 in anesthetized rat. In hypoxia-induced rat pulmonary hypertension model, pretreatment with GF063 (40 mg/kg, s.c.) significantly decreased pulmonary artery pressure and right ventricular hypertrophy, also significantly inhibited the increase of ET-1 level in lung, improved hemodynamics, and alleviated the wall thickness of pulmonary vessels. This study indicated that GF063, as a selective ETA receptor antagonist, could inhibit vasoconstriction effects in vivo and in vitro, could prevent pulmonary hypertension induced by hypoxia, and may have great potential to be developed as a new drug of antipulmonary hypertension.

• Authors: Ling-Di Yan, Ling-Lei Kong, Zheng Yong, Hua-Jin Dong, Mu-Gen Chi, Xue-Feng Pan, Cui Zhang, Yuan-Jun Liang, Ze-Hui Gong, Ke-Liang Liu
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 56 Issue 3 Pg. 246-54 (Sep 2010) ISSN: 1533-4023 [Electronic] United States
• PMID: 20531217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin A Receptor Antagonists
• Endothelin-1
• Oligopeptides
• di-n-butylaminocarbamyl-leucyl-tryptophyl-4-chlorophenylalanine

Topics

• Animals
• Aorta, Thoracic (drug effects, physiopathology)
• Blood Pressure (drug effects)
• Dose-Response Relationship, Drug
• Endothelin A Receptor Antagonists
• Endothelin-1 (antagonists & inhibitors)
• Hypertension, Pulmonary (drug therapy, etiology, physiopathology)
• Hypertrophy, Right Ventricular (drug therapy, etiology, physiopathology)
• Hypoxia (complications, physiopathology)
• In Vitro Techniques
• Lung (blood supply, drug effects, pathology)
• Male
• Oligopeptides (pharmacology)
• Pulmonary Artery (drug effects, pathology, physiopathology)
• Rats
• Rats, Wistar
• Vasoconstriction (drug effects)