Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension.

Abstract

BACKGROUND:

Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats.

METHODS:

Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed.

RESULTS:

The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling.

CONCLUSION:

The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension.

• Authors: Djuro Kosanovic, Baktybek Kojonazarov, Himal Luitel, Bhola K Dahal, Akylbek Sydykov, Teodora Cornitescu, Wiebke Janssen, Ralf P Brandes, Neil Davie, Hossein A Ghofrani, Norbert Weissmann, Friedrich Grimminger, Werner Seeger, Ralph T Schermuly
• Journal: Respiratory research (Respir Res) Vol. 12 Pg. 87 (Jun 23 2011) ISSN: 1465-993X [Electronic] England
• PMID: 21699729 (Publication Type: Journal Article)

Chemical References

• Antihypertensive Agents
• Endothelin A Receptor Antagonists
• Isoxazoles
• N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide
• Receptor, Endothelin A
• Sulfones
• Monocrotaline

Topics

• Administration, Oral
• Animals
• Antihypertensive Agents (administration & dosage, pharmacology)
• Disease Models, Animal
• Echocardiography, Doppler
• Endothelin A Receptor Antagonists
• Fibrosis
• Hemodynamics (drug effects)
• Hypertension, Pulmonary (chemically induced, diagnostic imaging, drug therapy, metabolism, physiopathology)
• Hypertrophy, Right Ventricular (diagnostic imaging, drug therapy, metabolism, physiopathology)
• Isoxazoles (administration & dosage, pharmacology)
• Male
• Monocrotaline
• Pulmonary Artery (drug effects, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Receptor, Endothelin A (metabolism)
• Sulfones (administration & dosage, pharmacology)
• Time Factors
• Ventricular Function, Right (drug effects)
• Ventricular Remodeling (drug effects)