A urotensin II receptor antagonist, KR36676, decreases vascular remodeling and inflammation in experimental pulmonary hypertension.

Abstract

The pathophysiological implications of binding of urotensin II (U-II) to urotensin II receptor (UT) in pulmonary arterial hypertension (PAH) have been proposed recently. Besides high expression of U-II in experimental models and patients with PAH, U-II has been shown to increase proliferation of pulmonary vascular smooth muscle cells and inflammatory responses, which were critical for PAH pathophysiology. However, the direct role of the urotensinergic system in the pathogenesis of PAH is yet to be understood. The aim of the present study was to determine whether a novel UT antagonist, KR36676, attenuates the pathophysiological progression of PAH in an animal model of PAH. PAH was induced by a single subcutaneous injection of monocrotaline (MCT, 60mg/kg) in rats. All the animals received KR36676 (30mg/kg/day) or vehicle by oral gavage. Three weeks after MCT-injection, changes in hemodynamic parameters, extent of right ventricular hypertrophy, fibrosis and pulmonary vascular remodeling, and degree of protein expression were determined. Oral administration of KR36676 effectively decreased the MCT-induced increase in right ventricular systolic pressure, hypertrophy and fibrosis. Furthermore, wall thickness of pulmonary arterioles, proliferation of pulmonary vascular cells, and inflammatory response significantly decreased in the KR36676-treated group following MCT injection compared to that in the MCT-treated vehicle group. These preventive effects of KR36676 are mediated, at least in part, by suppression of ERK1/2 and NF-κB signaling pathways. The novel UT antagonist, KR36676, effectively prevented MCT-induced PAH progression and pulmonary vascular remodeling in rat model. Our findings support the therapeutic efficacy of UT antagonist in PAH prevention and elucidate the possible underlying mechanisms of action.

• Authors: Jeong Hyun Lee, Byung Kil Park, Kwang-Seok Oh, Kyu Yang Yi, Chae Jo Lim, Ho Won Seo, Byung Ho Lee
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 40 Pg. 196-202 (Nov 2016) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 27611861 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Acetamides
• Anti-Inflammatory Agents
• Benzoxazines
• KR36676
• NF-kappa B
• Receptors, G-Protein-Coupled
• Tumor Necrosis Factor-alpha
• Uts2r protein, rat
• Monocrotaline
• Collagen

Topics

• Acetamides (pharmacology, therapeutic use)
• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Benzoxazines (pharmacology, therapeutic use)
• Collagen (metabolism)
• Heart Ventricles (metabolism, pathology)
• Hypertension, Pulmonary (chemically induced, drug therapy, metabolism, pathology)
• Hypertrophy, Right Ventricular (chemically induced, drug therapy, metabolism, pathology)
• MAP Kinase Signaling System (drug effects)
• Male
• Monocrotaline
• NF-kappa B (metabolism)
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (antagonists & inhibitors)
• Tumor Necrosis Factor-alpha (metabolism)
• Vascular Remodeling (drug effects)