The orally active urotensin receptor antagonist, KR36676, attenuates cellular and cardiac hypertrophy.

Abstract

BACKGROUND AND PURPOSE:

Blockade of the actions of urotensin-II (U-II) mediated by the urotensin (UT) receptor should improve cardiac function and prevent cardiac remodelling in cardiovascular disease. Here, we have evaluated the pharmacological properties of the recently identified UT receptor antagonist, 2-(6,7-dichloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)-N-methyl-N-(2-(pyrrolidin-1-yl)-1-(4-(thiophen-3-yl)phenyl) ethyl)acetamide (KR36676).

EXPERIMENTAL APPROACH:

Pharmacological properties of KR36676 were studied in a range of in vitro assays (receptor binding, calcium mobilization, stress fibre formation, cellular hypertrophy) and in vivo animal models such as cardiac hypertrophy induced by transverse aortic constriction (TAC) or myocardial infarction (MI).

KEY RESULTS:

KR36676 displayed high binding affinity for the UT receptor (Ki : 0.7 nM), similar to that of U-II (0.4 nM), and was a potent antagonist at that receptor (IC50 : 4.0 nM). U-II-induced stress fibre formation and cellular hypertrophy were significantly inhibited with low concentrations of KR36676 (≥0.01 μM). Oral administration of KR36676 (30 mg·kg(-1) ) in a TAC model in mice attenuated cardiac hypertrophy and myocardial fibrosis. Moreover, KR36676 restored cardiac function and myocyte size in rats with MI-induced cardiac hypertrophy.

CONCLUSIONS AND IMPLICATIONS:

A highly potent UT receptor antagonist exerted anti-hypertrophic effects not only in infarcted rat hearts but also in pressure-overloaded mouse hearts. KR36676 could be a valuable pharmacological tool in elucidating the complicated physiological role of U-II and UT receptors in cardiac hypertrophy.

• Authors: K S Oh, J H Lee, K Y Yi, C J Lim, S Lee, C H Park, H W Seo, B H Lee
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 10 Pg. 2618-33 (May 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 25597918 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The British Pharmacological Society.

Chemical References

• Acetamides
• Benzoxazines
• KR36676
• Receptors, G-Protein-Coupled
• Urotensins
• Uts2r protein, rat
• urotensin II

Topics

• Acetamides (administration & dosage, metabolism, pharmacology, therapeutic use)
• Administration, Oral
• Animals
• Benzoxazines (administration & dosage, metabolism, pharmacology, therapeutic use)
• Cardiomegaly (drug therapy, pathology)
• Cell Line
• Dose-Response Relationship, Drug
• Flushing (drug therapy)
• Humans
• Male
• Mice
• Muscle Cells (drug effects, pathology)
• Myocardial Infarction (drug therapy, pathology)
• Radioligand Assay
• Rats
• Receptors, G-Protein-Coupled (antagonists & inhibitors)
• Urotensins (pharmacology)