VCP746, a novel A1 adenosine receptor biased agonist, reduces hypertrophy in a rat neonatal cardiac myocyte model.

Abstract

VCP746 is a novel A1 adenosine receptor (A1 AR) biased agonist previously shown to be cytoprotective with no effect on heart rate. The aim of this study was to investigate the potential anti-hypertrophic effect of VCP746 in neonatal rat cardiac myocytes (NCM). NCM hypertrophy was stimulated with interleukin (IL)-1β (10 ng/mL), tumour necrosis factor (TNF)-α (10 ng/mL) or Ang II (100 nmol/L) and was assessed by (3) H-leucine incorporation assay. VCP746 significantly inhibited IL-1β-, TNF-α- and Ang II-stimulated NCM hypertrophy as determined by (3) H-leucine incorporation. The anti-hypertrophic effect of VCP746 was also more potent than that of the prototypical A1 AR agonist, N(6) -cyclopentyladenosine (CPA). Further investigation with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay showed that neither CPA nor VCP746 had any effect on cell viability, confirming that the reduction in (3) H-leucine incorporation mediated by CPA and VCP746 was not due to a reduction in cell viability. IL-1β, TNF-α and Ang II were also shown to increase the mRNA expression of hypertrophy biomarkers, ANP, β-MHC and α-SKA in NCM. Treatment with VCP746 at concentrations as low as 1 nmol/L suppressed mRNA expression of ANP, β-MHC and α-SKA stimulated by IL-1β, TNF-α or Ang II, demonstrating the broad mechanistic basis of the potent anti-hypertrophic effect of VCP746. This study has shown that the novel A1 AR agonist, VCP746, is able to attenuate cardiac myocyte hypertrophy. As such, VCP746 is potentially useful as a pharmacological agent in attenuating cardiac remodelling, especially in the post-myocardial infarction setting, given its previously established cytoprotective properties.

• Authors: Chung H Chuo, Shane M Devine, Peter J Scammells, Henry Krum, Arthur Christopoulos, Lauren T May, Paul J White, Bing H Wang
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 43 Issue 10 Pg. 976-82 (10 2016) ISSN: 1440-1681 [Electronic] Australia
• PMID: 27377874 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 John Wiley & Sons Australia, Ltd.

Chemical References

• Adenosine A1 Receptor Agonists
• Thiophenes
• VCP746
• Adenosine

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Adenosine A1 Receptor Agonists (pharmacology)
• Animals
• Animals, Newborn
• Cell Survival (drug effects, physiology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Myocytes, Cardiac (drug effects, pathology, physiology)
• Rats
• Rats, Sprague-Dawley
• Thiophenes (pharmacology)