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

VCP746 is a novel A₁ adenosine receptor (A₁AR) 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 ³H‐leucine incorporation assay. VCP746 significantly inhibited IL‐1β‐, TNF‐α‐ and Ang II‐stimulated NCM hypertrophy as determined by ³H‐leucine incorporation. The anti‐hypertrophic effect of VCP746 was also more potent than that of the prototypical A₁AR agonist, N⁶‐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 ³H‐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 A₁AR 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.