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

VCP746 is a novel A(1) adenosine receptor (A(1)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)-1 (10ng/mL), tumour necrosis factor (TNF)- (10ng/mL) or Ang II (100nmol/L) and was assessed by H-3-leucine incorporation assay. VCP746 significantly inhibited IL-1-, TNF-- and Ang II-stimulated NCM hypertrophy as determined by H-3-leucine incorporation. The anti-hypertrophic effect of VCP746 was also more potent than that of the prototypical A(1)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 H-3-leucine incorporation mediated by CPA and VCP746 was not due to a reduction in cell viability. IL-1, TNF- and Ang II were also shown to increase the mRNA expression of hypertrophy biomarkers, ANP, -MHC and -SKA in NCM. Treatment with VCP746 at concentrations as low as 1nmol/L suppressed mRNA expression of ANP, -MHC and -SKA stimulated by IL-1, TNF- or Ang II, demonstrating the broad mechanistic basis of the potent anti-hypertrophic effect of VCP746. This study has shown that the novel A(1)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.