Adenosine A1 receptor activation attenuates cardiac hypertrophy and fibrosis in response to 1-adrenoceptor stimulation in vivo

BACKGROUND AND PURPOSE Adenosine has been proposed to exert anti-hypertrophic effects. However, the precise regulation and the role of the different adenosine receptor subtypes in the heart and their effects on hypertrophic signalling are largely unknown. We aimed to characterize expression and function of adenosine A(1) receptors following hypertrophic stimulation in vitro and in vivo. EXPERIMENTAL APPROACH Pro- hypertrophic stimuli and adenosine A1 receptor stimulation of neonatal rat cardiomyocytes and male C57/Bl6 mice, sc. drug administration, real- time PCR, 3[ H]- leucine- incorporation assay, immunostaining, tissue staining, Western blots, gravimetric analyses and echocardiography were applied in this study. KEY RESULTS In neonatal rat cardiomyocyte cultures, phenylephrine, but not angiotensin II or insulin- like growth factor 1 ( IGF1), up- regulated adenosine A1 receptors concentration- dependently. The hypertrophic phenotype ( cardiomyocyte size, sarcomeric organization, total protein synthesis, c- fos expression) mediated by phenylephrine ( 10 mu M), but not that by angiotensinII ( 1 mu M) or IGF1 ( 20 ng center dot mL - 1), was counteracted by the selective A1 receptor agonist, N6- cyclopentyladenosine. In C57/ BL6 mice, continuous N6- cyclopentyladenosine infusion ( 2mg center dot kg - (1-)day -1; 21 days) blunted phenylephrine ( 120mg center dot kg (-1) .day (-1); 21 days) induced hypertrophy ( heart weight, cardiomyocyte size and fetal genes), fibrosis, MMP 2 up- regulation and generation of oxidative stress - all hallmarks of maladaptive remodelling. Concurrently, phenylephrine administration increased expression of adenosine A1 receptors. CONCLUSIONS AND IMPLICATIONS We have presented evidence for a negative feedback mechanism attenuating pathological myocardial hypertrophy following alpha(1)adrenoceptor stimulation. Our results suggest adenosine A(1) receptors as potential targets for therapeutic strategies to prevent transition from compensated myocardial hypertrophy to decompensated heart failure due to chronic cardiac pressure overload.