A132. An adaptive role of adenosine receptors to alpha1 adrenoceptor-mediated cardiomyocyte hypertrophy

Abstract

It has been suggested that adenosine functions as an endogenous antihypertrophic factor and that the adenosine system is upregulated in response to hypertrophic stimuli. To examine this phenomenon we studied the time-dependent effects of the hypertrophic agent phenylephrine on expression of adenosine A1, A2a and A3 receptor subtypes in cultured neonatal rat ventricular myocytes. Real-time PCR analysis revealed an increase in all three adenosine receptor subtypes after 6 and 24 hours of phenylephrine treatment [A1 (59 ± 3%, 91 ± 13%), A2a (54 ± 4%, 59 ± 3%) and A3 (62 ± 1%, 79 ± 1%) receptors (p < 0.05 vs ctrl, N = 6)]. In addition, Western blot analysis revealed a similar increase in adenosine receptor protein expression at 6 and 24 hours; A1 (15 ± 0.8%, 16 ± 0.8%), A2a (15 ± 0.1%, 9 ± 0.1%) and A3 (26 ± 0.5%, 19 ± 0.5%) (p < 0.05 vs ctrl, N = 6). Both gene and protein levels returned to baseline after 48 hours of phenylephrine treatment. These changes in adenosine receptor expression were associated with significant hypertrophy as demonstrated by increased cell surface area and increased expression of atrial natriuretic peptide. The upregulation of adenosine receptors was abrogated by their respective pharmacological agonists including the A1 agonist cyclopentyladenosine, the A2a agonist CGS21680 and the A3 agonist IB-MECA all of which also blocked the phenylephrine-induced hypertrophic response. Our results demonstrate that adenosine receptor expression is upregulated early in the hypertrophic response to α1 adrenoceptor stimulation. Although the mechanisms by which this phenomenon occurs need to be determined, the increased expression of adenosine receptors likely reflects a compensatory response by the cardiomyocyte to limit the hypertrophic phenotype.