Received for publication June 28, 2004.
Revised September 24, 2004.
Accepted for publication September 27, 2004.

Inhibition of Phenylephrine-induced Cardiomyocyte Hypertrophy by Activation of Multiple Adenosine Receptor Subtypes

Abstract

Plasma adenosine levels are elevated in cardiovascular disease including hypertension and heart failure and the nucleoside has been proposed to serve as an endogenous anti-myocardial remodelling factor. We studied the modulation of phenylephrine-induced hypertrophy by adenosine receptor activation in isolated neonatal cultured ventricular myocytes. Phenylephrine (10 µM) increased cell size by 35% and significantly increased expression of atrial natriuretic peptide. These effects were reduced by the stable adenosine analogue 2-chloro adenosine and completely blocked by the adenosine A₁ receptor agonist CPA (1 µM) , the A_2a receptor agonist CGS21680 (100 nM) and the A₃ receptor agonist IB-MECA (100 nM). The antihypertrophic effects of all three agonists were completely reversed by their respective antagonists. Phenylephrine significantly upregulated expression of the immediate early gene c-fos especially within the first 30 min of phenylephrine treatment. These effects were almost completely inhibited by all adenosine receptor agonists. Although phenylephrine also induced early stimulation of both p38MAPK and ERK, these responses were unaffected by adenosine agonists. The expression of the G-protein regulatory factors RGS2 and RGS4 were increased by nearly three-fold fold by phenylephrine treatment although this was completely prevented by adenosine receptor agonists. These agents also blocked the ability of phenylephrine to upregulate Na-H exchange isoform 1 (NHE1) expression in hypertrophied myocytes. Thus, our results demonstrate an antihypertrophic effect of adenosine acting via multiple receptor subtypes through a mechanism involving downregulation of NHE1 expression. The ability to prevent RGS upregulation further suggests that adenosine receptor activation minimizes signalling which leads to hypertrophic responses.

Key words: MAP kinase, Na-H exchange, RGS proteins, adenosine, adenosine receptors, cardiomyocyte hypertrophy

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