Selective Activation ofα1A-adrenergic Receptors in Neonatal Cardiac Myocytes is Sufficient to Cause Hypertrophy and Differential Regulation ofα1-adrenergic Receptor Subtype mRNAs

Prolonged stimulation of cardiacα1-adrenergic receptors causes myocyte hypertrophy, although the receptor subtypes involved remain controversial. We have used a potent and selectiveα1Aagonist, A-61603, to test whether activation of theα1A-adrenergic receptor subtype is sufficient to mediate the morphological, biochemical and molecular alterations associated with cardiomyocyte hypertrophy. In neonatal rat cardiomyocyte cultures, 48 h incubation with 50 n A-61603 led to a marked increase in myocardial cell size that was associated with a significant elevation in the rate of protein synthesis. The increased rate of incorporation of radiolabelled amino acids into protein stimulated by A-61603 was totally abolished by the selectiveα1Aantagonist KMD-3213. A-61603 increased ANF secretion three-fold, and ANF mRNA 12-fold above control levels in cardiomyocyte cultures. RNase protection analysis demonstrated a A-61603-mediated two to three-fold increase inα1A-adrenergic receptor mRNA with a concomitant 50% decrease inα1BmRNA levels by 48 h. Identical responses of differential regulation ofα1A- andα1B-adrenergic receptor mRNA were observed with phenylephrine. Both the stimulation ofα1A- and repressionα1B-adrenergic receptor mRNA caused by A-61603 could be abolished by 10–20 n KMD-3213. The present data provide evidence that selective activation ofα1A-adrenergic receptors on cardiomyocytes is sufficient to mediate the phenotypic changes associated with cardiac hypertrophy. In addition, the differential regulation ofα1Aandα1BmRNA in response to selectiveα1A-adrenergic receptor stimulation suggests that cross-talk between receptor subtypes may be involved in regulating receptor populations during chronic agonist exposure.