Selective activation of α1A-adrenergic receptors in neonatal cardiac myocytes is sufficient to cause hypertrophy and differential regulation of α1-adrenergic receptor subtype mRNAs

Prolonged stimulation of cardiac a,adrenergic receptors causes myocyte hypertrophy, although the receptor subtypes involved remain controversial. We have used a potent and selective alpha(1A) agonist, A-61603, to test whether activation of the alpha(1A)-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 nM 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 selective alpha(1A) antagonist 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 in alpha(1A)-adrenergic receptor mRNA with a concomitant 50% decrease in alpha(1B) mRNA levels by 48 h. Identical responses of differential regulation of alpha(1A)- and alpha(1B)-adrenergic receptor mRNA were observed with phenylephrine. Both the stimulation of alpha(1A)- and repression alpha(1B)-adrenergic receptor mRNA caused by A-61603 could be abolished by 10-20 nM KMD-3213. The present data provide evidence that selective activation of alpha(1A)-adrenergic receptors on cardiomyocytes is sufficient to mediate the phenotypic changes associated with cardiac hypertrophy. In addition, the differential regulation of alpha(1A) and alpha(1B) mRNA in response to selective alpha(1A)-adrenergic receptor stimulation suggests that cross-talk between receptor subtypes may be involved in regulating receptor populations during chronic agonist exposure. (C) 1998 Academic Press