Hypertrophic effect of selective beta(1)-adrenoceptor stimulation on ventricular cardiomyocytes from adult rat

We investigated whether selective beta(1)-adrenoceptor stimulation causes h ypertrophic growth on isolated ventricular cardiomyocytes from adult rat. A s parameters for the induction of hypertrophic growth, the increases of [C- 14] phenylalanine incorporation, protein and RNA mass, and cell size were d etermined. Isoproterenol (Iso, 10 mu M) alone had no growth effect. In the presence of the beta(2)-adrenoceptor antagonist ICI-118551 (ICI, 10 mu M), Iso caused an increase in [C-14] phenylalanine incorporation, protein and R NA mass, cell volume, and cross-sectional area. We showed for phenylalanine incorporation that the growth effect of Iso+ICI could be antagonized by be ta(1)-adrenoceptor blockade with atenolol (10 mM) or metoprolol (10 mM), in dicating that it was caused by selective beta(1)-adrenoceptor stimulation. The growth response to Iso+ICI was accompanied by an increase in ornithine decarboxylase (ODC) activity and expression. Inhibition of ODC by the ODC a ntagonist difluoromethylornithine (1 mM) attenuated this hypertrophic respo nse, indicating that ODC induction is causally involved. The growth respons e to Iso+ICI was found to be cAMP independent but was sensitive to genistei n (100 mu M) or rapamycin (0.1 mu M). The reaction was enhanced in the pres ence of pertussis toxin (10 mM). We conclude that selective beta(1)-adrenoc eptor stimulation causes hypertrophic growth of ventricular cardiomyocytes by a mechanism that is independent of cAMP but dependent on a tyrosine kina se and ODC.