Dual trophic effects of the alpha₁-adrenergic receptor in cultured neonatal rat heart muscle cells

The molecular signals regulating myocardial hypertrophy are unknown. We used a new model system to study this problem. Muscle cells from the neonatal rat ventricle were cultured in serum-free medium. Control cells did not change in size over time and did not show spontaneous contractile activity. Incubation with norepinephrine or epinephrine had two major trophic effects that developed over 1-2 days. The first was stimulation of muscle cell hypertrophy or increase in size. The second was induction of spontaneous contractile activity. The hypertrophic response was mediated through an alpha₁-adrenoceptor. The beating response required both alpha₁- and beta₁-adrenergic receptor stimulation. Alpha₁ stimulation alone produced enlarged cells that did not beat. Alpha₁ plus beta₁ stimulation induced contractile activity even when protein synthesis and hypertrophy were inhibited. Thus, the two alpha₁ responses could be dissociated, providing evidence for two independently-regulated cellular pathways for the dual alpha₁ trophic effects. One pathway leads to hypertrophy. The other, which requires concomitant beta₁ stimulation, controls the development of beating. Preliminary work raises the possibility that different products of inositol phospholipid hydrolysis might initiate the two alpha₁ trophic pathways. Other preliminary work suggests that the growth pathway is associated with the expression of specific genes and might reflect an action of the alpha₁- adrenoceptor on the cell nucleus. These studies define previously unsuspected trophic roles for the alpha₁-adrenergic receptor.