Alpha1-adrenergic stimulation has two chronic, developmental or trophic effects in cultured neonatal rat heart muscle cells: stimulation of hypertrophy and induction of beating activity. The effect on beating requires concomitant Beta1-adrenergic stimulation. Hypertrophy and beating can be experimentally dissociated, suggesting dual Alpha1-mediated pathways, and these may be regulated by different products of inositol phospholipid hydrolysis. Hypertrophied cells produced by some growth factors do not beat and/or have no increase in contractile proteins; they can be considered to be pathologically hypertrophied cells. These findings and other preliminary data provide the basis for the four aims of this continuing work, related to relevance, mechanisms, other growth factors, and the variability of the hypertrophic response. First, the general relevance of Alpha1-mediated trophic effects will be tested by studies on heart muscle cell cultures from the human fetus and from other small mammals, fetal or neonatal and adult. Second, the mechanisms of Alpha1 tropic effects will be explored by studies of phosphoinositide turnover, Alpha1-receptor translocation and nuclear effects, and a myocyte renin-angiotensin system. The mechanisms underlying the beating response will be clarified (cell electrophysiology, contractile strength and velocity, high energy phosphates, cyclic nucleotides), and the Alpha1 and Beta1 contributions will be defined. Third, confirmatory evidence for autocrine myocyte growth factors will be sought by studies of the growth-promoting activity of heart extracts and conditioned medium. Static stretch as a growth factor will be tested. Fourth, the variability of the hypertrophic response to different growth factors will be described in terms of contractile protein content and turnover, myosin and creatine kinase isoforms, contractile activity, nerve growth factor mRNA expression, collagen synthesis, and DNA synthesis and mitosis. The long-range goal is to understand how normal and abnormal myocardial hypertrophy are controlled. The basic hypothesis is that myocardial cell growth and function are chronically regulated by signal-receptor mechanisms.