What regulates myocardial hypertrophy is a problem of fundamental importance in cardiovascular disease and is the long-range aim of my work. Over the past three years I have developed a new approach to this problem, using pure cultures of neonatal rat myocardial cells (MCs) which are differentiated and do not proliferate (Circ Res 50:101-116, 1982). I have shown that these MCs grow by hypertrophy, a process that is regulated by serum and by catecholamines (Circ Res, in press). In that study, the hypertrophic effect of norepinephrine (NE) was not blocked by the beta-adrenergic antagonist, propranolol. I have found recently that the effect of NE is blocked by the alpha-adrenergic antagonist, phentolamine. This and other evidence strongly suggests that the MC hypertrophy induced by NE in serum-free cultures is an alpha-adrenegic response. Further characterization of this novel and important finding is the focus of the present work. This work will test the following ideas: that Ne and EPI are myocardial growth factors with actions analagous to other growth factors; that their hypertrophic effect is an alpha-adrenergic response; that hypertrophy is independent of any stimulation of beating, which may be predominantly a beta-adrenergic response; that the effective concentrations of NE and EPI are physiologically relevant; and that MC hypertrophy in culture shares characteristics with MC hypertrophy in vivo. Specific questions will include the following: the subspecificity of the alpha-adrenergic receptor; NE concentration, exposure duration, and possible uptake necessary to induce hypertrophy; the relation of growth to beating; the proportionate increase in myosin accumulation during hypertrophy; maximum hypertrophy and regression; the induction by NE of endogenous trophic factors; changes in cyclic nucleotides and alpha-adrenergic receptors; and interactions with other alpha-related hormones, extracellular calcium, and cell stretch. Similar studies will be done with the other active catecholamine, epinephrine (EPI). I will use defined, serum-free cultures with 90% MCs; an established experimental protocol; my published methods for cell size (protein, volume, and surface area); and assays for myosin (SDS-PAGE), catecholamines (radioenzymatic), cyclic nucleotides (radioimmunoassay), and alpha-adrenergic receptors (radioligand binding). The role of myocardial alpha receptors is unclear. It has not been expected that they mediate a hypertrophic effect, although the data is consistent with this possibility. This work will provide new perspectives on MC alpha responses and on NE and EPI as growth factors in cultured MCs.
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