Mammalian heart development involves an extraordinarily intricate set of processes that include cellular proliferation, migration, and differentiation. Growth factors have been localized to myocardial cells during many of these events. However, the precise function and mechanism of these factors during early embryonic cardiac development, as well as the ramifications of disturbances in the expression of these growth factors, are not known. This laboratory has examined the role of endogenous opioid systems in cardiac development, and found that acute opioid antagonist blockade by naltrexone (NTX) resulted in increases in DNA synthesis in epicardial and myocardial cells of the ventricles and atria in neonatal rat heart. Chronic exposure to NTX for 10 days resulted in increases in weight and size of the heart, as well as enhanced DNA synthesis. Moreover, they have identified [Met5]-enkephalin (termed the opioid growth factor (OGF)), as a potent inhibitor of DNA synthesis in both embryonic and neonatal heart. Preliminary evidence suggests the presence of both OGF and its receptor (zeta) in heart tissue. The hypothesis of this application is that endogenous opioid systems regulate cardiac development. These studies will examine the role of endogenous opioid systems in embryonic and postnatal heart development using NTX to disrupt the tonic interaction of opioids and opioid receptors.
Specific aims i nclude: 1) define the role of the endogenous opioid system on cardiac growth using [3H]-thymidine incorporation and autoradiography; and 2) explore the ramifications of chronic exposure to NTX during prenatal and postnatal life on cardiac morphology. This application also will focus on one opioid growth factor known to regulate cardiogenesis (OGF). Additional specific aims in this area include: 3) determine the temporal and spatial distribution of OGF by immunocytochemistry and radioimmunoassay, and prohormone gene expression by Northern blot analysis and in situ hybridization. 4) assess the biochemical characteristics of the zeta opioid receptor in the developing rat heart using receptor binding assays, and the presence and distribution of binding sites by in vitro autoradiography; and 5) ascertain the direct influence of OGF and NTX on growth of neonatal ventricular myocardium using tissue culture. These data will contribute to our knowledge of basic cardiac biology, and will examine the influence of endogenous opioid systems in regard to heart development and dysmorphogenesis.
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