Regulation of DNA synthesis of myocardial and epicardial cells in developing rat heart by [Met5]enkephalin.

Endogenous opioids serve as negative growth factors in neural and nonneural tissues in addition to being neuromodulators. This study investigated the hypothesis that native opioid peptides are inhibitory growth factors in heart development. DNA synthesis of ventricular myocardial and epicardial cells in 1-day-old rats was examined. Administration of a variety of opioids and peptides revealed that [Met5]enkephalin had the greatest inhibitory effect on DNA synthesis; peptides related to mu-, delta-, kappa-, epsilon-, and sigma-receptors had no influence on cell proliferation, even at concentrations as high as 10 mg/kg. [Met5]enkephalin, also termed opioid growth factor (OGF), depressed DNA synthesis at 1 and 10 mg/kg but not at 0.01 or 0.1 mg/kg. The effects of OGF were noted within 1 h of treatment, persisted for as long as 22 h after drug administration, and could depress DNA synthesis in myocardial and epicardial cells to 43 and 36%, respectively, of control values. The effect of OGF on DNA synthesis of heart cells was opioid receptor-mediated. Organ culture experiments revealed that opioids acted directly on developing cardiac cells. Both OGF and its receptor, zeta, were detected in heart cells of 1-day-old rats by immunocytochemistry. mRNA for preproenkephalin, the precursor to OGF, was observed in 1-day-old rat heart. These results indicate that an autocrine- or paracrine-produced endogenous opioid peptide (i.e., OGF) and its receptor (i.e., zeta) are present in the developing heart and govern DNA synthesis, with OGF acting directly as a tonic negative regulator of cell generation.