REGULATION OF ADRENOMEDULLIN PRODUCTION IN RAT ENDOTHELIAL-CELLS

Adrenomedullin (AM) is a potent vasorelaxant peptide recently identifi ed in extracts of pheochromocytoma. We have found that AM is actively secreted from endothelial cell (EC) and vascular smooth muscle cell(VS MC). To elucidate the function of AM secreted from EC, the effects of 43 substances on secretion of AM from cultured rat EC were examined in this study. We first confirmed that synthesized AM was not stored but constitutively secreted from EC, indicating that the amount secreted could be used as an index of ANI synthesis in EC. EC secreted AM at a rate 5.8 times higher than VSMC, and AM gene transcription in EC signi ficantly contributed to the total aortic AM messenger RNA. Tumor necro sis factor, interleukin-1, and lipopolysaccharide augmented AM secreti on from EC, showing cooperative effects, which suggests that AM secret ed from EC participates in the induction of hypotension in septic shoc k. Transforming growth factor beta(1) and FCS suppressed AM secretion but stimulated endothelin-1 (ET-1) secretion. Thrombin potently stimul ated AM secretion from EC but suppressed it from VSMC. Thyroid hormone and phorbol ester increased AM and ET-1 secretion but to a lesser ext ent. Interferon-gamma inhibited AM secretion from EC. whereas oxidized LDL stimulated it. Regulation of AM production in EC is found to be s imilar to that of VSMC with several exceptions, but AM and ET-1 produc tion in EC are deduced to be controlled independently and by different mechanisms. AM stimulates cAMP production in EC, though receptors exp ressed on cultured rat EC are not specific to AM but to calcitonin gen e-related peptide. Based on these findings, AM production in EC is tho ught to be regulated by a variety of substances coming from blood and neighboring cells, and the secreted AM is deduced to dilate blood vess els as an endothelium-derived relaxing factor competing with ET-1.