INTERACTION OF ADRENOMEDULLIN AND PLATELET-DERIVED GROWTH-FACTOR ON RAT MESANGIAL CELL PRODUCTION OF ENDOTHELIN

Adrenomedullin has recently been isolated from human pheochromocytoma. We designed the present study to examine the effect of adrenomedullin on the production of the vasoconstrictive and growth-promoting peptid e endothelin-1 (ET-1) after stimulation with platelet-derived growth f actor (PDGF) in cultured rat glomerular mesangial cells. PDGF stimulat ed ET-1 production in a concentration-dependent manner. Rat adrenomedu llin inhibited this stimulated ET-1 production in a concentration-depe ndent manner between 10(-7) and 10(-8) mol/L. Rat adrenomedullin also increased the cellular level of cAMP in a concentration-dependent mann er between 10(-7) and 10(-8) mol/L. Human adrenomedullin was less effe ctive than rat adrenomedullin with respect to inhibiting ET-1 producti on and increasing cAMP levels. The addition of 8-bromo-cAMP (10(-3) an d 10(-4) mol/L) reduced PDGF-induced ET-1 production. Furthermore, for skolin (10(-4) and 10(-5) mol/L), an activator of adenylate cyclase, r educed PDGF-induced ET-1 production. In contrast, the basal production of ET-1 was not significantly altered by rat and human adrenomedullin . These results indicate that adrenomedullin inhibits PDGF-induced ET- 1 production in cultured rat mesangial cells, probably through a cAMP- dependent process.