The present study was undertaken to determine whether adrenomedullin modulates the arginine vasopressin (AVP)-activated mitogen-activated protein (MAP) kinase in cultured rat glomerular mesangial cells. AVP dose-dependently increased cellular free calcium, and this increase was unaffected by adrenomedullin. Adrenomedullin increased cellular cAMP production in a dose-dependent manner and AVP activated MAP kinase in a dose-dependent manner. When cells were preincubated for 15 min with adrenomedullin at concentrations of 1 X 10(-8) M or higher, the AVP-activated MAP kinase was significantly reduced. In addition, the activation of MAP kinase by phorbol-12-myristate-13-acetate (PMA) was significantly inhibited by adrenomedullin. Similarly, forskolin also diminished the activation of MAP kinase by AVP and PMA. The inhibition by adrenomedullin or forskolin of AVP-activated MAP kinase disappeared when cells were preexposed to H-89, an inhibitor of protein kinase A. These results indicate that adrenomedullin inhibits the AVP activation of MAP kinase mediated through cAMP in glomerular mesangial cells and that the site of action of adrenomedullin is behind the site of activation of protein kinase C.