Adrenomedullin inhibits angiotensin AT1A receptor expression and function in cardiac fibroblasts.

Adrenomedullin (AM) is a multifunctional peptide hormone with wide-ranging actions related to cardiovascular homeostasis. AM receptors are highly expressed in the heart and AM has antihypertrophic and antiproliferative effects on cardiac myocytes and fibroblasts, respectively. We have investigated the interaction between AM and angiotensin II (Ang II) signalling in neonatal cardiac fibroblast cultures to determine whether the antagonistic effects of AM are mediated via the modulation of Ang II receptors. Cardiac fibroblasts exclusively expressed the Ang II type 1 receptor (AT(1)R) and binding to this site was downregulated by 35% following an 18-h incubation with 100 nM AM. Levels of AT(1A)R mRNA were dose-dependently lowered by AM, with a maximal 40-50% inhibition by 6 h. The decreases in both AT(1)R binding and AT(1A)R mRNA levels were mimicked by 8-Br-cAMP or forskolin, suggesting that the effects of AM were mediated via an elevation of cAMP. In cardiac fibroblasts pretreated with AM, the Ang II induction of collagen biosynthesis was attenuated, although basal collagen synthesis was unaffected. These data suggest that AM mediates the heterologous downregulation of AT(1)R expression via a relatively rapid decrease in AT(1A)R mRNA pools. This interaction may represent a relevant pathophysiological mechanism for modulating Ang II responsiveness in the diseased heart.