Atrial natriuretic peptide (ANP) contributes to the inhibition of such causes of inflammation as the lipopolysaccharide (LPS)-induced productions of nitric oxide (NO) and proinflammatory cytokines [including interleukin- I (IL-1)] in macrophages. In the present study we used primary cultures of rat brain macrophage-like cells (i.e., microglial cells) to investigate whether ANP binding to its receptors inhibits LPS-induced microglial activation via effects on the activation of the proinflammatory transcription factors NF-kappa B and AP-1. The productions of NO and IL-1, as well as morphological changes, were examined to assess LPS-induced activation of microglial cells. Our RTPCR study revealed that rat microglial cells express the mRNAs for ANP receptors (types A, B, and C) and that for the ANP molecule. LPS (100 ng/ml)-stimulated microglial cells showed increases in nitrite (a relatively stable metabolite of NO) and IL-I concentrations, and in the expression of IL-1 mRNA, as well as a morphological change from an amoeboid shape to a multipolar (mostly bipolar, but sometimes tripolar) rod shape. These effects were all significantly inhibited by treatment with ANP (at 10(-6) M or less). The inhibition by ANP of the LPS-induced nitrite response was abrogated by a NP-receptor antagonist, HS-142-1 (100 ng/ml). NF-kappa B and AP- I activities were enhanced in LPS-stimulated microglial cells, and these enhancements were significantly suppressed by ANP (10-6 M). These results suggest that ANP inhibits LPS-stimulated activities in microglial cells through activation of microglial ANP receptors, leading to inhibitions of NF-kappa B and AP-1. (c) 2006 Elsevier Inc. All rights reserved.