Somatostatin (SRIF) exerts anti-inflammatory effects, in part by deactivating monocytes/macrophages. Thus, the objective of this study was to characterize specific receptors for SRIF on these cells. Macrophages isolated from mouse peritoneal cells bound [125I]Tyr(0), D-Trp(8) SRIF(14) specifically. Scatchard analysis of saturation binding data revealed two classes of binding sites with an affinity of 0.44+/-0.13 and 2.58+/-0.56 nM, respectively. By sensitive and specific RT-PCR, the mRNAs for the five SRIF receptors (SSTR1 to SSTR5) could be detected. Evidence for the involvement of SSTR1 and SSTR2 in the binding of SRIF to the high and low affinity sites, respectively, was obtained by the demonstration that (1) only SSTR1 and SSTR2 subtype-specific agonists were active in competing for [125I]Tyr(0), D-Trp(8) SRIF(14) binding to high and low affinity sites, respectively, and (2) [125I]Tyr(0), D-Trp(8) SRIF(14) bound to high but not low affinity sites on macrophages isolated from SSTR2 knock-out mice. In conclusion, we have identified and characterized two different SRIF receptor subtypes in murine macrophages.