The effect of the peptide octarphin (TPLVTLFK), a selective agonist of the nonopioid β-endorphin receptor, on the activity of soluble (sGC) and membrane-bound guanylate cyclase (mGC) of peritoneal macrophages from mouse, rat, and guinea pig has been studied. It has been found that, in the concentration range of 10–1000 nM, octarphin increases the activity of sGC and has no effect on the activity of mGC in macrophages of these species. The activating effect of the peptide toward sGC was dose-dependent and was maximal at a concentration of 100 nM. These results indicate that the increase in the concentration of guanosine 3',5'-cyclophosphate in macrophages in the presence of octarphin occurs through the activation of sGC. It can be stated that the activating effect of octarphin on peritoneal macrophages is accomplished in the following way: an increase in the activity of inducible NO synthase → an increase in NO production → activation of sGC → an increase in the intracellular cGMP level.