A protein toxin synthesized by the bacterium Bordetella pertussis has the unique property of blocking a number of receptor-mediated inhibitory systems which are linked to adenylate cyclase. We found that pertussis toxin (PT) eliminates the ability of somatostatin to reduce both basal and GH-releasing factor-stimulated GH release in primary cultures of rat pituitary cells. Furthermore, the ability of somatostatin to reduce GH-releasing factor-induced cAMP accumulation in the cells is significantly attenuated after PT treatment. The PT effect, which is dose dependent and prevented by pretreatment with anti-PT antibodies, represents an alteration in somatostatin efficacy rather than potency. The modification of somatostatin responsiveness persists for at least 5 days after toxin removal. The PT actions on the somatotroph are similar to the effects on other eukaryotic cell types. The combination of available data indicates that the toxin acts on a highly conserved component(s) that is obligatory for transducing the inhibitory hormone message into the cell.