To determine whether hypothalamic somatostatin (SRIF) release might be modulated by a negative feedback loop, we examined the effects of exogenous SRIF on the release of SRIF immunoreactivity from dispersed adult rat hypothalamic cells. Added SRIF-(1-14) caused dose-dependent inhibition of endogenous SRIF release in this system (IC50, 140 pM). SRIF-(1-28) and Tyr1-SRIF also inhibited SRIF release, whereas other peptides present in the hypothalamus were without demonstrable effects when tested at a concentration of 100 pM. Ala9-SRIF, a SRIF analog with reduced bio- and immunoreactivities, had no effect on SRIF release at concentrations as high as 1 nM. SRIF release from hypothalamic cells increased with lengthening periods of incubation from 1-3 h, but the increase was not linear in nature. Likewise, when hypothalamic cell density in the incubation medium was increased, less than the expected increment in SRIF release was observed. Conversely, when the incubation volume was increased and cell density was reduced, an increment in SRIF release was observed. These data demonstrate that SRIF when added at physiologically relevant concentrations inhibited endogenous SRIF release, confirming the presence of an ultrashort loop feedback effect at a hypothalamic level. Our observations also suggest that endogenous SRIF may modulate and inhibit its own release. These findings may be of physiological relevance in the control of the hypothalamic-somatotropic axis.