To obtain a clearer understanding of the mechanisms by which somatostatin modulates stimulus-secretion coupling in neuroendocrine cells, we investigated the pharmacology of the somatostatin-activated inward rectifier in mouse pituitary tumour cells (AtT-20 corticotrophs). Individual AtT-20 cells displayed spontaneous, long-lasting action potentials that caused transient spikes in cytosolic [Ca2+] ([Ca]i). Application of 1–10 nM somatostatin led to membrane hyperpolarization and loss of [Ca]i spiking activity. Voltage-clamp recordings revealed that the somatostatin-induced hyperpolarization was due to an inwardly rectifying K+ current. Tetrabutylammonium (TBA+) inhibited both outward and inward currents through the inward rectifier, whereas Cs+ blocked only inward current and tetraethylammonium (TEA+) was completely ineffective in blocking somatostatin-activated currents. However TEA+, but neither TBA+ nor Cs+, blocked voltage-gated outward currents. Correspondingly, TBA+ abolished the hyperpolarizing effects of somatostatin and, of the three K+ channel blockers, only TBA+ prevented the somatostatin-induced inhibition of [Ca]i spiking. TBA+ may thus prove a useful tool in elucidating the underlying mechanisms by which somatostatin affects the secretory activity of neuroendocrine cells.