The neuropeptide somatostatin is an important regulator of hippocampal excitability and several lines of evidence implicate its involvement in temporal lobe epilepsy. In the present study we investigate the anticonvulsive effects of two distinct peptide inhibitors of insulin-regulated aminopeptidase (IRAP), Ang IV and LVV-H7, in the focal pilocarpine model for limbic seizures. Both IRAP inhibitors were administered into the hippocampus of freely moving rats using the microdialysis technique. The anticonvulsive effect of both Ang IV and LVV-H7 was abolished by pretreatment with the somatostatin sst2 receptor antagonist cyanamid 154806. Somatostatin similarly had a potent anticonvulsive effect through activation of the sst2 receptor subtype. Given that somatostatin has been characterized as a substrate of IRAP we hypothesized that IRAP inhibitors may exert their effects through inhibition of somatostatin degradation. We investigated the effects of IRAP inhibitors on extracellular hippocampal somatostatin levels before and after potassium-evoked somatostatin release. We found that both IRAP inhibitors did not affect extracellular hippocampal somatostatin but suppressed potassium-evoked somatostatin release. This suggests that the extracellular concentration of somatostatin is tightly controlled in the hippocampus. Indeed, we found that the sst1 receptor antagonist SRA880 increases extracellular hippocampal somatostatin levels. This demonstrates that the sst1 receptor is an autoreceptor in the hippocampus. We therefore propose that a potential effect of IRAP inhibitors on extracellular hippocampal somatostatin may be counteracted by further activation of the sst1 receptor. The observation that IRAP inhibitors suppressed potassium-evoked somatostatin release further supports the notion of an increased "somatostatin tonus". Further clarification of the mechanism of action of IRAP inhibitors may identify a novel anticonvulsive treatment strategy.