The reported loss of somatostatin-14 (S-14)-like immunoreactivity (LI) by cysteamine (CSH) could be mediated through an action on the S-14 disulfide bond. If so, then in the case of somatostatin-28 (S-28) (a linear 14 amino acid N-terminally extended form of S-14), it should be possible to demonstrate with region-specific antisera, a selective effect of CSH on the disulfide bond containing C-terminal half of the molecule. To obtain evidence for this, we have determined by RIAs, the effect of CSH on S-28 concentration measured separately as S-28(15-28) LI and S-28(1-14) LI in the jejunal mucosa, a tissue rich in S-28. Four hours after a single sc injection of CSH to rats, mucosal S-28(15-28) LI was reduced from 16.4 +/- 0.6 to 4.6 +/- 0.51 pmol/mg protein (P less than 0.01). By contrast, S-28(1-14) LI sustained no loss and in fact increased from 27.6 +/- 1.9 to 41.6 +/- 2.2 pmol/mg protein (P less than 0.01). On Sephadex G-50 columns (in 6 M urea) approximately 70% of S-28(15-28) LI and S-28(1-14) LI coeluted with synthetic S-28 marker. These data suggest that CSH acts on the 15-28 segment of the S-28 molecule and renders it nonimmunoreactive probably through interaction with the disulfide bond. This mechanism probably also accounts for CSH-induced S-14 loss.