Somatostatin, acting in a paracrine fashion, is the main inhibitor of gastric acid secretion (GAS). Somatostatin actions are mediated through five different receptors subtypes, termed sst₁ to sst₅, all of which are found in the stomach.

The aim of this study was to investigate the role of the different somatostatin receptor subtypes in the control of GAS in mice, using receptor-selective agonists and antagonists and sst₂ knockout mice.

In urethane (1.25 g kg^-1, I.P.) anaesthetized sst₂ knockout, and wild-type mice (Merck Research Laboratories), GAS was monitored at 10 min intervals by continuous intragastric perfusion with saline (pH 7.0, 36 °C) and backtitration to pH 7.0 with NaOH (0.001 N). The ileal veins were cannulated for I.V. infusion of compounds. The following receptor-selective somatostatin analogues were tested: L-797-591 (sst₁), DC 32-87 (sst₂), BIM-23056 (sst₃), L-803-087 (sst₄) and BIM-23052 (sst₅) (20-200 µg kg^-1, I.V.) (Robrer et al. 1998; Martínez et al. 2000). The effects on GAS of the sst₂ selective antagonist PRL 2903 (1.56 mg kg^-1; Rossowiski et al. 1998) and the in vivo immunoneutralization of somatostatin (somatostatin monoclonal antibody CURE.S6, 150 µg per mouse; CURE:DDRC, UCLA, Los Angeles) were also investigated. Data are means ± S.E.M. and were analysed using Student’s t test or one-way ANOVA, paired or unpaired as appropriate. At the end of the experiments animals were humanely killed accordingly to currently accepted procedures.

In wild-type animals the selective sst₂ agonist DC 32-87 inhibited pentagastrin-stimulated GAS in a dose-dependent manner (27.1 ± 6.3, 37.1 ± 7.1, 53.7 ± 8.8, 57.9 ± 14.3 and 63.7 ± 8.7 % for 1, 5, 10, 15 and 20 µg kg^-1, respectively, n = 5) Somatostatin-14 and DC 32-87 (20 µg kg^-1) inhibited pentagastrin-stimulated GAS with similar efficacy (somatostatin-14: 0.62 ± 0.07 µmol h^-1; DC 32-87: 0.69 ± 0.07 µmol h^-1; both P < 0.05 vs. vehicle: 1.27 ± 0.05 µmol h^-1; n = 4-8). None of the other receptor selective agonists, tested at doses up to 200 µg kg^-1, modified GAS (L-797-591: 1.29 ± 0.05 µmol h^-1; BIM-23056: 1.31 ± 0.12 µmol h^-1; L-803-087: 1.23 ± 0.17 µmol h^-1; BIM-23052: 1.27 ± 0.13 µmol h^-1; vehicle: 1.28 ± 0.16 µmol h^-1, n = 3-6). In sst₂ knockout mice basal GAS was approximately 15-fold higher than in wild-type animals (10.8 ± 1.7 vs. 0.7 ± 0.02 µmol h^-1, respectively; n = 4-5; P < 0.05). Neither somatostatin-14 nor DC 32-87 affected the high GAS observed in knockout mice. In wild-type mice, in vivo immunoneutralization of somatostatin or infusion of the selective sst₂ antagonist PRL 2903 increased basal GAS to 2.01 ± 0.14 µmol h^-1 (n = 5) and 6.1 ± 1.2 µmol h^-1 (n = 4), respectively (P < 0.05 vs. vehicle: 0.54 ± 0.09 µmol h^-1; n = 5). Neither somatostatin immunoneutralizacion nor PRL 2903 affected GAS in the knockout animals.

These results indicate that, in mice, somatostatin inhibits GAS through activation of sst₂ receptors, while other somatostatin receptors subtypes do not seem to play a significant role. Selective agonists and antagonists of sst₂ receptors, as well as sst₂ knockout mice, might be useful tools to characterize the mechanisms of control of gastric acid secretion.

This work was supported by Generalitat Valenciana (GV99-23-1-4).