Antropyloroduodenal motility was recorded in seven anesthetized dogs to assess the role of nitric oxide and L-arginine metabolites in nonadrenergic noncholinergic (NANC) mediation of pyloric relaxation. Pyloric activity induced by duodenal field stimulation was inhibited by antral field stimulation and electrical vagal stimulation. Intra-arterial NG-L-arginine-methyl-ester (L-NAME) reduced the inhibition from antral or vagal stimulation (P less than 0.05). Intravenous infusion of L-NAME also blocked the inhibitory effect of vagal and antral stimulation but left the tetrodotoxin-insensitive action of intra-arterial vasoactive intestinal peptide (VIP) and sodium nitroprusside unchanged. L-Arginine reversed the effect of L-NAME whereas D-arginine did not. L-NAME enhanced pyloric contractions to intra-arterial acetylcholine. The NANC inhibition of the substance P-stimulated pyloric response in vitro was blocked by L-NAME and reversed by addition of L-arginine. Sodium nitroprusside was effective as a relaxant in vitro but VIP was not. These data suggest that metabolites of L-arginine mediate neural inhibition of canine pyloric motor activity.

The aim of this study was to investigate the mechanism of action of somatostatin on the circular muscle of the isolated canine ileum using the microelectrode technique. The membrane potential from circular muscle cells was recorded in two preparations: 1) whole thickness circular and longitudinal muscle (with intact myenteric and deep muscular plexuses, n = 13) and 2) isolated circular muscle (with only deep muscular plexus, n = 9). In this preparation, inhibitory junction potentials (IJPs), elicited after field stimulation, are mediated by a nitric oxide-related (NO-R) compound. Somatostatin (10(-6) M) transiently (2-5 min) depolarized the circular muscle cells in both whole thickness (3.6 +/- 1.0 mV, P < 0.01) and isolated circular muscle preparations (8.0 +/- 0.8 mV, P < 0.01). Somatostatin did not reduce either the amplitude or duration of the IJP in the isolated circular muscle but reduced slow-wave amplitude. In contrast, a reduction (20-50%) in the amplitude of the IJP was observed in the whole thickness preparation, and there was little effect on slow-wave amplitude. Somatostatin did not affect the induced slow wave observed in the whole thickness preparation after field stimulation. Apamin significantly reduced the amplitude of the IJP in both preparations. Somatostatin (10(-6) M) did not modify the apamin-resistant IJP. A reduction in the slow-wave amplitude was observed in the isolated circular muscle preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

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Isolated perfused segments of canine ileum have no spontaneous motor activity and release large quantities of vasoactive intestinal polypeptide (VIP) continuously. Somatostatin perfusion was shown to decrease VIP release, accompanied by increased contractions and amplification of responses to low-frequency electrical field stimulation. After perfusion of higher somatostatin concentrations, the VIP output did not recover but quiescence returned. The actions of somatostatin on motor activity were not modified by hexamethonium, slightly reduced by atropine, and markedly reduced by tetrodotoxin. Inhibition of VIP output was not the major determinant of motor activity in the ileum because 1) a second infusion of somatostatin had similar motor effects despite markedly reduced VIP output, 2) abolition of tonic VIP output did not prevent induction of motor activity by somatostatin, and 3) artificial restoration of VIP levels did not prevent or antagonize somatostatin-induced ileal contractions. In contrast, the increment in motor responses induced by somatostatin was not apparent after N omega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide (NO) synthase, but recovered after reversal by L-arginine. We conclude that the mode of somatostatin activation of intestinal motor activity involves reduced NO output, enhanced excitatory mediator action or release, a direct action on smooth muscle, and possibly inhibition of VIP output. Of these, reduced NO output plays the most important role.

Mast cells (MCs) are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, and cancer, among others. MCs identify microorganisms by pattern recognition receptors (PRRs), activating a secretory response. Interleukin (IL)-10 has been described as an important modulator of MC responses; however, its role in PRR-mediated activation of MC is not fully understood. We analyzed the activation of TLR2, TLR4, TLR7 and Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in mucosal-like MCs (MLMCs) and peritoneum-derived cultured MCs (PCMCs) from IL-10−/− and wild-type (WT) mice. IL-10−/− mice showed a reduced expression of TLR4 and NOD2 at week 6 and TLR7 at week 20 in MLMC. In MLMC and PCMC, TLR2 activation induced a reduced secretion of IL-6 and TNFα in IL-10−/− MCs. TLR4- and TLR7-mediated secretion of IL-6 and TNFα was not detected in PCMCs. Finally, no cytokine release was induced by NOD2 ligand, and responses to TLR2 and TLR4 were lower in MCs at 20 weeks. These findings indicate that PRR activation in MCs depends on the phenotype, ligand, age, and IL-10.