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The present study evaluated the role of nitric oxide in the regulation of duodenal motility and pancreatic exocrine secretion in conscious sheep. Intravenous infusions of nitric oxide synthase inhibitors, Nomega-nitro-L-arginine-methyl ester (L-NAME) and Nomega-nitro-L-arginine, induced clusters of duodenal contractions like phase III of migrating motor complexes and simultaneously inhibited flow rate, bicarbonate ion and enzyme outputs of pancreatic juice. The effects of L-NAME were inhibited by simultaneous infusion of L-arginine, but not altered by adrenergic blockade using a combined infusion of phentolamine and propranolol. Inhibition of the pancreatic secretion occurred in coincidence with initiation of the duodenal contractions, while the pancreatic secretion was not inhibited when the premature duodenal contractions were abolished by the L-arginine infusion. The initiation of the cluster of duodenal contractions by L-NAME was not abolished by background infusion of atropine, whereas the amplitude of contractions was significantly inhibited by atropine. These results suggest that intrinsic nitric oxide plays a crucial role in the regulation of duodenal tone and maintenance of continuous secretion by the exocrine pancreas in sheep. These results also implied that inhibition of pancreatic exocrine secretion by the nitric oxide synthase inhibitor is presumably mediated in part through the contractile effect on the duodenum.

Elution profiles of kynurenic acid (KYNA) and 7-chlorokynurenic acid (Cl-KYNA) were examined by high-performance liquid chromatography (HPLC) using a triazole-bonded stationary phase column (Cosmosil® HILIC) under isocratic elution of a mobile phase consisting of CH3 CN-aqueous 10 mm ammonium formate between pH 3.0 and 6.0. The capacity factors of KYNA and Cl-KYNA varied with both the CH3 CN content and the pH of the mobile phase. The elution order of KYNA and Cl-KYNA was reversed between the CH3 CN- and H2 O-rich mobile phases, suggesting that hydrophilic interactions and anion-exchange interactions caused retention of KYNA and Cl-KYNA in the CH3 CN- and H2 O-rich mobile phases, respectively. The present HPLC method using a triazole-bonded column and fluorescence detection (excitation 250 nm, emission 398 nm) was applied to monitor in vitro production of KYNA from d-kynurenine (d-KYN) by d-amino acid oxidase (DAO) using Cl-KYNA as an internal standard. A single KYNA peak was clearly observed after enzymatic reaction of d-KYN with DAO. Production of KYNA from d-KYN was suppressed by the addition of commercial DAO inhibitors. The present HPLC method can be used to evaluate DAO activity and DAO inhibitory effects in candidate drugs for the treatment of schizophrenia.

Aimsd-Serine (d-Ser), a co-agonist of N-methyl-d-aspartate receptor (NMDAR), is effective for treating schizophrenia. The present study investigated changes in plasma and striatal d-Ser levels in Sprague-Dawley (SD) rats after intraperitoneal d-Ser administration alone or together with nicergoline (Nic), a commercial cerebral ameliorating drug, using in vivo microdialysis (MD) to explore the function of Nic.Main methodsPhosphate-buffered saline (PBS) or Nic (0, 1.0, or 3.0 mg/kg) followed by d-Ser (5.0, 10.0, 20.0, and 50.0 mg/kg for PBS or 20.0 mg/kg for Nic) was administered intraperitoneally to male SD rats, and the profiles of d-Ser levels in plasma and striatal MD samples were examined by high-performance liquid chromatography (HPLC) with fluorescence detection. The area under the curve (AUC) for the MD and plasma samples was also calculated and statistically compared among groups.Key findingsAUC values of d-Ser increased in a d-Ser dose-dependent manner in plasma samples, while a proportional increase in the AUC values of striatal MD samples was only observed in d-Ser doses up to 20 mg/kg. The Nic co-administered group showed a significant increase in the AUC of plasma d-Ser in a Nic dose-dependent manner, but the AUC in striatal d-Ser significantly decreased with increasing Nic doses suggesting that Nic may prevent excess d-Ser from penetrating the central nervous system (CNS).SignificanceNic may prevent an excessive distribution of exogenous d-Ser, such as that from a dietary origin, into the CNS by suppressing excitatory neurotransmission through NMDAR.

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