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Abstract: The effect of tachykinin neurokinin NK2 receptors activation on intestinal propulsion and colorectal sensitivity was studied in 7–15days old newborn rats. In a first set of experiments investigating the intestinal transit, the selective NK2 receptor agonist, [βAla8]NKA-(4-10) was used. It produced an increase of the small intestinal transit measured by charcoal test of 54%, that was inhibited in a dose-dependent manner by nepadutant ([N4-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-l-asparaginyl-l-aspartyl-l-tryptophyl-l-phenylalanyl-l-2,3-diaminopropionyl-l-leucyl]-C-4.2-N-3.5-lactam-C-1.6-N-2.1-lactam), a known selective NK2 receptor antagonist, orally administered 2–48h before the challenge with the NK2 receptor agonist. Nepadutant did not affect the basal intestinal propulsion and showed a good oral bioavailability and long duration of action. In another set of experiments investigating visceral sensitivity, a fixed distension volume of a balloon inserted intrarectally in 14–15days old newborns rats produced abdominal contractions (AC) that were increased after colonic application of acetic acid (50μl, 0.5%). In this latter condition nepadutant, at 0.5 and 2.5mg/kg p.o., significantly reduced the resulting AC. In control rats, untreated with acetic acid, nepadutant did not affect AC evoked by colorectal distension. These findings show for the first time two models to assess intestinal motility and visceral sensitivity in newborn rats and indicate nepadutant as a valuable tool to assess the role of NK2 receptors in the intestinal propulsive and nociceptive activity in infants. [Copyright &y& Elsevier]

Abstract: Pseudomonas putida, Aspergillus niger, Bacillus subtilis, Pseudomonas flourescens, Sphingomonas herbicidovorans and Rhodococcus rhodochrous growing on glucose in a medium containing one of three chlorophenoxy acids at a concentration of 0.1gL−1 (clofibric acid, (R)-2-(4-chloro-2-methylphenoxy)propionic acid (mecoprop or MCPP) and 4-chloro-2-methylphenoxyacetic acid (MCPA)) degraded these compounds to varying degrees; from nonmeasurable to almost complete removal. These results with the addition of glucose (2.5gL−1) as an easy to use carbon source indicated the formation of metabolites different from results reported in the literature for growth studies in which the chlorophenoxy acid was the sole carbon source. The metabolite, 4-chloro-2-methylphenol, which had been reported previously, was only observed in trace amounts for MCPP and MCPA in the presence of S. herbicidovorans and glucose. In addition, three other compounds (M1, M3 and M4) were observed. It is suggested that these unidentified metabolites resulted from ring opening of the metabolite 4-choloro-2-methylphenol (M2). The rate of biodegradation of the chlorophenoxy acids was influenced by the degree of steric hindrance adjacent to the internal oxygen bond common to all three compounds. The most hindered compound, clofibric acid, was converted to ethyl clofibrate by R. rhodochrous but was not degraded by any microorganisms studied. The more accessible internal oxygen bonds of the other two chlorophenoxy acids, MCPP and MCPA, were readily broken by S. herbicidovorans. [Copyright &y& Elsevier]

Abstract: The distribution and modification of the tachykinins Substance P (SP) and neurokinin A (NKA), their precursor β-preprotachykinins (β-PPT) and the receptors involved in their activity, NK-1 and NK-2, were studied in trinitrobenzensulphonic acid (TNB) colitis. Rats were intrarectally treated with a 120mg/ml of TNB solution and sacrificed at various times after colitis induction. During the acute phases of colitis, a marked decrease in tissue SP and NKA levels were observed along with an increased transcription of β-PPT mRNA in the neurons of the myenteric plexus and an increased myeloperoxidase activity, which is an index of the tissue’s inflammatory status. De novo expression of both NK1 and NK2 receptor mRNA was observed during the acute phase of TNB-colitis in mesenchymal cells around dilated submucosal vessels but their expression in smooth muscle cells of the muscularis mucosae and propria was moderately down-regulated. The peptide levels, myeloperoxidase activity and gene expression of tachykinin receptors were then restored during the late phases (2–4 weeks after the apten administration) while β-PPT mRNA remained highly expressed in the myenteric plexus ganglia showing that SP and NKA are involved in repair processes. These results point to the enhanced release of tachykinins during the initial phase of colitis and a restoration of this neuropeptide pool in the healing of the tissue. [Copyright &y& Elsevier]