Synthesis and antibacterial activity of nitro-furylvinylquinazolinones

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Up-regulation of brain-derived neurotrophic factor in primary afferent pathway regulates colon-to-bladder cross-sensitization in rat

Background In humans, inflammation of either the urinary bladder or the distal colon often results in sensory cross-sensitization between these organs. Limited information is known about the mechanisms underlying this clinical syndrome. Studies with animal models have demonstrated that activation of primary afferent pathways may have a role in mediating viscero-visceral cross-organ sensitization. Methods Colonic inflammation was induced by a single dose of tri-nitrobenzene sulfonic acid (TNBS) instilled intracolonically. The histology of the colon and the urinary bladder was examined by hematoxylin and eosin (H&E) stain. The protein expression of transient receptor potential (TRP) ion channel of the vanilloid type 1 (TRPV1) and brain-derived neurotrophic factor (BDNF) were examined by immunohistochemistry and/or western blot. The inter-micturition intervals and the quantity of urine voided were obtained from analysis of cystometrograms. Results At 3 days post TNBS treatment, the protein level of TRPV1 was increased by 2-fold (p \u3c 0.05) in the inflamed distal colon when examined with western blot. TRPV1 was mainly expressed in the axonal terminals in submucosal area of the distal colon, and was co-localized with the neural marker PGP9.5. In sensory neurons in the dorsal root ganglia (DRG), BDNF expression was augmented by colonic inflammation examined in the L1 DRG, and was expressed in TRPV1 positive neurons. The elevated level of BDNF in L1 DRG by colonic inflammation was blunted by prolonged pre-treatment of the animals with the neurotoxin resiniferatoxin (RTX). Colonic inflammation did not alter either the morphology of the urinary bladder or the expression level of TRPV1 in this viscus. However, colonic inflammation decreased the inter-micturition intervals and decreased the quantities of urine voided. The increased bladder activity by colonic inflammation was attenuated by prolonged intraluminal treatment with RTX or treatment with intrathecal BDNF neutralizing antibody. Conclusion Acute colonic inflammation increases bladder activity without affecting bladder morphology. Primary afferent-mediated BDNF up-regulation in the sensory neurons regulates, at least in part, the bladder activity during colonic inflammation

Effects of chloride channel blockers on hypotonicity-induced contractions of the rat trachea

1. We have investigated the inhibitory effects of blockers of volume-activated (Cl(vol)) and calcium-activated (Cl(Ca)) chloride channels on hypotonic solution (HS)-induced contractions of rat trachea, comparing their effects with those of the voltage-dependent calcium channel (VDCC) blocker nifedpine. 2. HS elicited large, stable contractions that were partially dependent on the cellular chloride gradient; a reduction to 41.45±7.71% of the control response was obtained when extracellular chloride was removed. In addition, HS-induced responses were reduced to 26.8±5.6% of the control by 1 μM nifedipine, and abolished under calcium-free conditions, indicating a substantial requirement for extracellular calcium entry, principally via VDCCs. 3. The established Cl(vol) blockers tamoxifen (⩽10 μM) and 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid (1–100 μM), at concentrations previously reported to inhibit Cl(vol) in smooth muscle, did not significantly inhibit HS-induced contractions. 4. In contrast, the recognized Cl(Ca) blocker niflumic acid (NFA; 1–100 μM) produced a reversible, concentration-dependent inhibition of HS responses, with a reduction to 36.6±6.4% of control contractions at the highest concentration. The mixed Cl(vol) and Cl(Ca) blocker, 5-nitro 2-(3-phenylpropylamine) benzoic acid (NPPB; 10–100 μM) also elicited concentration-related inhibition of HS-induced contractions, producing a decrease to 35.9±11.3% of the control at 100 μM. 5. Our results show that HS induces reversible, chloride-dependent contractions of rat isolated trachea that were inhibited by NFA and NPPB, while exhibiting little sensitivity to recognized blockers of Cl(vol). The data support the possibility that opening of calcium-activated chloride channels under hypotonic conditions in respiratory smooth muscle may ultimately lead to VDCC-mediated calcium entry and contraction