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Background and Purpose: Bradykinin, through the kinin B₂ receptor, is involved in inflammatory processes related to arthropathies. B₂ receptor antagonists inhibited carrageenan-induced arthritis in rats in synergy with anti-inflammatory steroids. The mechanism(s) underlying this drug interaction was investigated.Experimental Approach: Drugs inhibiting inflammatory mediators released by carrageenan were injected, alone or in combination, into the knee joint of pentobarbital anaesthetized rats 30 min before intra-articular administration of carrageenan. Their effects on the carrageenan-induced inflammatory responses (joint pain, oedema and neutrophil recruitment) and release of inflammatory mediators (prostaglandins, IL-1β, IL-6 and the chemokine GRO/CINC-1), were assessed after 6 h.Key Results: The combination of fasitibant chloride (MEN16132) and dexamethasone was more effective than each drug administered alone in inhibiting knee joint inflammation and release of inflammatory mediators. Fasitibant chloride, MK571, atenolol, des-Arg⁹-[Leu⁸]-bradykinin (B₂ receptor, leukotriene, catecholamine and B₁ receptor antagonists, respectively) and dexketoprofen (COX inhibitor), reduced joint pain and, except for the latter, also diminished joint oedema. A combination of drugs inhibiting joint pain (fasitibant chloride, des-Arg⁹-[Leu⁸]-bradykinin, dexketoprofen, MK571 and atenolol) and oedema (fasitibant chloride, des-Arg⁹-[Leu⁸]-bradykinin, MK571 and atenolol) abolished the respective inflammatory response, producing inhibition comparable with that achieved with the combination of fasitibant chloride and dexamethasone. MK571 alone was able to block neutrophil recruitment.Conclusions and Implications: Bradykinin-mediated inflammatory responses to intra-articular carrageenan were not controlled by steroids, which were not capable of preventing bradykinin effects either by direct activation of the B₂ receptor, or through the indirect effects mediated by release of eicosanoids and cytokines. [ABSTRACT FROM AUTHOR]

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: 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]

1 The effect of montelukast or MEN91507, selective leucotriene CysLT1 receptor antagonists, on antigen-induced airway inflammation and bronchoconstriction were compared in anaesthetized guinea-pigs. 2 In sensitized animals, ovalbumin (0.3 mg kg−1, i.v.)-induced microvascular leakage in trachea, intrapulmonary airways, total lung (parenchyma and intrapulmonary airways) and urinary bladder was reduced by MEN91507 (0.01–1 μmol kg−1, i.v.), whereas montelukast (0.01–1 μmol kg−1, i.v.) antagonized the effect of the antigen only in the lung and urinary bladder. 3 Ovalbumin (1 mg kg−1, i.v.)-induced bronchoconstriction was dose dependently antagonized by MEN91507 (10–30 μmol kg−1, i.v.), whereas the effect of montelukast (0.1–30 μmol kg−1, i.v.) was marginal (15–30% inhibition). Neither MEN91507 nor montelukast (30 μmol kg−1, i.v.) affected the bronchoconstrictor response induced by acetylcholine (0.3 μmol kg−1, i.v.) in sensitized animals. 4 It is concluded that montelukast and MEN91507 display a differential activity against the effect of endogenous leucotrienes, despite the fact that both compounds show a similar antagonist profile against exogenous leucotrienes acting through CysLT1 receptors. [ABSTRACT FROM AUTHOR]

In isolated strips of the hamster urinary bladder the selective tachykinin NK2 receptor agonist [βAla8]NKA(4–10) induced a concentration-dependent (1 nM-10 µM) contraction (EC50 104 nM) associated with significant release of prostaglandin E2 (PGE2, 50±17 pg/mg tissue). In mucosa-free bladder strips [βAla8]NKA(4–10) was as potent as in the presence of mucosa (EC50 46 nM), although the evoked PGE2 release was significantly less than in controls (6±1.7 pg/mg tissue). Dexketoprofen (10 µM) produced a significant but limited rightward shift of the concentration/response curve to [βAla8]NKA(4–10) both in the presence and absence of the mucosal layer: the EC50 for [βAla8]NKA(4–10) was increased five- and threefold, respectively. The evoked PGE2 release was abolished in both cases. The selective tachykinin NK2 receptor antagonist, nepadutant (10 nM–1 µM) produced a concentration-dependent and even inhibition of both contraction and PGE2 release induced by [βAla8]NKA(4–10). The L-type calcium channel blocker, nifedipine (1 µM) and the non-selective cationic channel blocker SKF 96365 (30 µM) both inhibited the contractile response to [βAla8]NKA(4–10) (89±2 and 83±2% inhibition, respectively). The evoked PGE2 release was not affected by nifedipine but was almost abolished by SKF 96365. Arachidonic acid (100 µM) induced a contractile response (5.9±0.7 mN) associated with a large production of PGE2 (383±78 pg/mg tissue). The contractile response to arachidonic acid was inhibited by both nifedipine (1 µM) and SKF 96365 (30 µM) (83±5 and 79±3% inhibition, respectively). The PGE2 production induced by arachidonic acid was markedly inhibited by SKF 96365 only (about 94% inhibition). Exogenous PGE2 contracted hamster bladder strips in the presence of dexketoprofen (EC50 1 µM) and strongly potentiated the contractile response to a submaximal concentration of [βAla8]NKA(4–10). In anaesthetized hamsters the administration of [βAla8]NKA(4–10) (10 nmol/kg, i.v.) produced a contractile response of the urinary bladder (13±0.4 mmHg) that was inhibited partly by dexketoprofen (25±3 and 35±4% inhibition for 0.2 and 2 mg/kg, i.v. dexketoprofen, respectively). We conclude that activation of tachykinin NK2 receptors determines prostanoid synthesis/release in the hamster urinary bladder and that this effect is largely ascribable to structures present in the bladder mucosa. Prostanoids generated following NK2 receptor activation amplify the direct contractile effect of NK2 receptor agonists. This latter response is largely due to activation of L-type calcium channels (nifedipine-sensitive) although this source of calcium apparently is not essential for activation of prostanoid synthesis. [ABSTRACT FROM AUTHOR]

Chemical stimulation of primary afferent nerves in the rat urinary bladder in vivo with topical capsaicin (1 µg in 50 µl saline) determines a dual motor response, consisting of a contractile effect mediated by tachykinins released from sensory nerves in the bladder wall and a transient activation of a bladder-to-bladder micturition reflex organized at the supraspinal level (chemoceptive micturition reflex). Both responses undergo complete desensitization upon repeated applications of capsaicin. The i.v. administration of the novel neuropeptide nociceptin (100 nmol/kg) produced a long-lasting protection from capsaicin desensitization of afferent nerves which mediate the chemoceptive micturition reflex. In fact a chemoceptive micturition reflex could be repeatedly evoked by topical capsaicin in nociceptin-pretreated rats. In sharp contrast, nociceptin did not influence the development of desensitization of the local response to capsaicin, corresponding to the 'efferent' function of capsaicin-sensitive afferent neurons. These results suggest that the afferent and 'efferent' function of capsaicin-sensitive primary afferent neurons (CSPANs) in the rat bladder are differentiated by nociceptin. Alternative mechanisms underlying this phenomenon are discussed. [ABSTRACT FROM AUTHOR]