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The aim of this article is to furnish a brief review of the role played by neurokinins in the inflammatory process. Further attention is given to the mechanisms, as well as to the receptor subtypes involved in neurokinin-mediated inflammation, in an attempt to clarify the participation of neurokinins in different models of acute and chronic inflammation. The involvement of SP, NKA and NKB is also examined in relation to the major signs of inflammation, including edema formation, protein plasma extravasation and vasodilatation. Finally, we provide a general overview on the potential clinical applications of neurokinin antagonists, along with the involvement of neurokinins in human diseases. Copyright 2000 Harcourt Publishers Ltd

Bradykinin (BK), des-Arg9-BK (DABK) and related kinins caused biphasic response (BR) in rat stomach fundus (RSF) precontracted with BaCl2. The B2 receptor antagonist HOE 140 (3-30 nM) produced parallel rightward shifts of the contractile concentration-response curve (CRC) for BK, yielding a pA(2) value of 9.07 +/- 0.27 and slope of 0.99, but caused only discrete rightward shift of the relaxant CRC for BK, leaving the BR CRC to DABK unaffected. The B1 receptor antagonist des-Arg9-NPC 17761 (10 nM to 1 microM) caused graded rightward shifts of the relaxant (but not the contractile) CRC to DABK, yielding a pA2 value of 8.35 +/- 0.05 and slope of 0.59, but had no effect on BK-induced BR. BK- and DABK- (100 nM) induced relaxation were almost suppressed by apamin (1 microM) or by nifedipine (1 nM), but were unaffected by nitric oxide synthase inhibitors, methylene blue, lipo and cyclooxygenase inhibitors, selective receptor antagonist for histamine (H1 and H2), nicotine, platelet activating factor, tachykinins (both NK1 and NK2, calcitonin gene-related peptide, vasoactive intestinal peptide and ganglion blocking agent. BK- and DABK-mediated relaxations were reduced in Ca2+ -free medium plus EGTA, although BK-mediated contraction was more resistant. Escherichia coli endotoxin treatment (10 microgram /rat), 24 hr before, potentiated DABK-induced relaxation, but not contraction, and reduced BK-mediated relaxation (P < .05). It is concluded that RSF express both B1 and B2 receptors. BK-induced contraction involves activation of B2 receptors, although DABK-induced relaxation is mediated by B1 receptors. Both B1 and B2 receptors in RSF are constitutive, but LPS treatment caused induction of B1 and down-regulation of B2 receptors. Finally, kinin-mediated relaxation in RSF are coupled to activation of Ca2+ activated K+ channels, and rely on Ca2+ influx via L-type voltage-sensitive channels.

The antinociceptive effect of the novel xanthoxyline derivative 2-(4-bromobenzoyl)-3-methyl-4-6-dimethoxy benzofuran) (BMDB), given i.p., p.o., s.c., subplantarly, intrathecally or by i.c.v. routes was assessed in five models of chemical and thermal nociception in mice, namely acetic acid-induced abdominal constriction, formalin and capsaicin-induced licking, hot-plate and tail-flick tests. BMDB given by i.p., s.c., subplantarly or by i.c.v. routes elicited dose-related and long-lasting (4 hr) antinociception, but had no significant effect by p.o. route. At the ID50 level, this compound was about 15- to 100-fold more potent than aspirin and acetaminophen, but it was about 2- to 50-fold less potent than morphine. Its analgesic action was not influenced by naloxone, L-arginine, antagonist of alpha-1 adrenoceptor, prazosin, tau -aminobutyric acid (B) antagonist, phaclofen, after adrenalectomy, but was reversed in part by p-chlorophenylalanine methyl ester. Its analgesic action was not secondary to an anti-inflammatory effect, or was it associated with nonspecific effect such as muscle relaxant or sedative actions of animals. We conclude that BMDB produces dose-dependent spinal and supraspinal antinociception as evaluated in several algesic models in mice, including the neurogenic nociception responses induced by formalin and capsaicin. Its antinociceptive effect was insensitive to naloxone, suggesting the lack of involvement of endogenous opioid, was not modulated by adrenal glands and does not involve interaction with the L-arginine-nitric oxide pathway, activation of alpha-1 adrenoceptors or tau-aminobutyric acidB receptors, but requires, at least in part, the serotoninergic pathway.

This study investigates the mechanisms involved in kinin-induced contractions in rings of rat portal vein (RPV). Bradykinin (BK), Lys-BK, Met-Lys-BK, Tyr8-BK (TBK) and des-Arg9-BK (DABK) all caused graded contractions in RPV, with the following order of potency (EC50, nanomolar): Met-Lys-BK (0.3) > Lys-BK (0.5) > BK (0.9) > TBK (2.3) > DABK (46.0). The potency of DABK and maximal contractions for DABK and BK, but not for TBK or NE, increased as a function of in vitro incubation period, reaching the maximum at 4.5 hr. Cycloheximide (a protein synthesis inhibitor, 70 microM), incubated for 4.5 hr, inhibited almost completely the CRCs for DABK and blocked the latter phase of CRCs for BK, not altering contractions induced by U46619 (9,11-dideoxy-9 alpha, 11 alpha-methano-epoxy prostaglandin F2 alpha) (a thromboxane A2/prostaglandin H2-mimetic). Incubation of RPV with D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (HOE 140, a selective B2 receptor antagonist, 0.01-100 nM), caused a parallel rightward displacement of the BK and TBK concentration-response curves (CRCs). Schild plots were linear, yielding pA2 values of 11.4 and 9.3, respectively. The slope for HOE 140 against TBK-induced contractions did not differ from unity (1.23 +/- 0.21), whereas against BK was significantly lesser than unity (0.72 +/- 0.20). The CRCs induced by DABK were not affected by HOE 140 (100 nM). In addition, the CRCs for DABK at 4.5 hr were shifted to the right in a parallel form in the presence of des-Arg9-[Leu8]-BK (a selective B1-receptor antagonist, 1 microM), yielding a pA2 value of 6.7.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of central injection of selective kinin B1and B2receptor antagonists on the febrile response induced by endotoxin (E. colilipopolysaccharide, LPS) in rats was investigated.Intracerebroventricular (i.c.v.) injection of a selective B2receptor antagonist (Hoe‐140, 8 nmol) reduced the early (0–2 h), but increased the late phase (4–6 h) of the febrile response induced by intravenous (i.v.) injection of LPS (0.5 μg kg−1).Co‐administration of Hoe‐140 (8 nmol, i.c.v.) with LPS (0.5 μg kg−1, i.v.), followed 2.5 h later by the i.c.v. injection of a selective B1receptor antagonist [des‐Arg9‐Leu8]‐bradykinin (BK, 8 nmol), significantly reduced the febrile response induced by LPS throughout the whole experimental period.Intravenous injection of Hoe‐140 (1 mg kg−1) significantly reduced the febrile response induced by LPS (0.5 μg kg−1, i.p.).Pretreatment (24 h) with LPS (0.5 μg kg−1, i.v.) reduced the febrile response induced by BK or [Tyr8]‐BK (both, 5 nmol, i.c.v.), but markedly increased the febrile response induced by [des‐Arg9]‐BK (5 nmol, i.c.v.). The response induced by [des‐Arg9]‐BK in LPS‐pretreated rats was significantly inhibited by co‐injection of [des‐Arg9‐Leu8]‐BK (15 nmol, i.c.v.).The results suggest that kinins are involved in the induction of LPS‐induced fever and that central B2and B1receptors are activated during the initial and late phase of this response, respectively. The results also suggest that downregulation and/or desensitization of B2receptors and induction and/or upregulation of B1receptors in LPS‐pretreated animals may have a significant pathophysiologcal role in the induction and maintenance of fever. These observations may be specifically important in the case of chronic inflammatory conditions, because the BK metabolite [des‐Arg9]‐BK, so far considered an inactive metabolite, acquires an active and relevant role with the progressive expression of B1receptors that occurs in such states.

The mechanisms underlying the biphasic response (BR) of the circular muscle of the guinea pig ileum (CMGPI) to bradykinin (BK) have been examined. Both BK and lysyl-BK (1 nM to 1 microM) caused graded contractions followed by relaxations of the CMGPI, yielding EC50 of 21 and 92 nM for contraction and of 10 and 27 nM for relaxation, respectively. The selective B1 receptor agonist Des-Arg9-BK was without effect up to 3 microM. The potencies of BK and lysyl-BK to evoke BR were markedly increased by enalapril (3 microM) and decreased by raising the preparation tone with the thromboxane A2/prostaglandin H2-mimetic U46619 (30 ng/ml). The BR of CMGPI to BK was unaffected by atropine, yohimbine, pyrilamine, propranolol, prazosin, phorbol ester, des-Arg9-[leu8]-BK (1 microM, each), tetrodotoxin (0.3 microM), [3,4,5-trimethoxybenzoic acid-8-(diethylamino) octyl ester (10 microM), [N-6-(aminohexyl)-5-chloro-1-naphthalenosulfonamide (10 microM), glibenclamide (0.3 microM), nordihydroguaiaretic acid (50 microM), phenidone (30 microM) or dexamethasone (0.1 microM). However, indomethacin (3 microM), ibuprofen (30 microM) and 3-amino, 1-(m-[trifluoromethyl] phenyl)2-pyrazoline (10 microM) each abolished the relaxant and increased the contractile response to BK, suggesting that a cyclo-oxygenase-derived eicosanoid mediates relaxation and limits contraction. Prostaglandin (PG) E2 (up to 100 nM) caused only graded relaxations, PGF2 alpha (up to 3 microM) and 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F2 alpha (up to 300 ng/ml) caused only contractions and the PGI2 analog iloprost was without effect up to 1 micrograms/ml.(ABSTRACT TRUNCATED AT 250 WORDS)