kallidin and Inflammation

The plasma contact system contributes to thrombosis in experimental models. Even though our standard blood coagulation tests are prolonged when plasma lacks contact factors, this enzyme system appears to have a minor (if any) role in hemostasis. In this review, we explore the clinical phenotype of C1 esterase inhibitor (C1-INH) deficiency. C1-INH is the key plasma inhibitor of the contact system enzymes, and its deficiency causes hereditary angioedema (HAE). This inflammatory disorder is characterized by recurrent aggressive attacks of tissue swelling that occur at unpredictable locations throughout the body. Bradykinin, which is considered to be a byproduct of the plasma contact system during in vitro coagulation, is the main disease mediator in HAE. Surprisingly, there is little evidence for thrombotic events in HAE patients, suggesting mechanistic uncoupling from the intrinsic pathway of coagulation. In addition, it is questionable whether a surface is responsible for contact system activation in HAE. In this review, we discuss the clinical phenotype, disease modifiers and diagnostic challenges of HAE. We subsequently describe the underlying biochemical mechanisms and contributing disease mediators. Furthermore, we review three types of HAE that are not caused by C1-INH inhibitor deficiency. Finally, we propose a central enzymatic axis that we hypothesize to be responsible for bradykinin production in health and disease.

Topics: Age of Onset; Angioedemas, Hereditary; Blood Coagulation; Bradykinin; Capillary Permeability; Complement Activation; Complement C1 Inhibitor Protein; Factor XIIa; Female; Hereditary Angioedema Types I and II; Humans; Inflammation; Kallidin; Kallikreins; Kininogen, High-Molecular-Weight; Male; Models, Biological; Phenotype; Polyphosphates; Serine Proteinase Inhibitors

The kinin B(1) receptor plays an important role in mediating the inflammatory effects of the kallikrein-kinin pathway. The recent development of orally available non-peptidic antagonists and genetically modified mice deficient in B(1) receptor expression have demonstrated that the receptor plays a pivotal role in the cellular, particularly neutrophil, recruitment associated with an acute inflammatory response. These tools have also enabled elucidation of the pathways involved in mediating this effect and have highlighted a major role for chemokines, particularly CXCL5 and CCL2. Neutrophil recruitment is involved in the pathogenesis of renal disease and has very recently been implicated in the early stages of atherosclerosis. In this review we discuss the most recent evidence linking the B(1) receptor with the pathogenesis of these two inflammatory cardiovascular diseases and highlight the therapeutic potential of the kinin B(1) receptor in these disease states.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Bradykinin; Bradykinin B1 Receptor Antagonists; Cardiovascular Diseases; Drug Delivery Systems; Humans; Inflammation; Inflammation Mediators; Kallidin; Kidney Diseases; Neutrophil Infiltration; Receptor, Bradykinin B1

Kinins, including bradykinin and kallidin, are peptides that are produced and act at the site of tissue injury or inflammation. They induce a variety of effects via the activation of specific B1 or B2 receptors that are coupled to a number of biochemical transduction mechanisms. In the periphery the actions of kinins include vasodilatation, increased vascular permeability and the stimulation of immune cells and peptide-containing sensory neurones to induce pain and a number of neuropeptide-induced reflexes. Mechanisms for kinin synthesis are also present in the CNS where kinins are likely to initiate a similar cascade of events, including an increase in blood flow and plasma leakage. Kinins are potent stimulators of neural and neuroglial tissues to induce the synthesis and release of other pro-inflammatory mediators such as prostanoids and cytotoxins (cytokines, free radicals, nitric oxide). These events lead to neural tissue damage as well as long lasting disturbances in blood-brain barrier function. Animal models for CNS trauma and ischaemia show that increases in kinin activity can be reversed either by kinin receptor antagonists or by the inhibition of kinin production. A number of other central actions have been attributed to kinins including an effect on pain signalling, both within the brain (which may be related to vascular headache) and within the spinal dorsal horn where primary afferent nociceptors can be stimulated. Kinins also appear to play a role in cardiovascular regulation especially during chronic spontaneous hypertension. Presently, however, direct evidence is lacking for the release of kinins in pathophysiological conditions of the CNS and it is not known whether spinal or central neurones, other than afferent nerve terminals, are sensitive to kinins. A more detailed examination of the effects of kinins and their central pharmacology is necessary. It is also important to determine whether the inhibition of kinin activity will alleviate CNS inflammation and whether kinin receptor antagonists are useful in pathological conditions of the CNS.

Topics: Amino Acid Sequence; Animals; Behavior, Animal; Bradykinin; Cardiovascular Physiological Phenomena; Humans; Inflammation; Kallidin; Kinins; Models, Biological; Molecular Sequence Data; Nervous System Physiological Phenomena; Pain; Rats; Receptors, Bradykinin; Vasomotor System; Wounds and Injuries

Topics: alpha-Macroglobulins; Bradykinin; Glycoproteins; Inflammation; Kallidin; Kallikreins; Kininogens; Kinins; Lysine Carboxypeptidase; Peptidyl-Dipeptidase A; Protease Inhibitors

Topics: Angioedema; Animals; Blood Vessels; Bradykinin; Capillary Permeability; Dilatation; Diuresis; Female; Gout; Humans; Hypertension; Inflammation; Kallidin; Kallikreins; Kinins; Labor, Obstetric; Malignant Carcinoid Syndrome; Muscle, Smooth; Pregnancy; Rats; Salivary Glands; Shock; Synovial Fluid

Topics: Anaphylaxis; Angioedema; Arthritis; Bradykinin; Burns; Dumping Syndrome; Half-Life; Humans; Inflammation; Kallidin; Kallikreins; Kinins; Malignant Carcinoid Syndrome; Pancreatitis; Shock; Shock, Septic; Vascular Diseases

Topics: Animals; Bradykinin; Fibrinolysin; Humans; Inflammation; Kallidin; Kallikreins; Kinins; Peptide Hydrolases; Peptides

Topics: Analgesics; Animals; Aspirin; Body Temperature Regulation; Bradykinin; Humans; Hydrocortisone; Hypothalamus; Inflammation; Kallidin; Kallikreins; Oxidative Phosphorylation; Peptide Hydrolases; Peripheral Nerves; Receptors, Drug

To further define the role of neural responses in the hyperreactivity of inflamed human upper airways to bradykinin (BK), we determined if repeated challenges with BK led to tachyphylaxis of neurally mediated responses in subjects with perennial allergic rhinitis. We also tested the hypothesis that enhanced reactivity to kinins in inflamed airways was caused by induction of B1-kinin receptors by comparing the effects of the selective B1-receptor agonist, des-Arg10-lysylbradykinin, and the B2 receptor agonist, BK, in the lower airways of asthmatics and in the upper airways of subjects with perennial allergic rhinitis. Repeated BK challenges led to tachyphylaxis of sneezing and of neurally mediated serous glandular secretion in subjects with perennial allergic rhinitis. Surprisingly, tachyphylaxis of increased local vascular permeability was also observed. By contrast, repeated challenges with BK in normal subjects led to reproducible increases in vascular permeability. Provocation with des-Arg10-lysylbradykinin did not cause bronchoconstriction in asthmatic subjects or increase glandular secretion or vascular permeability in the upper airways of subjects with rhinitis. We conclude that increased reactivity to kinins in inflamed human airways is mediated, at least in part, by neural reflexes, and is not caused by induction of B1-receptors.

Topics: Asthma; Bronchi; Bronchial Provocation Tests; Bronchoconstriction; Capillary Permeability; Cross-Over Studies; Double-Blind Method; Female; Follow-Up Studies; Humans; Inflammation; Kallidin; Kinins; Male; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Reflex; Rhinitis, Allergic, Perennial; Tachyphylaxis

Kinins are pro-inflammatory peptides that mimic the cardinal features of inflammation. We examined the concept that expression levels of endothelial intercellular adhesion molecule-1 (ICAM-1) and neutrophil integrins Mac-1 and LFA-1 are modulated by the kinin B1 receptor (B1R) agonist, Lys-des[Arg(9)]bradykinin (LDBK). Stimulation of endothelial cells with LDBK increased the levels of ICAM-1 mRNA transcripts/protein, and also of E-selectin and platelet endothelial adhesion molecule-1. ICAM-1 levels increased in a magnitude comparable with that produced by TNF-α. This stimulatory effect was reduced when endothelial cells, which had been previously transfected with a B1R small interfering RNA, were stimulated with LDBK, under comparable conditions. Similarly, LDBK produced a significant increase in protein levels of LFA-1 and Mac-1 integrins in human neutrophils, an effect that was reversed by pretreatment of cells with 10 µg/ml cycloheximide or a B1R antagonist. Functional experiments performed with post-confluent monolayers of endothelial cells stimulated with LDBK and neutrophils primed with TNF-α, and vice versa, resulted in enhanced adhesiveness between both cells. Neutralizing Abs to ICAM-1 and Mac-1 reduced the adhesion between them. Our results indicate that kinin B1R is a novel modulator that promotes adhesion of leukocytes to endothelial cells, critically enhancing the movement of neutrophils from the circulation to sites of inflammation.

Topics: Cell Adhesion; Cell Communication; Cell Movement; Cells, Cultured; Cycloheximide; Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Kallidin; Lymphocyte Function-Associated Antigen-1; Macrophage-1 Antigen; Neutrophils; Receptor, Bradykinin B1; RNA, Small Interfering

An upregulation of the endogenous opioid, dynorphin A, in the spinal cord is seen in multiple experimental models of chronic pain. Recent findings implicate a direct excitatory action of dynorphin A at bradykinin receptors to promote hyperalgesia in nerve injured rats, and its upregulation may promote, rather than counteract, enhanced nociceptive input due to injury. Here we examined a model of inflammatory pain by unilateral injection of complete Freund's adjuvant (CFA) into the rat hind paw. Rats exhibited tactile hypersensitivity and thermal hyperalgesia in the inflamed paw by 6 hours after CFA injection, whereas a significant elevation of prodynorphin transcripts in the lumbar spinal cord was seen at day 3 but not at 6 hours. Thermal hyperalgesia at day 3, but not at 6 hours, after CFA injection was blocked by intrathecal administration of anti-dynorphin antiserum or by bradykinin receptor antagonists. The antihyperalgesic effect of the latter was not due to de novo production of bradykinin or upregulation of spinal bradykinin receptors. These data suggest that elevated spinal dynorphin on peripheral inflammation mediates chronic inflammatory hyperalgesia. The antihyperalgesic effect of bradykinin receptor antagonists requires the presence of upregulated spinal dynorphin but not of de novo production of bradykinin, supporting our hypothesis that pathological levels of dynorphin may activate spinal bradykinin receptors to mediate inflammatory hyperalgesia.. This study shows that chronic peripheral inflammation induces a significant upregulation of the endogenous opioid peptide dynorphin. Elevated levels of spinal dynorphin and activation of spinal bradykinin receptors are essential to maintain inflammatory hyperalgesia. The results suggest that blockade of spinal bradykinin receptors may have therapeutic potential in chronic inflammatory pain.

Topics: Adjuvants, Immunologic; Analysis of Variance; Animals; Bradykinin; Dynorphins; Freund's Adjuvant; Hyperalgesia; Inflammation; Injections, Spinal; Kallidin; Kininogens; Male; Pain; Pain Measurement; Pain Threshold; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Tritium; Up-Regulation

The discovery of novel analgesic compounds that target some receptors can be challenging due to species differences in ligand pharmacology. If a putative analgesic compound has markedly lower affinity for rodent versus other mammalian orthologs of a receptor, the evaluation of antinociceptive efficacy in non-rodent species becomes necessary. Here, we describe a new, efficient method for measuring inflammation-associated nociception in conscious rabbits. An electronic von Frey device is used, consisting of a rigid plastic tip connected to a force transducer in a hand-held probe. The plastic tip is applied to the plantar surface of a hind paw with increasing force until a withdrawal response is observed. The maximum force (g) tolerated by the rabbit (i.e., withdrawal threshold) is recorded. In young, conscious rabbits (500-700 g), baseline hind paw withdrawal thresholds typically fell within the 60-80 g range. Three hours after injection of the inflammatory agent carrageenan (3%, 200 microL, intra-plantar), withdrawal thresholds dropped by approximately 30-40 g, indicating the presence of punctate mechanical hyperalgesia. The development of hyperalgesia was dose dependently prevented by the NSAID indomethacin (ED50=2.56 mg/kg, p.o.) or the bradykinin B2 receptor peptide antagonist HOE 140 (intra-paw administration). An established hyperalgesia was dose dependently reversed by morphine sulfate (ED50=0.096 mg/kg, s.c.) or the bradykinin B1 receptor peptide antagonist [des-Arg10, Leu9]-kallidin (ED50=0.45 mg/kg, s.c.). Rabbits treated with the novel B(1) receptor small molecule antagonist compound A also showed dose-dependent reversal of hyperalgesia (ED50=20.19 mg/kg, s.c.) and analysis of plasma samples taken from these rabbits showed that, unlike other rabbit pain models, the current method permits the evaluation of pharmacokinetic-pharmacodynamic (PK-PD) relationships (compound A plasma EC50=402.6 nM). We conclude that the Electrovonfrey method can be used in rabbits with inflammatory pain to generate reliable dose- and plasma concentration-effect curves for different classes of analgesics.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Carrageenan; Dose-Response Relationship, Drug; Drug Interactions; Ethers; Hydrocarbons, Fluorinated; Hyperalgesia; Indomethacin; Inflammation; Kallidin; Metacarpus; Pain; Pain Measurement; Pain Threshold; Rabbits; Reaction Time; Spectrum Analysis; Time Factors

1. Although endotoxaemia induces kinin B(1) receptors in several animal models, this condition is not documented in primates. This study examined the up-regulation of haemodynamic and pro-inflammatory responses to the B(1) agonist des-Arg(10)-kallidin (dKD) in a non-human primate model. 2. Green monkeys (Cercopithecus aethiops St Kitts) received lipopolysaccharide (LPS; 90 microg kg(-1)) or saline intravenously. After 4 h, anaesthetized monkeys were cannulated via the carotid artery to monitor blood pressure changes following intra-arterial injections of dKD or the B(2) agonist bradykinin (BK). Oedema induced by subcutaneous kinin administration was evaluated as the increase in ventral skin folds in anaesthetized monkeys injected with captopril at 4 h to 56 days post-LPS. 3. LPS increased rectal temperature but did not affect blood pressure after 4 h. dKD reduced blood pressure (E(max): 27+/-4 mmHg; EC(50): 130 pmol kg(-1)) and increased heart rate (E(max): 33 b.p.m.) only after LPS. In contrast, the dose-dependent fall in blood pressure with BK was comparable in all groups. The selective B(1) antagonist [Leu(9)]dKD (75 ng kg(-1) min(-1), intravenously) abolished responses to dKD but not BK. 4. dKD injection induced oedema dose-dependently (2.4+/-0.1 mm at 150 nmol) only following LPS (at 4 h to 12 days but not 56 days). In contrast, BK-induced oedema was present and stable in all monkeys. Co-administration of [Leu(9)]dKD (150 nmol) significantly reduced oedema induced by dKD (50 nmol). 5. These results suggest LPS up-regulation of B(1) receptor effects in green monkeys. This non-human primate model may be suitable for testing new, selective B(1) antagonists with therapeutic potential as anti-inflammatory agents.

Topics: Animals; Blood Pressure; Body Temperature; Bradykinin; Chlorocebus aethiops; Dose-Response Relationship, Drug; Edema; Endotoxins; Hemodynamics; Inflammation; Kallidin; Lipopolysaccharides; Male; Receptor, Bradykinin B1; Receptors, Bradykinin

We have shown that the portal hypertensive response to bradykinin in normal rats is mediated by B2 receptors.. By using isolated and exsanguinated rat liver perfusion, we studied the portal hypertensive response to bradykinin or des-Arg9-bradykinin (B1 agonist) in inflamed or cirrhotic rat livers. Livers were perfused with bovine serum albumin Krebs-Henseleit buffer (pH 7.4; 37 degrees C) at a constant flow rate, in the absence or presence of des-Arg9[Leu8]-bradykinin or HOE 140 (B1 and B2 receptor antagonists, respectively). Bradykinin (140 nmol) or des-Arg9-bradykinin was injected as a bolus via the afferent route to the liver.. Basal perfusion pressure in liver-cirrhotic rats was higher than in normal rats. In normal, inflamed, or liver-cirrhotic rats, the presence of the B1 antagonist did not change the portal hypertensive response to bradykinin, while the B2 antagonist abolished this response. A 140-nmol dose of des-Arg9-bradykinin did not change the perfusion pressure; 700 nmol of this B1 agonist produced an insignificant perfusion pressure increase. The perfusion pressure increase induced by bradykinin in cirrhotic livers was lower than in normal livers.. The portal hypertensive response to bradykinin in inflamed or cirrhotic rat livers is mediated by B2 receptors, but not B1 receptors, and there is a contracting hyporeactivity to bradykinin in cirrhotic rat livers.

Topics: Analysis of Variance; Animals; Bradykinin; Carbon Tetrachloride; Hypertension, Portal; Inflammation; Kallidin; Liver Cirrhosis; Male; Rats; Rats, Wistar; Receptors, Bradykinin; Turpentine

The effects of a p38 stress-activated protein kinase inhibitor, 4-(4-fluorophenyl)-2-(-4-methylsulfonylphenyl)-5-(4-pyridynyl) imidazole (SB203580), were evaluated in a rat model of inflammatory hyperalgesia. Oral, but not intrathecal, administration of SB203580 significantly reversed inflammatory mechanical hyperalgesia induced by injection of complete Freund's adjuvant into the hindpaw. SB203580 did not, however, affect the increased levels of interleukin-1beta and cyclo-oxygenase 2 protein observed in the hindpaw following complete Freund's adjuvant injection. Intraplantar injection of interleukin-1beta into the hindpaw elicited mechanical hyperalgesia in the ipsilateral paw, as well as in the contralateral paw, following intraplantar injection of the bradykinin B(1) receptor agonist des-Arg(9)-bradykinin. Oral administration of SB203580 1 h prior to interleukin-1beta administration prevented the development of hyperalgesia in the ipslateral paw and the contralateral bradykinin B(1) receptor-mediated hyperalgesia. In addition, following interleukin-1beta injection into the ipsilateral paw, co-administration of SB203580 with des-Arg(9)-bradykinin into the contralateral paw inhibited the bradykinin B(1) receptor-mediated hyperalgesia. In human embryonic kidney 293 cells expressing the human bradykinin B(1) receptor, its agonist des-Arg(10)-kallidin produced a rapid phosphorylation of endogenous p38 stress-activated protein kinase. Our data suggest that p38 stress-activated protein kinase is involved in the development of inflammatory hyperalgesia in the rat, and that its pro-inflammatory effects involve the induction of the bradykinin B(1) receptor as well as functioning as its downstream effector.

Topics: Animals; Cell Line; Cyclooxygenase 2; Cytokines; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hindlimb; Humans; Hyperalgesia; Imidazoles; Inflammation; Interleukin-1; Isoenzymes; Kallidin; Male; Membrane Proteins; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Prostaglandin-Endoperoxide Synthases; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptors, Bradykinin; Tumor Necrosis Factor-alpha

Bradykinin (BK), which has potent algesic and sensitizing effect on nociceptors, is of current interest in understanding the mechanisms of chronic pain. BK response is mediated by B2 receptor in normal conditions; however, findings that B1 receptor blockade alleviated hyperalgesia in inflammation have been highlighting the role of B1 receptor in pathological conditions. It has not yet been clear whether nociceptor activities are modified by B1 receptor agonists or antagonists during inflammation. In addition, previous studies reported the change in BK sensitivity of nociceptors during short-lasting inflammation, and data in persistent inflammation are lacking. Therefore we investigated whether an experimentally induced persistent inflammatory state modulates the BK sensitivity of nociceptors and which receptor subtype plays a more important role in this condition. Complete Freund's adjuvant was injected into the rat-tail and after 2-3 wk, persistent inflammation developed, which was prominent in the ankle joint. Using an in vitro skin-saphenous nerve preparation, single-fiber recordings were made from mechano-heat sensitive C-fiber nociceptors innervating rat hairy hindpaw skin, and their responses were compared with those obtained from C-fibers tested similarly in normal animals. BK at 10(-8) M excited none of the 10 C-fibers in normal animals while it excited 5 of 11 (45%) C-fibers of inflamed animals, and at 10(-6) M BK excited all of the 11 inflamed C-fibers (or 94% of 36 tested C-fibers) but only 4 of 10 (or 45% of 58 tested C-fibers) in normal animals. Thus the concentration-response curves based on the incidence of BK induced excitation, and the total number of impulses evoked in response to BK were significantly shifted to the left. Moreover, an increased percentage of the inflamed C-fibers responded to 10(-6) M BK with bursting or high-frequency discharges. Thirty-percent of inflamed C-fibers had spontaneous activity, and these fibers showed comparatively less tachyphylaxis to consecutive second and third 10(-6) M BK stimulation. A B2 receptor antagonist (D-Arg-[Hyp3, Thi5,8,D-phe7]-BK) completely eliminated BK responses in inflamed rats, while B1 receptor antagonists (B 9958 and Des-Arg9-[Leu8]-BK) had no effect. Selective B1 receptor agonist (Des-Arg10-Kallidin) excited 46% (n = 13) of inflamed C-fibers at 10(-5) M concentration, which is 1,000 times higher than that of BK needed to excite the same percentage of inflamed C-fibers. We conclude t

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Electrophysiology; Hot Temperature; In Vitro Techniques; Inflammation; Kallidin; Male; Nerve Fibers; Nociceptors; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Receptors, Bradykinin; Skin; Stimulation, Chemical; Tachyphylaxis

Prostaglandin (PG) release in cells expressing constitutive cyclooxygenase-1 is known to be regulated by liberation of arachidonic acid by phospholipase A2 followed by metabolism by cyclooxygenase. However, the relative contribution of phospholipase A2 to the release of PGs in cells expressing cyclooxygenase-2 is not clear. We addressed this question by using radioimmunoassay to measure PGE2 release by human cells (A549) induced to express cyclooxygenase-2 (measured by Western blot analysis) by interleukin-1beta. Cells were either unstimulated or stimulated with agents known to activate phospholipase A2 (bradykinin, Des-Arg10-kallidin, or the calcium ionophore A23187) or treated with exogenous arachidonic acid. When cells were treated to express cyclooxygenase-2, the levels of PGE2 released over 15 min were undetectable; however, in the same cells stimulated with bradykinin, A23187, or arachidonic acid, large amounts of prostanoid were produced. Using selective inhibitors/antagonists, we found that the effects of bradykinin were mediated by B2 receptor activation and that prostanoid release was due to cyclooxygenase-2, and not cyclooxygenase-1, activity. In addition, we show that the release of PGE2 stimulated by either bradykinin, A23187, or arachidonic acid was inhibited by the phospholipase A2 inhibitor arachidonate trifluoromethyl ketone. Hence, we have demonstrated that PGE2 is released by two components: induction of cyclooxygenase-2 and supply of substrate, probably via activation of phospholipase A2. This is illustrated in A549 cells by a clear synergy between the cytokine interleukin-1beta and the kinin bradykinin.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Arachidonic Acid; Bradykinin; Calcimycin; Cell Line; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Humans; Inflammation; Interleukin-1; Isoenzymes; Kallidin; Membrane Proteins; Phospholipases A; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Receptors, Bradykinin

The effects of BK agonists and antagonists, and other hyperalgesic/antihyperalgesic drugs were measured (3 h after injection of hyperalgesic drugs) in a model of mechanical hyperalgesia (the end-point of which was indicated by a brief apnoea, the retraction of the head and forepaws, and muscular tremor). DALBK inhibited responses to carrageenin, bradykinin, DABK, and kallidin. Responses to kallidin and DABK were inhibited by indomethacin or atenolol and abolished by the combination of indomethacin + atenolol. DALBK or HOE 140, given 30 min before, but not 2 h after, carrageenin, BK, DABK and kallidin reduced hyperalgesic responses to these agents. A small dose of DABK+ a small dose of BK evoked a response similar to the response to a much larger dose of DABK or BK, given alone. Responses to BK were antagonized by HOE 140 whereas DALBK antagonized only responses to larger doses of BK. The combination of a small dose of DALBK with a small dose of HOE 140 abolished the response to BK. The hyperalgesic response to LPS (1 microg) was inhibited by DALBK or HOE 140 and abolished by DALBK + HOE 140. The hyperalgesic response to LPS (5 microg) was not antagonized by DALBK + HOE 140. These data suggest: (a) a predominant role for B2 receptors in mediating hyperalgesic responses to BK and to drugs that stimulate BK release, and (b) activation of the hyperalgesic cytokine cascade independently of both B1 and B2 receptors if the hyperalgesic stimulus is of sufficient magnitude.

Topics: Adrenergic beta-Antagonists; Animals; Atenolol; Bradykinin; Bradykinin Receptor Antagonists; Carrageenan; Dinoprostone; Dose-Response Relationship, Drug; Drug Synergism; Hyperalgesia; Indomethacin; Inflammation; Interleukin-8; Kallidin; Lipopolysaccharides; Male; Mice; Pain Measurement; Pain Threshold; Rats; Rats, Wistar; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Sheep; Time Factors; Tumor Necrosis Factor-alpha

The effects of selected bradykinin receptor antagonists on leukocyte infiltration into the lungs were studied in a model of guinea pig lung inflammation induced by the intravenous injection of Sephadex beads. The bradykinin B1 receptor antagonist, [Leu8]desArg9-BK (40 mg kg(-1) 24 h(-1)) and the bradykinin B2 receptor antagonist, DArg[Hyp3,Thi5,DTic7,Oic8]BK (code name HOE 140; 4 mg kg(-1) 24 h(-1)), administered intravenously by osmotic pumps, significantly reduced eosinophil counts by 33% and 42% in bronchoalveolar fluid, respectively. HOE 140 decreased neutrophil counts by 35%. LysLys[Hyp3,Igl5,D-Igl7,Oic8]desArg9BK+ ++ (code name B 9858), a newly described bradykinin B1 receptor antagonist, administered intraperitoneally (1 mg kg(-1)), decreased eosinophil and neutrophil counts by 45% in bronchoalveolar fluid. D-Arg[Hyp3,Igl5,D-Igl7,Oic8]BK (code name B 9430), a non-selective bradykinin B1/B2 receptor antagonist, also administered intraperitoneally (1 mg kg(-1)), decreased eosinophil and macrophage counts by 62% and 80% in bronchoalveolar fluid. These results suggest that bradykinin B1 and B2 receptors are involved in leukocyte recruitment in our model of lung inflammation.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Bronchoalveolar Lavage Fluid; Cell Count; Dextrans; Guinea Pigs; Indicators and Reagents; Inflammation; Kallidin; Leukocytes; Lung Diseases; Male; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin

1 The characterization of the B1 kinin receptor, and some mediators involved in the inflammatory response elicited by intrathoracic (i.t.) administration of des-Arg9-bradykinin (BK) in the mouse model of pleurisy, was investigated. 2 An i.t. injection of des-Arg9-BK (10-100 nmol per site), a selective B1 agonist, caused a significant and dose-related increase in the vascular permeability observed after 5 min, which peaked at 1 h, associated with an increase in cell influx, mainly neutrophils, and, to a lesser extent, mononuclear cell influx, peaking at 4 h and lasting for up to 48 h. The increase in fluid leakage caused by des-Arg9-BK was completely resolved 4 h after peptide injection. I.t. injection of Lys-des-Arg9-BK (30 nmol per site) caused a similar inflammatory response. 3 Both the exudation and the neutrophil influx elicited by i.t. injection of des-Arg9-BK were significantly antagonized (P<0.01) by an i.t. injection of the selective B1 antagonists des-Arg9-[Leu8]-BK (60 and 100 nmol per site) or des-Arg9-NPC 17731 (5 nmol per site), administered in association with des-Arg9-BK (P<0.01), or 30 and 60 min before the cellular peak, respectively. In contrast, an i.t. injection of the B2 bradykinin selective receptor antagonist Hoe 140 (30 nmol per site), at a dose which consistently antagonized bradykinin (10 nmol per site)-induced pleurisy, had no significant effect on des-Arg9-BK-induced pleurisy. 4 An i.t. injection of the selective tachykinin receptor antagonists (NK1) FK 888 (1 nmol per site), (NK2) SR 48968 (20 nmol per site) or (NK3) SR 142801 (10 nmol per site), administered 5 min before pleurisy induction, significantly antagonized neutrophil migration caused by i.t. injection of des-Arg9-BK. In addition, FK 888 and SR 142801, but not SR 48968, also prevented the influx of mononuclear cells in response to i.t. injection of des-Arg9-BK (P<0.01). However, the NK3 receptor antagonist SR 142801 (10 nmol per site) also significantly inhibited des-Arg9-BK-induced plasma extravasation. An i.t. injection of the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8-37 (1 nmol per site), administered 5 min before pleurisy induction, inhibited des-Arg9-BK-induced plasma extravasation (P<0.01), without significantly affecting the total and differential cell migration. 5 The nitric oxide synthase inhibitors L-NOARG and L-NAME (1 pmol per site), administered 30 min beforehand, almost completely prevented des-Arg9-BK (i.t.)-induced neutrophil ce

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Capillary Permeability; Cell Cycle; Disease Models, Animal; Edema; Inflammation; Kallidin; Kinins; Lipopolysaccharides; Male; Mice; Neuropeptides; Nitric Oxide; Pleura; Pleurisy; Receptors, Bradykinin; Receptors, Tachykinin

The bradykinin B1-receptor is strongly upregulated under chronic inflammatory conditions. However, the mechanism and reason are not known. Because a better understanding of the mechanism of the upregulation will help in understanding its potential importance in inflammation, we have studied the molecular mechanism of B1-receptor upregulation in cultured human lung fibroblasts (IMR 90) in response to IL-1beta and the B1-agonist [des-Arg10]-kallidin. We show that treatment of human IMR 90 cells by IL-1beta stimulates the expression of both B1-receptor mRNA and protein. The latter was studied by Western blot analysis using antipeptide antibodies directed against the COOH-terminal part of the human B1-receptor. We furthermore report the novel observation that the B1-receptor is upregulated by its own agonist which was completely blocked by the specific B1-antagonist [des-Arg10-Leu9]-kallidin, indicating an upregulation entirely mediated through cell surface B1-receptors. The increased population of B1-receptors was functionally coupled as exemplified by an enhancement of the B1-agonist induced increase in free cytosolic calcium. Upregulation by the B1-agonist was blocked by a specific protein kinase C inhibitor. B1-agonist-induced upregulation was correlated to the induction of transcription factor nuclear factor kappaB (NF-kappaB) which efficiently bound to the NF-kappaB-like sequence located in the promoter region of the human B1-receptor gene. This correlation was further confirmed by reporter gene assays which showed that this NF-kappaB-like sequence, in the B1-receptor promoter context, could contribute to IL-1beta and DLBK-induced B1-receptor transcription activation, and by the effect of NF-kappaB inhibitor pyrrolidinedithiocarbamate which diminished both B1-receptor upregulation and NF-kappaB activation. NF-kappaB is now recognized as a key inflammatory mediator which is activated by the B1-agonist but which is also involved in B1-receptor upregulation.

Topics: Amino Acid Sequence; Cell Line; Cholera Toxin; DNA-Binding Proteins; Fibroblasts; Humans; Inflammation; Interleukin-1; Kallidin; Lung; Molecular Sequence Data; NF-kappa B; Proline; Pyrrolidines; Receptor, Bradykinin B1; Receptors, Bradykinin; RNA, Messenger; Thiocarbamates; Transcriptional Activation; Up-Regulation; Virulence Factors, Bordetella

B1 bradykinin receptors were visualized by using the B1 bradykinin receptor agonist [3H]des-Arg10-kallidin in receptor autoradiography experiments. Cryosections were prepared from arterial vessels from a healthy control pig, a pig with pre-existing inflammation and an animal with experimental sepsis induced by an infusion of bacterial lipopolysaccharide (LPS). Only diffusely scattered silver grains with no preference for a distinct tissue structure were detected on emulsion-coated coverslips above the cryosections from the healthy control animal. This indicates that under normal circumstances no or only minute amounts of B1 bradykinin receptors are present in these tissues. In contrast, a 3-fold increase in specific B1 bradykinin receptor binding was observed on both the corresponding preparations of the sick piglet and of that with experimentally induced sepsis. A similar enhancement of specific [3H]des-Arg10-kallidin binding occurred in preparations devoid of endothelium. By comparison with the stained cryosection on the slide the silver grains showed a preferential distribution above smooth muscle cells. Taken together our data are consistent with the hypothesis that B1 bradykinin receptors are induced in the muscle layer of large vessels not only after experimentally-induced sepsis but also in pre-existing inflammatory disease.

Topics: Animals; Aorta, Thoracic; Autoradiography; Blood Vessels; Inflammation; Kallidin; Lipopolysaccharides; Pulmonary Artery; Receptor, Bradykinin B1; Receptors, Bradykinin; Sepsis; Swine

Peptide analogs of bradykinin (BK) containing unusual amino acids are potent antagonists of the actions of BK in various smooth muscle preparations. Apparent pA2 values above 7.0 could be demonstrated for Lys-Lys-[Hyp3, Thi5.8, D-Phe7]-BK (B4310) in the rat uterus and the rat duodenum. Actions of BK that are related to its possible role in inflammation could be antagonized in a specific and dose-dependent manner by B4310. Stimulation by BK of C fiber afferent neurons was investigated in the rabbit ear reflex preparation and in the isolated rabbit iris sphincter muscle. In both preparations, B4310 caused a parallel shift of the dose-response curves to BK. In the latter case, a pA2 value was established that agrees well with the values found on smooth muscles. However, the short duration of action of the antagonists suggested a rapid inactivation by peptidases.

Topics: Animals; Blood Pressure; Bradykinin; Female; In Vitro Techniques; Inflammation; Kallidin; Kinins; Lung; Mice; Muscle Contraction; Muscle, Smooth; Neurons, Afferent; Rats; Rats, Inbred Strains; Regional Blood Flow; Skin

A comparison of the effects of bradykinin (BK), sigma-cyclo-BK and sigma-cyclo-kallidin (sigma-cyclo-KD) to induce oedema, hyperalgesia and blood flow in the rat paw was made. BK produced dose-dependent increases in oedema and blood flow and a reduction in the nociceptive pressure threshold. Sigma-Cyclo-BK and sigma-cyclo-KD were more potent than BK at inducing oedema and increasing blood flow but had no effect on nociceptive pressure threshold at the doses used. The relative lack of hyperalgesic activity of sigma-cyclo-BK and sigma-cyclo-KD compared with BK raises the possibility of differences between kinin receptors mediating permeability and blood flow changes and those involved in nociception in this model.

Topics: Animals; Body Temperature; Bradykinin; Edema; Female; Foot; Hyperalgesia; Inflammation; Kallidin; Rats; Regional Blood Flow

Topics: Angioedema; Bradykinin; Carboxypeptidases; Fibrinolysis; Humans; Hypotension; Inflammation; Kallidin; Kallikreins; Kinins; Malignant Carcinoid Syndrome; Meningitis; Pancreas; Pancreatitis; Peptide Hydrolases; Salivary Glands; Urticaria

Topics: Angioedema; Animals; Blood Coagulation Factors; Bradykinin; Carboxypeptidases; Carcinoid Tumor; Catecholamines; Chemical Phenomena; Chemistry; Colchicine; Complement System Proteins; Female; Glucocorticoids; Guinea Pigs; Haplorhini; Humans; Inflammation; Kallidin; Kallikreins; Kidney; Kinins; Muscle Contraction; Phenothiazines; Rats; Salicylates; Sheep; Shock, Septic; Stimulation, Chemical; Uterus; Vascular Diseases; Vascular Resistance; Vasodilator Agents

Topics: Animals; Anti-Inflammatory Agents; Bradykinin; Burns; Capillary Permeability; Carbamates; Inflammation; Kallidin; Kallikreins; Lymph Nodes; Male; Pleurisy; Rats; Skin; Turpentine

Topics: Animals; Bradykinin; Carboxypeptidases; Cathepsins; Cysteine; Enzymes; Guinea Pigs; Ileum; In Vitro Techniques; Inflammation; Iodoacetates; Kallidin; Kinins; Spleen; Sulfites

Topics: Animals; Antigen-Antibody Complex; Biological Products; Bradykinin; Capillary Permeability; Enzyme Inhibitors; Globulins; Hypersensitivity; Inflammation; Isoflurophate; Kallidin; Kallikreins; Peptide Hydrolases; Permeability; Rabbits; Research; Serum Globulins; Tissue Extracts; Trypsin; Vascular Endothelial Growth Factor A

Topics: Adrenal Cortex Hormones; Animals; Edema; Inflammation; Kallidin; Phenylbutazone; Rats; Salicylates

Topics: Animals; Antigen-Antibody Reactions; Bradykinin; Capillary Permeability; Fibroblasts; Globulins; Inflammation; Kallidin; Kallikreins; Leukocytes; Peptide Hydrolases; Peptides; Rabbits; Research; Tissue Culture Techniques; Toxicology