kallidin and Disease-Models--Animal

Treatment of malignant glioma with chemotherapy is limited mostly because of delivery impediment related to the blood-brain tumor barrier (BTB). B1 receptors (B1R), inducible prototypical G-protein coupled receptors (GPCR) can regulate permeability of vessels including possibly that of brain tumors. Here, we determine the extent of BTB permeability induced by the natural and synthetic peptide B1R agonists, LysdesArg(9)BK (LDBK) and SarLys[dPhe(8)]desArg(9)BK (NG29), in syngeneic F98 glioma-implanted Fischer rats. Ten days after tumor inoculation, we detected the presence of B1R on tumor cells and associated vasculature. NG29 infusion increased brain distribution volume and uptake profiles of paramagnetic probes (Magnevist and Gadomer) at tumoral sites (T(1)-weighted imaging). These effects were blocked by B1R antagonist and non-selective cyclooxygenase inhibitors, but not by B2R antagonist and non-selective nitric oxide synthase inhibitors. Consistent with MRI data, systemic co-administration of NG29 improved brain tumor delivery of Carboplatin chemotherapy (ICP-Mass spectrometry). We also detected elevated B1R expression in clinical samples of high-grade glioma. Our results documented a novel GPCR-signaling mechanism for promoting transient BTB disruption, involving activation of B1R and ensuing production of COX metabolites. They also underlined the potential value of synthetic biostable B1R agonists as selective BTB modulators for local delivery of different sized-therapeutics at (peri)tumoral sites.

Topics: Adult; Aged; Animals; Biological Transport; Bradykinin; Brain Neoplasms; Capillary Permeability; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glioma; Humans; Kallidin; Male; Middle Aged; Permeability; Rats; Rats, Inbred F344; Receptor, Bradykinin B1

Dendritic cells play a major role in the induction of both innate and acquired immune responses against pathogenic invaders. These cells are also able to sense endogenous activation signals liberated by injured tissues even in the absence of infection. In the present work, we demonstrate that kinins mobilize dendritic cells to produce IL-12 through activation of the B(2) bradykinin receptor subtype and that bradykinin-induced IL-12 responses are tightly regulated both by angiotensin-converting enzyme, a kinin-degrading peptidase, and by endogenous IL-10. Using a mouse model of allergic inflammation, we further show that addition of bradykinin to OVA during immunization results in decreased eosinophil infiltration on Ag challenge. The latter effect was demonstrated to be due to IL-12-driven skewing of Ag-specific T cell responses to a type 1 cytokine profile. Our data thus indicate that kinin peptides can serve as danger signals that trigger dendritic cells to produce IL-12 through activation of B(2) bradykinin receptors.

Topics: Adjuvants, Immunologic; Animals; Bradykinin; Cell Movement; Dendritic Cells; Disease Models, Animal; Eosinophils; Female; Immunity, Innate; Injections, Intraperitoneal; Interleukin-12; Kallidin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin; Pleurisy; Receptor, Bradykinin B2; Receptors, Bradykinin; Spleen; Th1 Cells

We evaluated roles of kinins in allergen-induced nasal blockage and sneezing, and development of nasal hyperresponsiveness to leukotriene D4 in a Japanese cedar pollen-induced allergic rhinitis model of guinea pigs. Sensitised guinea pigs were repeatedly challenged by pollen inhalation once every week. Neither a bradykinin B1 receptor antagonist, des-Arg9-[Leu8]bradykinin nor a bradykinin B2 receptor antagonist, icatibant suppressed allergen-induced sneezing and nasal blockage. However, development of nasal hyperresponsiveness to leukotriene D4 was significantly suppressed by them. The amount of bradykinin in nasal cavity lavage fluid was immediately increased after the challenge. In non-sensitised animals, hyperresponsiveness to leukotriene D4 was developed by a bradykinin B2 receptor agonist, bradykinin, but not by a bradykinin B1 receptor agonist, des-Arg10-kallidin, while in the sensitised-challenged animal, both agonists developed hyperresponsiveness. In conclusion, the nasal hyperresponsiveness appeared to be induced by kinins produced in response to the antigen challenge through activation of not only bradykinin B2 but also B1 receptors.

Topics: Airway Resistance; Allergens; Animals; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Guinea Pigs; Kallidin; Kinins; Leukotriene D4; Male; Nasal Lavage Fluid; Pollen; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Rhinitis, Allergic, Seasonal; Time Factors

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

Previous experiments in anesthetized pigs have demonstrated that blockade of the bradykinin B2 receptor in experimental endotoxin shock attenuates LPS-induced organ failure, lung dysfunction and mortality. Additional B1 receptor blockade in this situation seems to counteract the beneficial effects of B2 blockade. This suggests that the upregulation of B1 receptors during porcine LPS shock may be a useful mechanism of host defense. Furthermore, infusion of a B1 agonist during septic shock may be of therapeutic benefit. In order to prepare an experiment with B1 stimulation in LPS shock, we conducted a study in anesthetized pigs, in which the B1 receptor has been upregulated by infusion of bacterial lipopolysaccharide (LPS), by evaluating the effect of constant intravenous infusions of the B1 agonist des-Arg10-kallidin on the hypotensive response to bolus doses of this agonist. Following infusions of lipopolysaccharide from S. abortus equi, anesthetised pigs received repeated intra-arterial bolus injections of des-Arg10-kallidin before and during continuous infusions of this agonist in doses of 3, 10, 30 and 100 ng/kg/min. We found that all doses greater than 3 ng/kg/min produced attenuation of the hypotensive response produced by bolus administration of the B1 agonist des-Arg10-kallidin. We conclude that tachyphylaxis is an important feature to be considered in experiments with continuous administration of a B1 agonist in LPS shock.

Topics: Animals; Blood Pressure; Bradykinin Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Infusions, Intravenous; Injections, Intra-Arterial; Kallidin; Lipopolysaccharides; Receptor, Bradykinin B1; Receptors, Bradykinin; Shock, Septic; Swine; Tachyphylaxis; Up-Regulation

In order to investigate the contribution of kinin receptor antagonism in the treatment of LPS-induced shock we conducted a randomized study with anaesthetized piglets. Before randomization the animals were stratified according to predetermined health criteria under baseline conditions. One group of control animals received LPS from S. abortus equi (2 micrograms/kg/h i.v. for 8 h) and saline (Group 1). Another group received LPS and the B2 antagonist CP-0127 (3 micrograms/kg/min), beginning 1 h after LPS (Group 2). Group 3 received LPS and the B2 antagonist in the aforementioned doses, and the B1 antagonist Leu9-des-Arg10-kallidin (3 micrograms/kg/min), also beginning 1 h after LPS. Overall survival figures after 8 h of LPS infusion were: Group 1, 10/22 (45%); Group 2, 10/17 (59%); Group 3, 10/28 (36%). Fifty percent (29/58) of animals that were healthy at baseline survived, but only 11% (1/9) of sick animals survived (Log Rank p = 0.0001). In the subset of healthy animals, survival rates for Groups 2 and 3 were 77% and 38%, respectively (p = 0.0519). It appears, therefore, that B2 blockade attenuates LPS-induced mortality whereas additional B1 blockade seems to reverse these beneficial effects. This suggests that in this animal model the B1 receptor does not serve the same purpose as the B2 receptor, and that up-regulation of B1 receptors during LPS shock may be an important mechanism of host defence.

Topics: Animals; Bradykinin Receptor Antagonists; Disease Models, Animal; Drug Interactions; Kallidin; Lipopolysaccharides; Peptides; Random Allocation; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Shock, Septic; Swine

Topics: Anaphylaxis; Animals; Blood Pressure; Bradykinin; Bronchial Spasm; Disease Models, Animal; Dogs; Female; Histamine; Injections, Intravenous; Kallidin; Male; Respiration