fr-173657 and Disease-Models--Animal

Kinins are proinflammatory peptides that mediate a variety of pathophysiological responses. These actions occur through stimulation of two pharmacologically distinct receptor subtypes B1 and B2. In both human and animal airways, the majority of kinin-induced effects including bronchoconstriction, increases in vascular permeability and mucus secretion and cholinergic and sensory nerve stimulation appear to be bradykinin B2-receptor mediated. Peptidic and non-peptidic receptor antagonists have been developed as potential therapeutic agents. These antagonists are effective in blocking kinin-induced effects in a variety of animal models and in some instances, have been used effectively in animal models of allergic airway disease to alleviate allergen-induced pathophysiological airway responses. This review summarizes relevant studies supporting the evidence that bradykinin B2 receptor antagonism and/or upstream inhibition of tissue kallikrein will be beneficial in the treatment of inflammatory airway diseases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Bradykinin; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Humans; Quinolines; Receptor, Bradykinin B2; Respiratory System; Tissue Kallikreins

To clarify the role of bradykinin in urogenital pain, we investigated bradykinin involvement in rat models of testicular pain.. Bradykinin (0.1, 0.3, 1, 3 and 10 mmol/L) or distilled water was injected into the testes of male Wistar rats, and induced pain behaviors in conscious rats were evaluated. The effect of pretreatment with bradykinin B2 receptor antagonist FK3657 on bradykinin-induced pain behavior was then examined. We also evaluated the analgesic effect of FK3657 in a rat acetic acid-induced testicular pain as well as changes in the intratesticular bradykinin concentration after testicular injection of acetic acid.. An injection of bradykinin into the testes of conscious rats induced pain behaviors that were dose-proportionally reduced by prior administration of FK3657. In addition, FK3657 dose-dependently inhibited the pain responses induced by testicular injection of 1% acetic acid. An increase in intratesticular bradykinin concentration was detected after the testicular injection of 1% acetic acid.. Here, we found that intratesticular bradykinin evokes pain behavior via stimulation of bradykinin B2 receptors and that intratesticular acetic acid injection induces intratesticular bradykinin synthesis, consequently leading to pain behavior. These findings suggest that the potential utility of bradykinin B2 receptor antagonists as a novel target for treating urogenital pain.

Topics: Acetic Acid; Animals; Behavior, Animal; Bradykinin; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Injections; Male; Pain; Quinolines; Rats; Rats, Wistar; Receptor, Bradykinin B2; Testis

Activation of the proteinase-activated receptor-2 (PAR-2) induces scratching behaviour in mice. Here, we have investigated the role of kinin B(1) and B(2) receptors in the pruritogenic response elicited by activators of PAR-2.. Scratching was induced by an intradermal (i.d.) injection of trypsin or the selective PAR-2 activating peptide SLIGRL-NH(2) at the back of the mouse neck. The animals were observed for 40 min and their scratching response was quantified.. I.d. injection of trypsin or SLIGRL-NH(2) evoked a scratching behaviour, dependent on PAR-2 activation. Mice genetically deficient in kinin B(1) or B(2) receptors exhibited reduced scratching behaviour after i.d. injection of trypsin or SLIGRL-NH(2). Treatment (i.p.) with the non-peptide B(1) or B(2)receptor antagonists SSR240612 and FR173657, respectively, prevented the scratching behaviour caused by trypsin or SLIGRL-NH(2). Nonetheless, only treatment i.p. with the peptide B(2)receptor antagonist, Hoe 140, but not the B(1)receptor antagonist (DALBK), inhibited the pruritogenic response to trypsin. Hoe 140 was also effective against SLIGRL-NH(2)-induced scratching behaviour when injected by i.d. or intrathecal (i.t.) routes. Also, the response to SLIGRL-NH(2) was inhibited by i.t. (but not by i.d.) treatment with DALBK. Conversely, neither Hoe 140 nor DALBK were able to inhibit SLIGRL-NH(2)-induced scratching behaviour when given intracerebroventricularly (i.c.v.).. The present results demonstrated that kinins acting on both B(1) and B(2) receptors played a crucial role in controlling the pruriceptive signalling triggered by PAR-2 activation in mice.

Topics: Animals; Antipruritics; Behavior, Animal; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Dioxoles; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Intradermal; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Spinal; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligopeptides; Pain Threshold; Pruritus; Quinolines; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptor, PAR-2; Sulfonamides; Trypsin

We investigated the mechanisms underlying the pruritogenic response induced by trypsin in mice, to assess the relevance of neurogenic inflammation components in this response.. Itching was induced by an intradermal injection of trypsin in the mouse neck. The animals were observed for 40 min and their scratching behaviour was quantified.. Trypsin-induced itching was blocked by the lima bean trypsin inhibitor, the selective proteinase-activated receptor-2 (PAR-2) antagonist FSLLRY and PAR-2 receptor desensitization. An important involvement of mast cells was observed, as chronic pretreatment with the mast cell degranulator compound 48/80 or the mast cell stabilizer disodium cromoglycate prevented scratching. Also, trypsin response was inhibited by the selective COX-2 inhibitor celecoxib and by the selective kinin B2 (FR173657) and B1 (SSR240612) receptor antagonists. Moreover, an essential role for the mediators of neurogenic inflammation was established, as the selective NK1 (FK888), NK3 (SR142801) and calcitonin gene-related peptide (CGRP(8-37) fragment) receptor antagonists inhibited trypsin-induced itching. Similarly, blockade of transient receptor potential vanilloid 1 (TRPV1) receptors by the selective TRPV1 receptor antagonist SB366791, or by genetic deletion of TRPV1 receptor reduced this behaviour in mice. C-fibre desensitization showed a very similar result.. Trypsin intradermal injection proved to be a reproducible model for the study of itching and the involvement of PAR-2 receptors. Also, trypsin-induced itching seems to be widely dependent on neurogenic inflammation, with a role for TRPV1 receptors. In addition, several other mediators located in the sensory nerves and skin also seem to contribute to this process.

Topics: Anilides; Animals; Antipruritics; Behavior, Animal; Bradykinin Receptor Antagonists; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Celecoxib; Cell Degranulation; Cinnamates; Cromolyn Sodium; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dioxoles; Disease Models, Animal; Injections, Intradermal; Male; Mast Cells; Mice; Mice, Knockout; Nerve Fibers, Unmyelinated; Neurogenic Inflammation; Oligopeptides; p-Methoxy-N-methylphenethylamine; Peptide Fragments; Plant Proteins; Pruritus; Pyrazoles; Quinolines; Receptor, PAR-2; Receptors, Bradykinin; Receptors, Calcitonin Gene-Related Peptide; Reproducibility of Results; Signal Transduction; Sulfonamides; TRPV Cation Channels; Trypsin

In congestive heart failure, angiotensin-converting enzyme inhibitors (ACEIs) may prevent cardiac fibrosis via interaction with both angiotensin II and endothelin-1, which enhance myocardial collagen synthesis. However, whether endogenous bradykinin with an ACEI modifies the cardiac collagen architecture, affecting the endothelin system, has not yet been fully elucidated. We evaluated the changes in circulating hormonal factors, myocardial fibrosis and cardiac gene expression closely linked with heart failure, using an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg/day, n = 6), with an ACEI, enalapril (1 mg/kg/day), in dogs with tachycardia-induced congestive heart failure (270 p.p.m., 22 days) and compared the effects with enalapril alone (n = 6). Although there were no differences observed in blood pressure, plasma renin activity, aldosterone and endothelin-1 levels, combined FR173657 significantly increased the cardiac expression of preproendothelin- 1 mRNA (P < 0.05) and collagen type I and type III mRNA (P < 0.05), and cardiac collagen deposits (P < 0.05), and decreased eNOS gene expression (P < 0.05) in the left ventricle compared with the ACEI-treated group. Furthermore, there was a significant negative correlation between the expression of preproendothelin- 1 and eNOS mRNA levels (r = -0.708, P < 0.001). In conclusion, bradykinin may prevent cardiac fibrosis in part via suppression of the local endothelin system in the failing heart through the enhancement of nitric oxide production under chronic angiotensin-converting enzyme inhibition.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Collagen; Disease Models, Animal; Dogs; Enalapril; Endothelin-1; Fibrosis; Heart Failure; Hemodynamics; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Quinolines; Receptor, Bradykinin B2; Renin; RNA, Messenger

To investigate the effect of bradykinin B(2) receptor antagonist FR173657 on cough response in guinea pigs sensitized and challenged with ovalbumin.. 40 normal and 40 sensitized guinea pigs were challenged with the aerosol of ovalbumin. 24 hours later, 10 animals from the normal group and 10 from the sensitized group were intraperitoneally injected either with saline or with 0.03 mg/kg, 0.3 mg/kg and 3 mg/kg of FR173657 respectively, and then cough response to inhaled capsaicin was measured. Specific airway resistance was recorded with a noninvasive technique only in normal, sensitized and FR173657 (0.3 mg/kg)-treated sensitized guinea pigs.. FR173657 did not influence cough response and airway resistance in normal guinea pigs. Compared with normal animals, sensitized guinea pigs presented an increased cough frequency and specific airway resistance [(21.7 +/- 3.0) times/3 min vs (8.3 +/- 1.4) times/3 min, (9.4 +/- 0.5) cm H(2)O/s vs (7.9 +/- 0.9) cm H(2)O/s], (P < 0.05) after inhalation of 10(-4) mol/L capsaicin. The cough frequency and specific airway resistance were decreased to [(12.2 +/- 1.3) times/1 min and (7.5 +/- 0.9) cm H(2)O/s] after administration of 0.3 mg/kg of FR173657 (P < 0.05).. Bradykinin B(2) receptor antagonist inhibited increased cough response and airway resistance in guinea pigs sensitized and challenged with ovalbumin. Bradykinin may be an important mediator in cough associated with eosinophilic airway inflammation.

Topics: Airway Resistance; Animals; Asthma; Bradykinin Receptor Antagonists; Capsaicin; Cough; Disease Models, Animal; Guinea Pigs; Male; Ovalbumin; Quinolines; Receptor, Bradykinin B2

We have compared the in vivo activity of the bradykinin B(2) receptor peptide antagonists MEN 11270 and Icatibant versus the nonpeptide antagonist FR 173657, after intravenous (i.v.) and intratracheal (i.t.) administration, on the bradykinin (BK)-induced bronchoconstriction and hypotension in anesthetized guinea pigs. We have also assessed the affinity of these antagonists for B(2) receptors in guinea pig lung membranes by radioligand binding and the metabolic stability of peptide antagonists in guinea pig plasma and tissue homogenates. The i.v. administration of MEN 11270, Icatibant, or FR 173657 induced a dose-dependent (10-100 nmol/kg) inhibition of both hypotension and bronchoconstriction induced by bradykinin (10 nmol/kg i.v.). The inhibitory effect of MEN 11270 and Icatibant was comparable both in terms of potency and time course, whereas FR 173657 was less potent and shorter acting. After i.t. administration MEN 11270 and Icatibant (10-100 nmol/kg) dose dependently inhibited both bronchoconstriction and hypotension, whereas FR 173657 (10-100 nmol/kg) reduced bronchoconstriction without affecting hypotension. The antibronchoconstrictor effect of MEN 11270 was more prolonged than that of Icatibant and FR 173657, whereas no differences were found between the peptide antagonists in inhibiting hypotension. These findings indicated that, in vivo, the peptide antagonists are more potent and longer lasting than FR 173657 acting on bradykinin B(2) receptors in guinea pig airways and in the vascular system. The greater efficacy of the antagonists in blocking airway compared with vascular B(2) receptors after topical administration suggests that they can block airway B(2) receptors with little systemic effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Bronchoconstriction; Cell Membrane; Disease Models, Animal; Drug Interactions; Drug Stability; Guinea Pigs; Hypotension; Infusions, Intravenous; Lung; Male; Oligopeptides; Peptides, Cyclic; Quinolines; Receptor, Bradykinin B2; Tritium

Inflammatory pain was induced following an intradermal injection of carrageenin into rat paws, and the hyperalgesia was measured in terms of withdrawal time following thermal pain stimulation of the inflamed paw. This hyperalgesia was significantly less in kininogen-deficient Brown Norway (B/N)-Katholiek rats, which also showed less swelling in carrageenin-induced paw edema, than in normal B/N-Kitasato rats at 1 approximately 4 hr after the carrageenin injection (at the early phase). However, 24 hr after the injection, hyperalgesia and the swelling volume of the kininogen-deficient rats were almost the same as those in normal rats. The bradykinin B2 receptor antagonist FR173657, (E)-3-(6-acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide, attenuated the carrageenin-induced swelling and hyperalgesia of the normal rats at the early phase to almost the levels of the B/N-Katholiek rats. Pretreatment with indomethacin, a cyclooxygenase inhibitor, also inhibited the carrageenin-induced responses significantly in normal rats. These results indicate that bradykinin, acting on the B2 receptor, is the main mediator at the early phase of inflammatory pain of carrageenin edema and that prostaglandins, produced by cyclooxygenase, potentiate the effects of bradykinin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Carrageenan; Disease Models, Animal; Edema; Female; Indomethacin; Kininogens; Male; Pain; Quinolines; Rats