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1
Dixon, B. S., R. Breckon, J. Fortune, R. J. Vavrek, J. M. Stewart, R. Marzec-Calvert, and S. L. Linas. "Effects of kinins on cultured arterial smooth muscle." American Journal of Physiology-Cell Physiology 258, no. 2 (February 1, 1990): C299—C308. http://dx.doi.org/10.1152/ajpcell.1990.258.2.c299.
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The present study uses various kinin agonists and antagonists to examine the cellular mechanisms of bradykinin's actions on intracellular calcium, prostaglandins, and adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in cultured arterial smooth muscle cells (casmc) obtained from rat mesenteric arteries. Exposure to bradykinin produced a rapid release of calcium (peak less than or equal to 20 s) from intracellular stores and an increase in prostaglandin (PG) E2 and cAMP production in casmc. Compared with bradykinin, the bradykinin B1-agonist [des-Arg9]BK produced only a small increase in intracellular calcium. The bradykinin-mediated increase in intracellular calcium was competitively blocked by the B2 receptor antagonist [D-Arg-O-Hyp3-Thi5,8-D-Phe7]BK (B4307) but not the B1-antagonist ([des-Arg9-Leu8]BK). In addition, the similarity of the dose-response curves for the bradykinin-mediated increase in Ca2+, PGE2, and cAMP (half-maximal stimulation of 12, 11, and 13 nM, respectively) and the ability of the B2-antagonist (B4307) to block each of these effects of bradykinin suggest that all three effects are mediated by the same bradykinin (B2) receptor. Further studies revealed that increases in intracellular calcium are necessary for the bradykinin-mediated increase in PGE2 formation and the subsequent PGE2-dependent formation of cAMP. Taken together, these results suggest that bradykinin acts via a B2-receptor on arterial smooth muscle cells to release calcium from intracellular stores, leading to increases in PGE2 production and the PGE2-dependent activation of adenylate cyclase.
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Ma, Jie, Yu Luo, Lilin Ge, Lei Wang, Mei Zhou, Yingqi Zhang, Jinao Duan, Tianbao Chen, and Chris Shaw. "Ranakinestatin-PPF from the Skin Secretion of the Fukien Gold-Striped Pond Frog,Pelophylax plancyi fukienensis: A Prototype of a Novel Class of BradykininB2Receptor Antagonist Peptide from Ranid Frogs." Scientific World Journal 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/564839.
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The defensive skin secretions of many amphibians are a rich source of bradykinins and bradykinin-related peptides (BRPs). Members of this peptide group are also common components of reptile and arthropod venoms due to their multiple biological functions that include induction of pain, effects on many smooth muscle types, and lowering systemic blood pressure. While most BRPs are bradykinin receptor agonists, some have curiously been found to be exquisite antagonists, such as the maximakinin gene-related peptide, kinestatin—a specific bradykinin B2-receptor antagonist from the skin of the giant fire-bellied toad,Bombina maxima. Here, we describe the identification, structural and functional characterization of a heptadecapeptide (DYTIRTRLHQGLSRKIV), named ranakinestatin-PPF, from the skin of the Chinese ranid frog,Pelophylax plancyi fukienensis, representing a prototype of a novel class of bradykinin B2-receptor specific antagonist. Using a preconstricted preparation of rat tail arterial smooth muscle, a single dose of 10−6 M of the peptide effectively inhibited the dose-dependent relaxation effect of bradykinin between 10−11 M and 10−5 M and subsequently, this effect was pharmacologically-characterized using specific bradykinin B1- (desArg-HOE140) and B2-receptor (HOE140) antagonists; the data from which demonstrated that the antagonism of the novel peptide was mediated through B2-receptors. Ranakinestatin—PPF—thus represents a prototype of an amphibian skin peptide family that functions as a bradykinin B2-receptor antagonist herein demonstrated using mammalian vascular smooth muscle.
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Willars, Gary B., Werner Müller-Esterl, and Stefan R. Nahorski. "Receptor phosphorylation does not mediate cross talk between muscarinic M3 and bradykinin B2 receptors." American Journal of Physiology-Cell Physiology 277, no. 5 (November 1, 1999): C859—C869. http://dx.doi.org/10.1152/ajpcell.1999.277.5.c859.
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This study examined cross talk between phospholipase C-coupled muscarinic M3 and bradykinin B2 receptors coexpressed in Chinese hamster ovary (CHO) cells. Agonists of either receptor enhanced phosphoinositide signaling (which rapidly desensitized) and caused protein kinase C (PKC)-independent, homologous receptor phosphorylation. Muscarinic M3 but not bradykinin B2 receptors were also phosphorylated after phorbol ester activation of PKC. Consistent with this, muscarinic M3 receptors were phosphorylated in a PKC-dependent fashion after bradykinin B2 receptor activation, but muscarinic M3 receptor activation did not influence bradykinin B2receptor phosphorylation. Despite heterologous phosphorylation of muscarinic M3 receptors, phosphoinositide and Ca2+signaling were unaffected. In contrast, marked heterologous desensitization of bradykinin-mediated responses occurred despite no receptor phosphorylation. This desensitization was associated with a sustained component of muscarinic receptor-mediated signaling, whereas bradykinin's inability to influence muscarinic receptor-mediated responses was associated with rapid and full desensitization of bradykinin responses. Thus the mechanism of functional cross talk most likely involves depletion of a shared signaling component. These data demonstrate that receptor phosphorylation is not a prerequisite for heterologous desensitization and that such desensitization is not obligatory after heterologous receptor phosphorylation.
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Morgan-Boyd, R., J. M. Stewart, R. J. Vavrek, and A. Hassid. "Effects of bradykinin and angiotensin II on intracellular Ca2+ dynamics in endothelial cells." American Journal of Physiology-Cell Physiology 253, no. 4 (October 1, 1987): C588—C598. http://dx.doi.org/10.1152/ajpcell.1987.253.4.c588.
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The purpose of this study was to investigate the effects of angiotensin II and bradykinin on intracellular Ca2+ dynamics in cultured endothelial cells. We used the "second-generation" fluorescent Ca2+ indicator fura-2, in conjunction with dual-wavelength fluorescence spectroscopy, in cultured adherent pulmonary arterial endothelial cells. Angiotensin II (up to 2 microM) had no consistent effect on intracellular Ca2+ levels. In contrast, bradykinin (10 nM) elicited a transient increase of cytosolic free Ca2+, from the resting value of 37 +/- 5 to 647 +/- 123 nM, followed by a decline to a steady-state value of 113 +/- 14 nM, which was significantly higher than the resting Ca2+ levels. Bradykinin's Ca-stimulatory effect was dose dependent, having a half-maximally effective concentration of approximately 1 nM and a maximally effective concentration of 10 nM. A B1-receptor agonist, Des-Arg9-bradykinin, was much less effective than bradykinin as modulator of cytosolic Ca2+. Moreover, a B1-receptor antagonist, Des-Arg9, [Leu8]-bradykinin, did not significantly affect the increase of cytosolic Ca2+ elicited by bradykinin. On the other hand, the bradykinin-elicited increase of Ca2+ was almost completely inhibited by a novel B2-receptor antagonist, D-Arg-[Hyp3, Thi5,8, D-Phe7]-bradykinin. Bradykinin increased cytosolic free Ca2+ levels in cells maintained in Ca2+-deficient extracellular medium, suggesting that the peptide mobilized Ca2+ from intracellular stores. However, the absence of extra-cellular Ca2+ resulted in an 80-90% attenuation of the transient Ca2+ response, whereas the posttransient steady-state response was completely absent. These findings are consistent with the notion that the bradykinin-elicited transient Ca2+ response is dependent on both extra- and intracellular Ca2+ and that the posttransient steady-state response is entirely dependent on extracellular Ca2+. Endothelial cells were responsive to a second dose of bradykinin after a 10-min interim period of incubation in the absence of the peptide hormone. The absence of extracellular Ca2+ during the interim period, or the pretreatment of cells with ionomycin in the absence of extracellular Ca2+, prevented the response of the cells to a second dose of bradykinin. Bradykinin- or ionomycin-desensitized cells could be resensitized by a brief incubation period in Ca2+-replete medium. The results are consistent with the notions that cellular resensitization requires the replenishment of intracellular Ca2+ and that bradykinin, but not angiotensin II, modulates intracellular Ca2+ dynamics in endothelial cells by interacting with a B2-type receptor.
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CUGNO, Massimo, Francesco SALERNO, Jürg NUSSBERGER, Bianca BOTTASSO, Elettra LORENZANO, and Angelo AGOSTONI. "Bradykinin in the ascitic fluid of patients with liver cirrhosis." Clinical Science 101, no. 6 (November 20, 2001): 651–57. http://dx.doi.org/10.1042/cs1010651.
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Bradykinin, a nonapeptide with vasodilatory and permeabilizing activity, is generated through the cleavage of high-Mr (‘high-molecular-weight’) kininogen by kallikrein, and its generation is facilitated by plasmin. In the ascitic fluid of patients with cirrhosis, there is massive cleavage of high-Mr kininogen and activation of fibrinolysis, but bradykinin has never been measured directly. In the ascitic fluid of 24 patients with cirrhosis, we measured bradykinin-(1-9)-nonapeptide levels by RIA after liquid-phase and subsequent HPLC extraction, and those of its catabolic product bradykininin-(1-5)-pentapeptide by ELISA after liquid-phase extraction. Cleaved high-Mr kininogen, activated factor XII and plasmin-antiplasmin complexes were measured in ascitic fluid and plasma. Plasma renin activity (PRA) was also determined. As a control, we also analysed plasma from 24 healthy subjects matched for sex and age with the patients. In the ascitic fluid from patients with cirrhosis, the median bradykinin-(1-9) concentration was 3.3fmol/ml (range 0.2-29.0fmol/ml), and the median bradykinin-(1-5) concentration was 210fmol/ml (range 58-7825 fmol/ml). The levels of bradykinin-(1-5) in ascitic fluid were higher in patients with refractory ascites [median 1091fmol/ml (range 58-7825fmol/ml)] than in patients with responsive ascites [134 fmol/ml (72-1084fmol/ml)] (P = 0.010). Ascitic fluid levels of bradykinin-(1-9) were not related to the severity of ascites. PRA was higher in patients with refractory ascites [23.0ngċh-1ċml-1 (7.9-80.0ngċh-1ċml-1)] than in patients with responsive ascites [6.9ngċh-1ċml-1 (0.9-29.4ngċh-1ċml-1)] (P = 0.002). In ascitic fluid, 48% (19-68%) of high-Mr kininogen was cleaved, and plasmin-antiplasmin complexes were more concentrated than in plasma (P = 0.0001). In conclusion, in the ascitic fluid of patients with cirrhosis, both bradykinin-(1-9) and bradykinin-(1-5) are present, with cleavage of high-Mr kininogen and activation of fibrinolysis. The highest levels of the long-lived metabolite bradykinin-(1-5) were found in the ascitic fluid of patients with refractory ascites and high PRA. Activation of the kinin system may therefore be involved in decompensating cirrhosis, but a cause-effect relationship remains to be established.
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Pan, H. L., C. L. Stebbins, and J. C. Longhurst. "Bradykinin contributes to the exercise pressor reflex: mechanism of action." Journal of Applied Physiology 75, no. 5 (November 1, 1993): 2061–68. http://dx.doi.org/10.1152/jappl.1993.75.5.2061.
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This study determined the receptors responsible for mediating bradykinin's effect on skeletal muscle afferents that cause the pressor reflex in anesthetized cats. In eight cats, 1 microgram of bradykinin was injected intra-arterially into the gracilis muscle before and after intravenous injection of a kinin B2-receptor antagonist (NPC 17731, 20 micrograms/kg). Initial injection of bradykinin reflexly increased mean arterial pressure by 23 +/- 7 mmHg, maximal change in pressure over time by 439 +/- 272 mmHg/s, and heart rate by 11 +/- 4 beats/min. The hemodynamic response to bradykinin was abolished by kinin B2-receptor blockade. Similar injection of the kinin B1-receptor agonist des-Arg9-bradykinin caused no cardiovascular responses (n = 6). In eight different animals, mean arterial pressure, maximal change in left ventricular pressure over time, and heart rate responses to 30 s of electrically stimulated hindlimb contraction were attenuated by 50 +/- 6, 55 +/- 7, and 41 +/- 8%, respectively, after kinin B2-receptor blockade. In eight other animals, mean arterial pressure, maximal change in left ventricular pressure over time, and heart rate responses were reduced by 58 +/- 8, 66 +/- 6, and 40 +/- 12%, respectively, after inhibition of prostaglandin synthesis with indomethacin (2.5–3 mg/kg iv) and were then abolished by subsequent B2-receptor blockade. These data suggest that bradykinin contributes to the exercise pressor reflex through its action on kinin B2 receptors located on the nerve endings of the muscle afferents.(ABSTRACT TRUNCATED AT 250 WORDS)
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Todoriko, L. D. "Problem issues of the pathogenesis of inflammatory reaction and the course of coronavirus infection." Tuberculosis, Lung Diseases, HIV Infection, no. 1 (March 23, 2021): 76–86. http://dx.doi.org/10.30978/tb2021-1-76.
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Objective — to analysis and systematization of literature data about pathogenesis of the inflammatory reaction and the clinical course of coronavirus infection caused by SARS-CoV-2.
Materials and methods. Access to various full-text and abstract databases was used for the search query «coronavirus», «COVID-19», «SARS-CoV-2» and their systematic evaluation was carried out. The most complete database of available literature sources (about 70) was obtainedon the molecular pathophysiology of COVID-19.
Results and discussion. The results of the analysis of the molecular pathophysiology of COVID-19 showed that the biomedical terms associated with COVID-19/SARS-CoV-2 form several clusters: cluster 1 is inflammation and the formation of a cytokine storm; cluster 2 — pathophysiological justification of the treatment of coronavirus infection, cluster 3 — comorbid conditions. Analytics of cluster 1 showed one of the most interesting working hypotheses today is model of bradykinin storm. This hypothesis can explain the multisymptomatic nature of COVID-19, including some of its strangest manifestations. The essence of the theory of bradykinin is that, when the virus begins to affect the regulation of renin-angiotensin-aldosterone system (RAAS) through the activation of angiotensin-converting enzyme type II, it causes the mechanisms that regulate bradykinin levels to fail. Bradykinin’s receptors repeatedly are sensitized and the body also ceases to efficiently break down bradykinin. ACE break down bradykinin, but when the virus suppresses its activity, it cannot work with the same efficiency. The end result of such an imbalance is the release of excessive amounts of bradykinin, due to its mass unrestrained accumulation with the formation of a phenomenon — bradykinin storm. According to the bradykinin hypothesis, this particular variant of the storm is ultimately responsible for the polymorbidity of the clinical picture and the fatal effects cause d by COVID-19.
Conclusions. The bradykinin hypothesis of the development of a systemic inflammatory response in SARS-CoV-2 virus is a model that contributes to a better understanding of the pathogenesis and course of COVID-19 and adds novelty to data that are already known. It predicts almost all known symptoms today and offers quality treatments for the disease. Analysis of the processed data from the literature of cluster 2, devoted to the pathophysiological rationale treatment of coronavirus infection led to the role of vitamin D — as a nutrient involved in regulatory processes with participation of RAAS.
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Sheikh, Iftikhar A., and Allen P. Kaplan. "Studies of the digestion of bradykin, lys-bradykinin, and des-Arg9-bradykinin by angiotensin converting enzyme." Biochemical Pharmacology 35, no. 12 (June 1986): 1951–56. http://dx.doi.org/10.1016/0006-2952(86)90726-4.
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Gouda, Ahmed S., and Bruno Mégarbane. "Molecular Bases of Serotonin Reuptake Inhibitor Antidepressant-Attributed Effects in COVID-19: A New Insight on the Role of Bradykinins." Journal of Personalized Medicine 12, no. 9 (September 11, 2022): 1487. http://dx.doi.org/10.3390/jpm12091487.
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Widely available effective drugs to treat coronavirus disease-2019 (COVID-19) are still limited. Various studies suggested the potential contribution of selective serotonin-reuptake inhibitor (SSRI) antidepressants to alleviate the clinical course of COVID-19. Initially, SSRI antidepressant-attributed anti-COVID-19 activity was attributed to their direct agonistic or indirect serotonin-mediated stimulation of sigma-1 receptors (Sig1-R). Thereafter, attention was drawn to the property of SSRI antidepressants to decrease ceramide production, as functional inhibitors of acid sphingomyelinase. Ceramides are cell membrane waxy lipids formed by sphingosine and a fatty acid, playing a major role in receptor signaling and infection. In COVID-19 patients, ceramide production is increased due to acid sphingomyelinase activation. Here, we aimed to review the relationships between bradykinins and the proposed pathways supporting SSRI antidepressant-attributed effectiveness in COVID-19. In COVID-19 patients, bradykinin receptor-B1 stimulation is enhanced following the downregulation of angiotensin-converting enzyme-2, which is responsible for the inactivation of des-Arg9-bradykinin, a bradykinin metabolite, contrasting with the decrease in bradykinin receptor-B2 (BDKRB2) stimulation, which results from the inhibition of cathepsin L, a kininogenase involved in bradykinin production and present at the infection site. Sig1-R stimulation modulates the inflammatory response by regulating cytokine production and counterbalances COVID-19-attributed BDKRB2 inhibition by potentiating its effects on the cytosolic calcium concentration. Moreover, the beneficial effects obtained with acid sphingomyelinase inhibition are parallel to those expected with BDKRB2 stimulation in COVID-19. Altogether, these findings suggest that one ultimate pathway of SSRI antidepressant-attributed anti-COVID-19 activity is the potentiation of BDKRB2 effects shown to be inhibited in COVID-19. In conclusion, SSRI antidepressants are able to interact positively with the pathophysiological mechanisms involved in COVID-19. However, their exact benefits in preventing morbidities or improving the outcome in COVID-19 patients remain unknown.
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Öztürk, Yusuf, V. Melih Altan, Nuray Yıdızoğlu-Arı, and Orhan Altınkurt. "Bradykinin receptors in intestinal smooth muscles and their post-receptor events related to calcium." Mediators of Inflammation 2, no. 4 (1993): 309–15. http://dx.doi.org/10.1155/s0962935193000432.
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The effects of trifluoperazine and verapamil on bradykinin- and des-Arg9-bradykinin induced responses of isolated rat duodenum and guinea-pig ileum were investigated to elucidate post-bradykinin receptor events. Verapamil and trifluoperazine inhibited bradykinin induced relaxations and contractions and des-Arg9- bradykinin induced contractions in rat duodenum. Bradykinin induced contractions of ileum were also inhibited by trifluoperazine and. verapamil. Since non-competitive affinity constants of trifluoperazine and verapamil for the relaxant responses to bradykinin in duodenum and for the contractile responses to bradykinin in ileum are different, post-bradykinin receptor events related to calcium may be different in ileum and duodenum. In addition, affinity constants of bradykinin in guinea-pig ileum and rat duodenum are also disparate suggesting the presence of different types of bradykinin B2receptors in these two organs.
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Chen, Zu-Lin, Pradeep Singh, Jyen Wong, Katharina Horn, Sidney Strickland, and Erin H. Norris. "An antibody against HK blocks Alzheimer’s disease peptide β-amyloid−induced bradykinin release in human plasma." Proceedings of the National Academy of Sciences 116, no. 46 (October 28, 2019): 22921–23. http://dx.doi.org/10.1073/pnas.1914831116.
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Bradykinin is a proinflammatory factor that mediates angioedema and inflammation in many diseases. It is a key player in some types of hereditary angioedema and is involved in septic shock, traumatic injury, Alzheimer’s disease (AD), and stroke, among others. Activation of the plasma contact system leads to elevated levels of plasma kallikrein, which cleaves high molecular weight kininogen (HK) to release bradykinin. Drug development for bradykinin-meditated pathologies has focused on designing inhibitors to the enzymes that cleave HK (to prevent bradykinin release) or antagonists of endothelial bradykinin receptors (to prevent downstream bradykinin action). Here we show a strategy to block bradykinin generation by using an HK antibody that binds to HK, preventing its cleavage and subsequent bradykinin release. We show that this antibody blocks dextran sodium sulfate-induced HK cleavage and bradykinin production. Moreover, while the pathogenic AD peptide β-amyloid (Aβ)42 cleaves HK and induces a dramatic increase in bradykinin production, our HK antibody blocked these events from occurring. These results may provide strategies for developing treatments for bradykinin-driven pathologies.
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Duncan, Ann-Maree, Athena Kladis, Garry L. Jennings, Anthony M. Dart, Murray Esler, and Duncan J. Campbell. "Kinins in humans." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 278, no. 4 (April 1, 2000): R897—R904. http://dx.doi.org/10.1152/ajpregu.2000.278.4.r897.
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The kinin peptide system in humans is complex. Whereas plasma kallikrein generates bradykinin peptides, glandular kallikrein generates kallidin peptides. Moreover, a proportion of kinin peptides is hydroxylated on proline3 of the bradykinin sequence. We established HPLC-based radioimmunoassays for nonhydroxylated and hydroxylated bradykinin and kallidin peptides and their metabolites in blood and urine. Both nonhydroxylated and hydroxylated bradykinin and kallidin peptides were identified in human blood and urine, although the levels in blood were often below the assay detection limit. Whereas kallidin peptides were more abundant than bradykinin peptides in urine, bradykinin peptides were more abundant in blood. Bradykinin and kallidin peptide levels were higher in venous than arterial blood. Angiotensin-converting enzyme inhibition increased blood levels of bradykinin, but not kallidin, peptides. Reactive hyperemia had no effect on antecubital venous levels of bradykinin or kallidin peptide levels. These studies demonstrate differential regulation of the bradykinin and kallidin peptide systems, and indicate that blood levels of bradykinin peptides are more responsive to angiotensin-converting enzyme inhibition than blood levels of kallidin peptides.
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Bathon, J. M., and D. Proud. "Bradykinin Antagonists." Annual Review of Pharmacology and Toxicology 31, no. 1 (April 1991): 129–62. http://dx.doi.org/10.1146/annurev.pa.31.040191.001021.
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Hilgenfeldt, U., R. Linke, and W. König. "Bradykinin Antibodies." Journal of Cardiovascular Pharmacology 15 (1990): S17—S19. http://dx.doi.org/10.1097/00005344-199000156-00004.
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Hilgenfeldt, U., R. Linke, and W. König. "Bradykinin Antibodies." Journal of Cardiovascular Pharmacology 15, Supplement (1990): S17—S19. http://dx.doi.org/10.1097/00005344-199015061-00004.
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Hall, Judith M. "Bradykinin receptors." General Pharmacology: The Vascular System 28, no. 1 (January 1997): 1–6. http://dx.doi.org/10.1016/s0306-3623(96)00174-7.
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Kaplan, Allen P., Kusumam Joseph, Yoji Shibayama, Yoshitaka Nakazawa, Berhane Ghebrehiwet, Sesha Reddigari, and Michael Silverberg. "Bradykinin formation." Clinical Reviews in Allergy & Immunology 16, no. 4 (December 1998): 403–29. http://dx.doi.org/10.1007/bf02737659.
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HARVEY, Justine S., and Gillian M. BURGESS. "Cyclic GMP regulates activation of phosphoinositidase C by bradykinin in sensory neurons." Biochemical Journal 316, no. 2 (June 1, 1996): 539–44. http://dx.doi.org/10.1042/bj3160539.
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Prior exposure of cultured neonatal rat dorsal root ganglion (DRG) neurons to bradykinin resulted in marked attenuation of bradykinin-induced activation of phosphoinositidase C (PIC). The (logconcentration)–response curve for bradykinin-induced [3H]inositol trisphosphate ([3H]IP3) formation was shifted to the right and the maximum response was reduced. Bradykinin increases cyclic GMP (cGMP) in DRG neurons [Burgess, Mullaney, McNeill, Coote, Minhas and Wood (1989) J. Neurochem. 53, 1212–1218] and treatment of the neurons with dibutyryl cGMP (dbcGMP) had a similar, inhibitory, effect on bradykinin-induced [3H]IP3 formation. NG-Nitro-L-arginine (LNNA) blocked bradykinin-induced formation of cGMP. It prevented the functional uncoupling induced by pretreatment with bradykinin, but not the inhibitory effect of dbcGMP on [3H]IP3 formation. The ability of LNNA to prevent desensitization was reversed by excess L-arginine, indicating that its actions were mediated through inhibition of nitric oxide synthase. In addition to functional desensitization, exposure to bradykinin reduced the number of cell-surface receptors detected with [3H]bradykinin, without affecting its KD value for the remaining sites. In contrast to bradykinin, pretreatment with dbcGMP had no effect on either the KD or Bmax for [3H]bradykinin binding. This implies that the inhibitory effect of dbcGMP was downstream from the binding of bradykinin to its receptor and upstream of IP3 formation. The lack of effect of dbcGMP on [3H]bradykinin binding suggests that the decrease in receptor number induced by bradykinin was mediated by a different mechanism and was not a key factor in the rapid phase of desensitization in these cells.
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McAllister, B. S., F. Leeb-Lundberg, and M. S. Olson. "Bradykinin inhibition of EGF- and PDGF-induced DNA synthesis in human fibroblasts." American Journal of Physiology-Cell Physiology 265, no. 2 (August 1, 1993): C477—C484. http://dx.doi.org/10.1152/ajpcell.1993.265.2.c477.
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Bradykinin exhibits proliferative influences in several types of cells; however, in the present study, bradykinin did not promote DNA synthesis but actually inhibited the DNA synthesis induced by epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) in human gingival fibroblasts (HGF). This dose-dependent inhibitory effect was a specific intracellular interaction in that increasing concentrations of EGF did not counteract the inhibitory actions of bradykinin when added at 100 nM. The phosphoinositide-calcium signaling cascade is a likely point of interaction for the inhibitory influences of bradykinin; however, no interactions between bradykinin and EGF were observed with the generation of inositol phosphates or intracellular calcium fluxes. The inhibitory influences of bradykinin do not appear to be the result of a transmodulation of the EGF receptor, since EGF-mediated autophosphorylation was not negatively affected by bradykinin. Bradykinin-stimulated prostaglandin E2 (PGE2) release was potentiated by EGF, and, in the presence of indomethacin, the inhibition of the EGF-induced DNA synthesis by bradykinin was minimized. The results presented demonstrate that bradykinin can inhibit EGF- and PDGF-induced DNA synthesis and suggest that PGE2 synthesis is responsible for the observed bradykinin inhibition of EGF-induced DNA synthesis.
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Gauthier, Kathryn M., Cody J. Cepura, and William B. Campbell. "ACE inhibition enhances bradykinin relaxations through nitric oxide and B1 receptor activation in bovine coronary arteries." Biological Chemistry 394, no. 9 (September 1, 2013): 1205–12. http://dx.doi.org/10.1515/hsz-2012-0348.
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Abstract Bradykinin causes vascular relaxations through release of endothelial relaxing factors including prostacyclin, nitric oxide (NO) and epoxyeicosatrienoic acids (EETs). Bradykinin is metabolized by angiotensin converting enzyme (ACE) and ACE inhibition enhances bradykinin relaxations. Our goal was to characterize the role of bradykinin receptors and endothelial factors in ACE inhibitor-enhanced relaxations in bovine coronary arteries. In U46619 preconstricted arteries, bradykinin (10-11-10-8m) caused concentration-dependent relaxations (maximal relaxation ≥100%, log EC50=-9.8±0.1). In the presence of the NO synthase inhibitor, N-nitro-L-arginine (L-NA, 30 μm) and the cyclooxygenase inhibitor, indomethacin (10 μm), relaxations were reduced by an inhibitor of EET synthesis, miconazole (10 μm) (maximal relaxation=55±10%). Bradykinin relaxations were inhibited by the bradykinin 2 (B2) receptor antagonist, D-Arg0-Hyp3-Thi5,8-D-Phe7-bradykinin (1 μm) (log EC50=-8.5±0.1) but not altered by the B1 receptor antagonist, des-Arg9[Leu8]bradykinin (1 μm). Mass spectrometric analysis of bovine coronary artery bradykinin metabolites revealed a time-dependent increase in bradykinin (1–5) and (1–7) suggesting metabolism by ACE. ACE inhibition with captopril (50 μm) enhanced bradykinin relaxations (log EC50=-10.3±0.1). The enhanced relaxations were eliminated by L-NA or the B1 receptor antagonist but not the B2 receptor antagonist. Our results demonstrate that ACE inhibitor-enhanced bradykinin relaxations of bovine coronary arteries occur through endothelial cell B1 receptor activation and NO.
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Asano, Masayuki, Hiroe Sawai, Chie Hatori, Noriaki Inamura, Tatsujiro Fujiwara, and Kunio Nakahara. "Effects of a nonpeptide bradykinin B2 receptor antagonist, FR167344, on guinea-pig tracheal smooth muscle bradykinin receptors." Canadian Journal of Physiology and Pharmacology 76, no. 10-11 (October 1, 1998): 1051–55. http://dx.doi.org/10.1139/y98-098.
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It is speculated that bradykinin may play an important role in asthma. Thus, bradykinin receptor antagonists may have therapeutic potential against asthma. Orally active bradykinin antagonists would be more desirable for the treatment of the disease. In the present study, we examined the effects of a novel, potent, selective, and orally active nonpeptide bradykinin B2 receptor antagonist, FR167344 (N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]- 2,4-dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethylaminocarbonyl)cinnamylamide hydrochloride), on guinea-pig tracheal smooth muscle bradykinin receptors. FR167344 inhibited [3H]bradykinin binding to bradykinin receptors in epithelium-denuded guinea-pig tracheal membrane with an IC50 of 2.1 nM and a Ki of 0.44 nM. This compound also inhibited bradykinin-induced contraction of epithelium-denuded guinea-pig trachea with a pKB of 10.8, but had no effect on carbachol-induced contraction of the trachea even at 10-6 M. These results indicate that FR167344 has the specific antagonistic activity against guinea-pig tracheal smooth muscle bradykinin receptors.Key words: bradykinin, receptor, antagonist, FR167344, trachea.
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Grafe, M., C. Bossaller, K. Graf, W. Auch-Schwelk, C. R. Baumgarten, A. Hildebrandt, and E. Fleck. "Effect of angiotensin-converting-enzyme inhibition on bradykinin metabolism by vascular endothelial cells." American Journal of Physiology-Heart and Circulatory Physiology 264, no. 5 (May 1, 1993): H1493—H1497. http://dx.doi.org/10.1152/ajpheart.1993.264.5.h1493.
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The degradation of bradykinin by angiotensin-converting-enzyme (ACE) activity in cultured human endothelial cells was studied by direct measurement of bradykinin and by its effect on the release of endothelium-derived relaxing factors. The half-life of exogenous bradykinin (10,000 pg/ml) was calculated from the decay of the bradykinin concentration as 46 +/- 2 min in cell monolayers, 133 +/- 15 min in conditioned medium, and 24 +/- 2 min in homogenates. Most of the bradykinin-degrading activity in cell monolayers could be inhibited in a concentration-dependent manner by the ACE inhibitors lisinopril, ramiprilat, and captopril. Bradykinin-degrading activity was released into the culture medium containing one-fourth of the bradykinin-degrading activity found in the presence of cell monolayers. In cell homogenates higher unspecific bradykinin-degrading activities were present. The functional consequence of bradykinin degradation was demonstrated by the potentiating effect of ramiprilat on the generation of endothelium-derived relaxing factors nitric oxide and prostacyclin from endothelial cells. The study supports the concept of increased vasodilatory effects of bradykinin during ACE inhibition.
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Berman, A. R., A. G. Togias, G. Skloot, and D. Proud. "Allergen-induced hyperresponsiveness to bradykinin is more pronounced than that to methacholine." Journal of Applied Physiology 78, no. 5 (May 1, 1995): 1844–52. http://dx.doi.org/10.1152/jappl.1995.78.5.1844.
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Bradykinin reduces airflow in asthmatic patients via indirect mechanism(s), possibly involving sensory nerve stimulation and increased vascular permeability. We hypothesized that allergen inhalation, which affects reactivity of nerves and vessels, would differentially alter reactivity to bradykinin and the smooth muscle spasmogen methacholine. We compared reactivity to methacholine and bradykinin 1, 2, 4, 7, 11, and 14 days after allergen provocation in 12 atopic asthmatic patients with stable baseline reactivity to bradykinin. Maximal allergen-induced shifts from baseline in reactivity were 0.73 +/- 0.12 log unit for bradykinin compared with 0.27 +/- 0.13 log units for methacholine (P = 0.0005). Nine subjects showed significant increases in bradykinin reactivity, with four subjects increasing reactivity by > 1 log unit. Moreover, the maximal mean change in bradykinin reactivity occurred 2 days postallergen. Thus, allergen-induced changes in reactivity to bradykinin and methacholine differ in magnitude and time course. Bradykinin inhalational challenge provides a sensitive index of the airway's response to allergen.
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Kajekar, Radhika, and Allen C. Myers. "Effect of bradykinin on membrane properties of guinea pig bronchial parasympathetic ganglion neurons." American Journal of Physiology-Lung Cellular and Molecular Physiology 278, no. 3 (March 1, 2000): L485—L491. http://dx.doi.org/10.1152/ajplung.2000.278.3.l485.
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The effect of bradykinin on membrane properties of parasympathetic ganglion neurons in isolated guinea pig bronchial tissue was studied using intracellular recording techniques. Bradykinin (1–100 nM) caused a reversible membrane potential depolarization of ganglion neurons that was not associated with a change in input resistance. The selective bradykinin B2 receptor antagonist HOE-140 inhibited bradykinin-induced membrane depolarizations. Furthermore, the cyclooxygenase inhibitor indomethacin attenuated bradykinin-induced membrane depolarizations to a similar magnitude (∼70%) as HOE-140. However, neurokinin-1 and -3 receptor antagonists did not have similar inhibitory effects. The ability of bradykinin to directly alter active properties of parasympathetic ganglion neurons was also examined. Bradykinin (100 nM) significantly reduced the duration of the afterhyperpolarization (AHP) that followed four consecutive action potentials. The inhibitory effect of bradykinin on the AHP response was reversed by HOE-140 but not by indomethacin. These results indicate that bradykinin can stimulate airway parasympathetic ganglion neurons independent of sensory nerve activation and provide an alternative mechanism for regulating airway parasympathetic tone.
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SCHANSTRA, JOOST P., MARIA E. MARIN-CASTAÑO, FRANÇOISE PRADDAUDE, IVAN TACK, JEAN-LOUIS ADER, JEAN-PIERRE GIROLAMI, JEAN-LOUP BASCANDS, and BENOIT JEUNIER. "Bradykinin B1Receptor-Mediated Changes in Renal Hemodynamics during Endotoxin-Induced Inflammation." Journal of the American Society of Nephrology 11, no. 7 (July 2000): 1208–15. http://dx.doi.org/10.1681/asn.v1171208.
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Abstract. Kinins have been shown to influence renal hemodynamics and function. Under physiologic conditions, most kinin effects involve bradykinin B2receptors, but bradykinin B1receptors are often induced during inflammation. The purpose of this study was to examinein vivothe effects of bradykinin B1receptor activation on renal hemodynamics under normal and inflammatory conditions. In anesthetized rats, activation of bradykinin B1receptors by arterial infusion of bradykinin B1receptor agonist des-Arg9-bradykinin reduced renal plasma flow and GFR. Prior administration (18 h) of lipopolysaccharide to induce inflammation resulted in a larger bradykinin B1receptor-induced reduction in renal plasma flow. Values of other parameters remained unchanged, thus resulting in an increased filtration fraction. The presence and the functionality of the bradykinin B1receptor at the level of glomerular afferent and efferent arterioles were studied by mRNA expression analysis and intracellular calcium ([Ca2+]i) mobilization studies. Stimulation with des-Arg9-bradykinin of microdissected afferent arterioles from control and lipopolysaccharide-treated rats induced [Ca2+]imobilization without any significant difference in amplitude between control and lipopolysaccharidetreated rats. However, des-Arg9-bradykinin only induced [Ca2+]imobilization in efferent arterioles from lipopolysaccharide-treated rats. It is suggested that activation of bradykinin B1receptors located along the efferent arteriole may participate in the modification of renal hemodynamics in inflammatory states.
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Bertrand, C., P. Geppetti, J. Baker, G. Petersson, G. Piedimonte, and J. A. Nadel. "Role of peptidases and NK1 receptors in vascular extravasation induced by bradykinin in rat nasal mucosa." Journal of Applied Physiology 74, no. 5 (May 1, 1993): 2456–61. http://dx.doi.org/10.1152/jappl.1993.74.5.2456.
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We used Evans blue dye to assess the effects of bradykinin on vascular extravasation in nasal mucosa of pathogen-free F344 rats. There was a dose-dependent increase in Evans blue extravasation when bradykinin was delivered by topical instillation in the nose (doses, 25–100 nmol). Only the highest intravenous doses (2 and 5 mumol/kg) of bradykinin caused increased extravasation. When bradykinin was delivered by either route, its effect on extravasation was exaggerated by pharmacological inhibition of the enzymes neutral endopeptidase (NEP) and kininase II [angiotensin-converting enzyme (ACE)]. When bradykinin was instilled locally, the effect of NEP inhibition was predominant; when bradykinin was injected intravenously, the effect of ACE inhibition was predominant. The mechanism of extravasation also varied with the mode of bradykinin delivery: when bradykinin was instilled locally in the nose, the selective neurokinin 1 (NK1) receptor antagonist CP-96,345 markedly inhibited the response, whereas it had no effect on Evans blue extravasation when bradykinin was injected intravenously. We conclude that bradykinin causes dose-related increases in Evans blue dye extravasation in the nose and that these effects are exaggerated when NEP and ACE are inhibited. Topically instilled bradykinin causes vascular extravasation to a large extent via NK1 receptor stimulation, thus suggesting a major role for tachykinins released from sensory nerve endings.
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Feletou, M., M. Germain, and B. Teisseire. "Converting-enzyme inhibitors potentiate bradykinin-induced relaxation in vitro." American Journal of Physiology-Heart and Circulatory Physiology 262, no. 3 (March 1, 1992): H839—H845. http://dx.doi.org/10.1152/ajpheart.1992.262.3.h839.
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Experiments were designed to study the effects of converting-enzyme inhibitors (captopril and S 10211) on the endothelium-dependent relaxation to bradykinin in isolated porcine arteries. Rings of femoral arteries with and without endothelium were suspended in organ chambers to record isometric tension. Rings of coronary arteries without endothelium were used as bioassay tissue to record release of endothelium-derived relaxing factor (EDRF) from perfused femoral arteries. In organ chambers, bradykinin induced endothelium-dependent relaxation and, inconsistently, endothelium-independent contraction of the femoral artery rings. The relaxation is mediated by endothelial B2 bradykinin receptors, the contraction through B1 bradykinin receptors. Converting-enzyme inhibitors induced a weak potentiation of the contractile response and weak or no potentiation of the endothelium-dependent relaxation. In the presence of indomethacin, the response to bradykinin was not modified and no potentiation from the inhibitor could be observed. Blockade of the contractile response with a B1 bradykinin antagonist did not unmask a potentiation of the bradykinin endothelium-dependent relaxation by the converting-enzyme inhibitors. However, in the presence of B2 bradykinin antagonist, when high concentrations of bradykinin are required to induce relaxation, converting-enzyme inhibitors potentiated the effects of bradykinin. In contrast, in bioassay conditions with a perfused vascular segment, converting-enzyme inhibitors selectively enhanced the release of EDRF by bradykinin. This effect is observed in the bioassay tissue and in the donor segment. These results suggest that converting enzyme is indeed a powerful modulator of bradykinin action and that other enzymatic pathways of bradykinin metabolism present in the vascular wall could mask its action.
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Wilkes, B. M., and P. F. Mento. "Bradykinin-induced vasoconstriction and thromboxane release in perfused human placenta." American Journal of Physiology-Endocrinology and Metabolism 254, no. 6 (June 1, 1988): E681—E686. http://dx.doi.org/10.1152/ajpendo.1988.254.6.e681.
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This investigation was performed to study the effects of bradykinin on the human fetoplacental circulation. The artery to a single placental cotyledon was perfused with RPMI medium (0.764 ml/min). Bradykinin caused a dose-related increase in vascular resistance. Because bradykinin is generally a vasodilator, we investigated the possibility that bradykinin-induced vasoconstriction was due to interactions with other pressor systems. Bradykinin and 9,11-dideoxy-9 alpha, 11 alpha-epoxymethanoprostaglandin F2 alpha (a stable thromboxane agonist) caused a dose-related increase in perfusion pressure. The bradykinin response was not mediated by angiotensin II, because bradykinin-induced vasoconstriction was not inhibited by saralasin, a competitive angiotensin antagonist. Bradykinin increased thromboxane B2 production by 62.0%. Prostaglandin E2 levels were increased by 86.7%, but prostaglandin E2 did not affect fetoplacental vascular resistance. Angiotensin II did not stimulate thromboxane B2 production and caused only a slight increase in prostaglandin E2. Indomethacin decreased the pressor response to angiotensin II. SQ29548, a specific thromboxane antagonist, caused a 61.6% inhibition of the bradykinin pressor response but did not change angiotensin II responsiveness. The data demonstrate that thromboxane is an important mediator of bradykinin-induced vasoconstriction in the isolated perfused human placenta.
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Yamawaki, I., P. Geppetti, C. Bertrand, B. Chan, and J. A. Nadel. "Airway vasodilation by bradykinin is mediated via B2 receptors and modulated by peptidase inhibitors." American Journal of Physiology-Lung Cellular and Molecular Physiology 266, no. 2 (February 1, 1994): L156—L162. http://dx.doi.org/10.1152/ajplung.1994.266.2.l156.
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We studied the effect of exogenous bradykinin on blood flow in the airway microcirculation of anesthetized F344 rats in vivo. We made three successive determinations of airway blood flow and cardiac output using a modification of the reference sample microsphere technique. Injection of bradykinin into the left ventricle increased airway blood flow in a dose-related manner. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, completely abolished bradykinin-, but not histamine-induced vasodilation. A bradykinin B1 receptor agonist, [des-Arg9]bradykinin, did not affect airway blood flow. We also studied the effect of inhibitors of angiotensin-converting enzyme (captopril) and neutral endopeptidase (phosphoramidon) on bradykinin-induced vasodilation. Pretreatment with captopril, but not phosphoramidon, potentiated the bradykinin-induced vasodilation. However, the addition of phosphoramidon further potentiated the effect of captopril. We conclude that injection of bradykinin into the left ventricle produces a dose-related vasodilation in the airway microcirculation mediated via B2 receptors, an effect that is modulated primarily by angiotensin-converting enzyme and, to a lesser extent, by neutral endopeptidase.
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Polosa, R., K. Rajakulasingam, G. Prosperini, LV Milazzo, G. Santonocito, and ST Holgate. "Cross-tachyphylactic airway response to inhaled bradykinin, kallidin and [desArg9]-bradykinin in asthmatic subjects." European Respiratory Journal 6, no. 5 (May 1, 1993): 687–93. http://dx.doi.org/10.1183/09031936.93.06050687.
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Kinins are oligopeptides that may act as mediators in the pathogenesis of bronchial asthma by interacting with specific cell surface receptors designated B1 and B2. When administered by inhalation to asthmatic subjects, bradykinin and kallidin, but not [desArg9]-bradykinin, provoke potent bronchoconstriction, thus suggesting a specific effect compatible with the stimulation of B2 receptors. To characterize further the receptor(s) mediating this bronchospastic response we have carried out cross-tachyphylactic studies with inhaled bradykinin, kallidin, and [desArg9]-bradykinin, administered in a randomized double-blind fashion in a group of 10 asthmatic subjects. Inhalation of bradykinin and kallidin, but not [desArg9]-bradykinin, elicited concentration-related falls in forced expiratory volume in one second (FEV1) in all the subjects studied. The geometric mean provocation concentrations of inhaled agonists reducing FEV1 by 20% of baseline (PC20) were 0.12 and 0.28 mg.ml-1 for bradykinin and kallidin, respectively. When inhaled at concentrations up to 10.62 mg.ml-1, [desArg9]-bradykinin failed to provoke any significant fall in FEV1 from baseline in any of the subjects studied. Following recovery from the second bradykinin challenge, provocation with kallidin revealed a reduced response to this agonist, the PC20 value increasing from 0.28 to 1.23 mg.ml-1. Similarly, once the airways had recovered from the second kallidin challenge, provocation with bradykinin also showed a reduced response, the PC20Bk increasing from 0.12 to 0.94 mg.ml-1. Surprisingly, despite failing to cause bronchoconstriction, repeated exposures with inhaled [desArg9]-bradykinin reduced the airway response to bradykinin, the PC20Bk increasing from 0.12 to 0.41 mg.ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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Yang, C., and W. H. Hsu. "Stimulatory effect of bradykinin on insulin release from the perfused rat pancreas." American Journal of Physiology-Endocrinology and Metabolism 268, no. 5 (May 1, 1995): E1027—E1030. http://dx.doi.org/10.1152/ajpendo.1995.268.5.e1027.
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Rat pancreas perfusion was performed to study the effect of bradykinin on insulin release. At the perfusate glucose concentration of 6 mM, bradykinin (0.01-1 microM) increased insulin release in a concentration-dependent manner. In addition, bradykinin (1 microM) increased the glucose (10 mM)-induced insulin release. HOE-140 (0.1 microM), a bradykinin B2-receptor antagonist, decreased the baseline insulin release and abolished the bradykinin (1 microM)-induced increase in insulin release. In addition, HOE-140 (0.1 microM) attenuated the glucose (10 mM)-induced increase in insulin release. Because the blockade of bradykinin receptors by HOE-140 attenuated the glucose-induced increased insulin release, our present findings suggest that bradykinin may play a physiological role in the regulation of insulin release.
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GRANESS, Angela, Sabine HANKE, Frank D. BOEHMER, Peter PRESEK, and Claus LIEBMANN. "Protein-tyrosine-phosphatase-mediated epidermal growth factor (EGF) receptor transinactivation and EGF receptor-independent stimulation of mitogen-activated protein kinase by bradykinin in A431 cells." Biochemical Journal 347, no. 2 (April 10, 2000): 441–47. http://dx.doi.org/10.1042/bj3470441.
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Transactivation of the epidermal growth factor (EGF) receptor (EGFR) has been proposed to represent an essential link between G-protein-coupled receptors and the mitogen-activated protein kinase (MAPK) pathway in various cell types. In the present work we report, in contrast, that in A431 cells bradykinin transinactivates the EGFR and stimulates MAPK activity independently of EGFR tyrosine phosphorylation. Both effects of bradykinin are mediated by a pertussis-toxin-insensitive G-protein. Three lines of evidence suggest the activation of a protein tyrosine phosphatase (PTP) by bradykinin: (i) treatment of A431 cells with bradykinin decreases both basal and EGF-induced EGFR tyrosine phosphorylation, (ii) this effect of bradykinin can be blocked by two different PTP inhibitors, and (iii) bradykinin significantly increased the PTP activity in total A431 cell lysates when measured in vitro. The transmembrane receptor PTP σ was identified as a putative mediator of bradykinin-induced downregulation of EGFR autophosphorylation. Activation of MAPK in response to bradykinin was insensitive towards AG 1478, a specific inhibitor of EGFR tyrosine kinase, but was blocked by wortmannin or bisindolylmaleimide, inhibitors of phosphatidylinositol 3-kinase (PI3-K) and protein kinase C (PKC) respectively. These results also suggest that the bradykinin-induced activation of MAPK is independent of EGFR and indicate a pathway involving PI3-K and PKC. In addition, bradykinin evokes a rapid and transient increase in Src kinase activity. Although Src does not participate in bradykinin-induced stimulation of PTP activity, inhibition of Src by 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine leads to an increase in MAPK activation by bradykinin. Our results suggest that in A431 cells the Gq/11-protein-coupled bradykinin B2 receptor may stimulate PTP activity and thereby transinactivate the EGFR, and may simultaneously activate MAPK by an alternative signalling pathway which can bypass EGFR.
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Lebrun, Ivo, Olga B. Henriques, Fabiana L. A. S. Lebrun, Adriana K. Carmona, Luiz Juliano, and Antonio C. M. Camargo. "Isolation and characterization of a new bradykinin potentiating octapeptide from γ-casein." Canadian Journal of Physiology and Pharmacology 73, no. 1 (January 1, 1995): 85–91. http://dx.doi.org/10.1139/y95-012.
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Peptides that display bradykinin-potentiating activity have been obtained from a number of distinct sources, such as snake venoms, fibrinogen, and casein. This paper describes the isolation and sequencing of a novel bradykinin-potentiating peptide, generated by tryptic hydrolysis of the γ-casein chain. No homology was found to other known vasoactive or vasopotentiating peptides. The octapeptide Tyr-Pro-Val-Gln-Pro-Phe-Thr-Glu, corresponding to the γ-casein(114–121) sequence, was isolated from the tryptic hydrolysis of γ-casein and also synthesized by solid-phase peptide synthesis. Both natural and synthetic peptides had the same retention time in HPLC and displayed a selective potentiating activity on isolated guinea-pig ileum for bradykinin and Lys-bradykinin but were not able to potentiate the effects of Met-Lys-bradykinin, Ile-Ser-bradykinin, angiotensin II, acetylcholine, or histamine. Intravenous injections of bradykinin and of bradykinin-potentiating octapeptide produced a persistent hypotension in conscious rats, a pattern that was not obtained when the octapeptide was replaced by captopril. This bradykinin-potentiating octapeptide is a strong competitive inhibitor of endo-oligopeptidase A (EC 3.4.24.15, formerly EC 3.4.22.19), but it has low inhibitory potency towards angiotensin-converting enzyme (EC 3.4.15.1). Thus, our results suggest that other peptidases in addition to angiotensin-converting enzyme, such as endo-oligopeptidase A, may contribute to the reduction of the effective concentration of bradykinin in the circulation.Key words: bradykinin, potentiating peptides, casein, endo-oligopeptidase A, angiotensin-converting enzyme, smooth muscle, rat arterial blood pressure.
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Santiago, J. A., E. A. Garrison, and P. J. Kadowitz. "Analysis of responses to bradykinin: effects of Hoe-140 in the hindquarters vascular bed of the cat." American Journal of Physiology-Heart and Circulatory Physiology 267, no. 2 (August 1, 1994): H828—H836. http://dx.doi.org/10.1152/ajpheart.1994.267.2.h828.
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The mechanisms and receptor subtype mediating vasodilator responses to bradykinin were investigated in the hindquarters vascular bed of the cat under constant flow conditions. Intraarterial injections of bradykinin in doses of 10–1,000 ng into the hindquarters vascular bed caused dose-related decreases in perfusion pressure that were inhibited by Hoe-140, a bradykinin B2-receptor antagonist. Injections of des-Arg9-bradykinin (in doses 10-fold higher than for bradykinin) caused smaller dose-related decreases in hindquarters perfusion pressure that were not blocked by Hoe-140. Administration of atropine, glibenclamide, or cyclooxygenase inhibitors did not alter vasodilator responses to bradykinin, suggesting that activation of muscarinic receptors, ATP-sensitive K+ channels, or prostaglandin release is not involved in the response to the peptide. Administration of N omega-nitro-L-arginine and its methyl ester reduced vasodilator responses to bradykinin, acetylcholine, and substance P, whereas responses to endothelium-independent vasodilator agents were not attenuated. Decreases in systemic arterial pressure and in hindquarters perfusion pressure in response to bradykinin were enhanced by the angiotensin-converting enzyme inhibitors captopril and enalaprilat. These results suggest that hindquarters vasodilator responses to bradykinin are mediated by activation of kinin B2 receptors and in part by the release of nitric oxide. These data also suggest the presence of bradykinin B1 receptors, mediating vasodilation in the hindquarters vascular bed. These results indicate that bradykinin is rapidly inactivated by angiotensin-converting enzyme in the lung and in the hindquarters vascular bed of the cat.
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Yokoyama, S., and J. N. Benoit. "Effects of bradykinin on lymphatic pumping in rat mesentery." American Journal of Physiology-Gastrointestinal and Liver Physiology 270, no. 5 (May 1, 1996): G752—G756. http://dx.doi.org/10.1152/ajpgi.1996.270.5.g752.
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The effects of bradykinin on lymphatic pump activity of rat mesenteric collecting duct were studied, and the receptor subtype responsible for the bradykinin response was evaluated. Rats were anesthetized with intraperitoneal alpha-chloralose and urethan, and exteriorized mesenteries were studied using intravital microscopic techniques. The diameter of the collecting lymph vessels (approximately 100 microns) was continuously monitored and lymphatic pump parameters (end diastolic diameter, end systolic diameter, stroke volume index, ejection fraction, contraction frequency, and pump flow index) were calculated. Bradykinin (0.1-1.0 nM) did not affect end diastolic diameter, end systolic diameter, stroke volume index, and ejection fraction. Bradykinin increased lymphatic contraction frequency and pump flow index in a dose-dependent manner. Des-Arg9-[Leu8]bradykinin (B1 antagonist, 0.1 microM) had no effect on baseline lymphatic pumping but completely inhibited the bradykinin-induced increase in contraction frequency. N-acetyl-D-Arg-[Hyp3,Thi5,8,D-Phe7] bradykinin (B2 antagonist, 0.1 microM) significantly depressed lymphatic contraction frequency in baseline conditions but had no effect on bradykinin-induced increases in contraction frequency. These results indicate that bradykinin induces positive chronotropic but not inotropic effects on lymphatic pump activity through the stimulation of B1 receptors.
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Ignarro, L. J., R. E. Byrns, G. M. Buga, and K. S. Wood. "Mechanisms of endothelium-dependent vascular smooth muscle relaxation elicited by bradykinin and VIP." American Journal of Physiology-Heart and Circulatory Physiology 253, no. 5 (November 1, 1987): H1074—H1082. http://dx.doi.org/10.1152/ajpheart.1987.253.5.h1074.
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The objective of this study was to elucidate the mechanisms by which bradykinin and vasoactive intestinal polypeptide (VIP) relax bovine intrapulmonary artery and bradykinin, but not VIP, relaxes intrapulmonary vein. Bradykinin and VIP elicited entirely endothelium-dependent relaxation of phenylephrine-precontracted arterial rings, and this was associated with arterial accumulation of both guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP). Bradykinin, but not VIP, relaxed precontracted venous rings and increased cGMP, but not cAMP levels, by endothelium-dependent mechanisms. Neither arteries nor veins relaxed in response to substance P, thrombin, bombesin, arginine vasopressin, or angiotensin II. Methylene blue or indomethacin each partially antagonized, whereas both, when together, abolished arterial relaxant responses to bradykinin and VIP. Methylene blue or indomethacin, respectively, abolished arterial cGMP or cAMP accumulation elicited by bradykinin and VIP. Venous relaxation and cGMP accumulation elicited by bradykinin was abolished by methylene blue but was unaltered by indomethacin. Thus bradykinin and VIP relaxed bovine intrapulmonary artery by endothelium-dependent mechanisms involving the actions of cGMP and cAMP whose formation may be stimulated by endothelium-derived relaxing factor and prostacyclin, respectively. In contrast, bradykinin relaxed intrapulmonary vein by endothelium-dependent mechanisms involving only cGMP.
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Krieg, Thomas, Qining Qin, Sebastian Philipp, Mikhail F. Alexeyev, Michael V. Cohen, and James M. Downey. "Acetylcholine and bradykinin trigger preconditioning in the heart through a pathway that includes Akt and NOS." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 6 (December 2004): H2606—H2611. http://dx.doi.org/10.1152/ajpheart.00600.2004.
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In the rabbit heart, bradykinin and ACh trigger preconditioning by a mechanism involving ATP-sensitive potassium channel-dependent production of reactive oxygen species (ROS). Recent evidence indicates that the pathway by which bradykinin causes ROS generation includes nitric oxide synthase (NOS) and protein kinase G (PKG). On the other hand, Akt was shown to be essential for ACh to generate ROS. This study determines whether these two G-coupled receptor agonists indeed have similar signaling targets, i.e., whether Akt is involved in bradykinin's pathway and whether NOS is involved in ACh's pathway. Isolated adult rabbit cardiomyocytes were incubated for 15 min in reduced MitoTracker red, which becomes fluorescent only after exposure to ROS. Bradykinin (400 nM) and ACh (250 μM) caused a 51.4 ± 14.8% and 39.8 ± 11.7% increase, respectively, in ROS production ( P < 0.005). Coincubation of either agonist with Akt inhibitor (20 μM) or infection of cells with an adenovirus containing dominant negative Akt abolished this increase. The NO donor S-nitroso- N-acetyl penicillamine (SNAP, 1 μM) also increased the ROS signal by 40.8 ± 15.7%, but this increase was unaffected by Akt inhibitor (39.0 ± 6.4%), implying that Akt is upstream of NOS. ACh-induced ROS production could be abolished by either of the NOS inhibitors Nω-monomethyl-l-arginine monoacetate (100 μM) and l- N5-(1-iminoethyl)ornithine hydrochloride (l-NIO, 5 μM). l-NIO also blocked the anti-infarct effect of ACh (550 μM) in isolated rabbit hearts exposed to 30 min of regional ischemia. We conclude that both bradykinin and ACh trigger ROS generation by sequentially activating Akt and NOS.
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Majumder, Syamantak, Ravi Gupta, Himabindu Reddy, Swaraj Sinha, Ajit Muley, Gopi Krishna Kolluru, and Suvro Chatterjee. "Cadmium attenuates bradykinin-driven nitric oxide production by interplaying with the localization pattern of endothelial nitric oxide synthase." Biochemistry and Cell Biology 87, no. 4 (August 2009): 605–20. http://dx.doi.org/10.1139/o09-018.
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Cadmium, a ubiquitous heavy metal, interferes with endothelial functions and angiogenesis. Bradykinin is a Ca-mobilizing soluble peptide that acts via nitric oxide to promote vasodilation and capillary permeability. The objective of the present study was to explore the Cd implications in bradykinin-dependent endothelial functions. An egg yolk angiogenesis model was employed to evaluate the effect of Cd on bradykinin-induced angiogenesis. The results demonstrate that 100 nmol/L Cd attenuated bradykinin-dependent angiogenesis. The results of the in vitro wound healing and tube formation assays by using EAhy 926, a transformed endothelial cell line, suggest that Cd blocked bradykinin-mediated endothelial migration and tube formation by 38% and 67%, respectively, while nitric oxide supplementation could reverse the effect of Cd on bradykinin-induced endothelial migration by 94%. The detection of nitric oxide by using a DAF-2DA fluorescent probe, Griess assay, and ultrasensitive electrode suggests that Cd blocked bradykinin-induced nitric oxide production. Fluorescence imaging of eNOS-GFP transfected endothelial cells, immunofluroscence, and Western blot studies of Cd and bradykinin-treated cells show that Cd interfered with the localization pattern of eNOS, which possibly attenuates nitric oxide production in part. Additionally, Ca imaging of Cd- and bradykinin-treated cells suggests that Cd blocked bradykinin-dependent Ca influx into the cells, thus partially blocking Ca-dependent nitric oxide production in endothelial cells. The results of this study conclude that Cd blunted the effect of bradykinin by interfering with the Ca-associated NOS activity specifically by impeding subcellular trafficking of eNOS.
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Rollins, Korynne S., Joshua R. Smith, Peter J. Esau, Evan A. Kempf, Tyler D. Hopkins, and Steven W. Copp. "Bradykinin does not acutely sensitize the reflex pressor response during hindlimb skeletal muscle stretch in decerebrate rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 313, no. 4 (October 1, 2017): R463—R472. http://dx.doi.org/10.1152/ajpregu.00187.2017.
Full textAbstract:
Hindlimb skeletal muscle stretch (i.e., selective activation of the muscle mechanoreflex) in decerebrate rats evokes reflex increases in blood pressure and sympathetic nerve activity. Bradykinin has been found to sensitize mechanogated channels through a bradykinin B2 receptor-dependent mechanism. Moreover, bradykinin B2 receptor expression on sensory neurons is increased following chronic femoral artery ligation in the rat (a model of simulated peripheral artery disease). We tested the hypothesis that injection of bradykinin into the arterial supply of a hindlimb in decerebrate, unanesthetized rats would acutely augment (i.e., sensitize) the increase in blood pressure and renal sympathetic nerve activity during hindlimb muscle stretch to a greater extent in rats with a ligated femoral artery than in rats with a freely perfused femoral artery. The pressor response during static hindlimb muscle stretch was compared before and after hindlimb arterial injection of 0.5 µg of bradykinin. Injection of bradykinin increased blood pressure to a greater extent in “ligated” ( n = 10) than “freely perfused” ( n = 10) rats. The increase in blood pressure during hindlimb muscle stretch, however, was not different before vs. after bradykinin injection in freely perfused (14 ± 2 and 15 ± 2 mmHg for pre- and post-bradykinin, respectively, P = 0.62) or ligated (15 ± 3 and 14 ± 2 mmHg for pre- and post-bradykinin, respectively, P = 0.80) rats. Likewise, the increase in renal sympathetic nerve activity during stretch was not different before vs. after bradykinin injection in either group of rats. We conclude that bradykinin did not acutely sensitize the pressor response during hindlimb skeletal muscle stretch in freely perfused or ligated decerebrate rats.
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Merker, Marilyn P., Said H. Audi, Becky M. Brantmeier, Kasem Nithipatikom, Robert S. Goldman, David L. Roerig, and Christopher A. Dawson. "Proline in vasoactive peptides: consequences for peptide hydrolysis in the lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 276, no. 2 (February 1, 1999): L341—L350. http://dx.doi.org/10.1152/ajplung.1999.276.2.l341.
Full textAbstract:
To examine the hypothesis that trans isomers of bradykinin and [Gly6]bradykinin are preferentially hydrolyzed by lung peptidases, we studied the fractional inactivation of these peptides in the perfused rat lung using a bioassay after a single-pass bolus injection and high-performance liquid chromatography after lung recirculation. In the bioassay studies, when the peptides passed through the lung, 25.6-fold more bradykinin or 7-fold more [Gly6]bradykinin was required to elicit a contraction equivalent to that produced when the peptides did not pass through the lung. In the recirculation studies, hydrolysis progress curves with rapid and slow phases were observed, with a higher fraction of bradykinin than [Gly6]bradykinin hydrolyzed in the rapid phase. Cyclophilin increased the hydrolysis rate during the slow phase for both peptides. Kinetic analysis indicated that the slowly hydrolyzed peptide fraction, presumably the cis fraction, was 0.13 for bradykinin and 0.43 for [Gly6]bradykinin with cis- transisomerization rate constants of 0.074 and 0.049 s−1, respectively, consistent with published nuclear magnetic resonance studies.
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Nerdrum, T., D. G. Baker, H. M. Coleridge, and J. C. Coleridge. "Interaction of bradykinin and prostaglandin E1 on cardiac pressor reflex and sympathetic afferents." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 250, no. 5 (May 1, 1986): R815—R822. http://dx.doi.org/10.1152/ajpregu.1986.250.5.r815.
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Bradykinin applied to the epicardium stimulates cardiac sympathetic afferents and evokes a reflex increase in arterial blood pressure. In anesthetized cats we examined the potentiation of these effects by prostaglandin E1 (PGE1) applied to the ventricular epicardium. We recorded cardiac afferent impulses from the second to the fifth left thoracic sympathetic rami. PGE1 (0.1 microgram/ml) alone had little effect on blood pressure, but it significantly increased the pressor response to bradykinin, and it reduced or abolished tachyphylaxis to repeated applications of bradykinin. Both mechanosensitive and chemosensitive sympathetic cardiac afferents were stimulated by bradykinin. Indomethacin (intravenous) caused a small reduction in the afferent response to bradykinin. Epicardial application of PGE1 significantly increased the response (magnitude and duration) of chemosensitive endings to bradykinin but not that of mechanosensitive endings; however, PGE1 abolished the tachyphylaxis of both chemosensitive and mechanosensitive endings to repeated applications of bradykinin. Because both bradykinin and prostaglandins are released in the ischemic myocardium, their interactive effect on cardiac sympathetic afferents could play a part in the sensory and reflex responses to myocardial ischemia.
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Sun, Ding-Ping, Yuan-Wen Lee, Jui-Tai Chen, Yung-Wei Lin, and Ruei-Ming Chen. "The Bradykinin-BDKRB1 Axis Regulates Aquaporin 4 Gene Expression and Consequential Migration and Invasion of Malignant Glioblastoma Cells via a Ca2+-MEK1-ERK1/2-NF-κB Mechanism." Cancers 12, no. 3 (March 13, 2020): 667. http://dx.doi.org/10.3390/cancers12030667.
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Glioblastoma multiforme (GBM) is the most common form of brain tumor and is very aggressive. Rapid migration and invasion of glioblastoma cells are two typical features driving malignance of GBM. Bradykinin functionally prompts calcium influx via activation of bradykinin receptor B1/B2 (BDKRB1/2). In this study, we evaluated the roles of bradykinin in migration and invasion of glioblastoma cells and the possible mechanisms. Expressions of aquaporin 4 (AQP4) mRNA and protein were upregulated in human glioblastomas. Furthermore, exposure of human U87 MG glioblastoma cells to bradykinin specifically increased levels of BDKRB1. Successively, bradykinin stimulated influx of calcium, phosphorylation of MEK1 and extracellular signal-regulated kinase (ERK)1/2, translocation and transactivation of nuclear factor-kappaB (NF-κB), and expressions of AQP4 mRNA and protein. Concomitantly, migration and invasion of human glioblastoma cells were elevated by bradykinin. Knocking-down BDKRB1 concurrently decreased AQP4 mRNA expression and cell migration and invasion. The bradykinin-induced effects were further confirmed in murine GL261 glioblastoma cells. Therefore, bradykinin can induce AQP4 expression and subsequent migration and invasion through BDKRB1-mediated calcium influx and subsequent activation of a MEK1-ERK1/2-NF-κB pathway. The bradykinin-BDKRB1 axis and AQP4 could be precise targets for treating GBM patients.
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Maruo, Keishi, Takaaki Akaike, Tomomichi Ono, and Hiroshi Maeda. "Involvement of Bradykinin Generation in Intravascular Dissemination of Vibrio vulnificus and Prevention of Invasion by a Bradykinin Antagonist." Infection and Immunity 66, no. 2 (February 1, 1998): 866–69. http://dx.doi.org/10.1128/iai.66.2.866-869.1998.
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ABSTRACT Involvement of bradykinin generation in bacterial invasion was examined by using a gram-negative bacillus, Vibrio vulnificus, which is known to invade the blood circulatory system and cause septicemia. V. vulnificus was injected intraperitoneally (i.p.) into mice with or without bradykinin or a bradykinin (B2 receptor) antagonist. Dissemination of V. vulnificus from peritoneal septic foci to the circulating blood was assessed by counting of viable bacteria in venous blood by use of the colony-forming assay. Intravascular dissemination of V. vulnificus in mice was significantly potentiated by simultaneous injection with bradykinin but was markedly reduced by coadministration with the B2 antagonist d-Arg,[Hyp3, Thi5,8, d-Phe7]-bradykinin. Furthermore, V. vulnificus lethality was significantly increased when bradykinin was administered simultaneously with the bacillus, whereas it was definitely suppressed by treatment withd-Arg,[Hyp3, Thi5,8,d-Phe7]-bradykinin. Similarly, ovomacroglobulin, a potent inhibitor of the V. vulnificusprotease, showed a strong suppressive effect on the V. vulnificus septicemia. We also confirmed appreciable bradykinin production in the primary septic foci in the mouse peritoneal cavity after i.p. inoculation with V. vulnificus. It is thus concluded that bradykinin generation in infectious foci is critically involved in facilitation of intravascular dissemination of V. vulnificus.
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Schaffel, Rony, Mozart S. Rodrigues, and Jamil Assreuy. "Potentiation of bradykinin effects and inhibition of kininase activity in isolated smooth muscle." Canadian Journal of Physiology and Pharmacology 69, no. 7 (July 1, 1991): 904–8. http://dx.doi.org/10.1139/y91-137.
Full textAbstract:
Prolongation of bradykinin half-life following kininase inhibition has been proposed as the reason for the potentiation of kinin effects. We have reassessed this assumption by using three different isolated smooth muscle preparations and simultaneously studying the inhibition of kininase activity and the potentiation of bradykinin effects by enalaprilat and BPP9a. Rat duodenum displayed higher total kininase activity, metabolizing half of the added bradykinin in 6.5 min, while this time for rat uterus was greater than 60 min. Guinea-pig ileum showed the intermediate value of 14.6 min. Enalaprilat and BPP9a slowed the metabolism of bradykinin by 50–100% in rat duodenum and by 50–180% in guinea-pig ileum, showing that a significant fraction of total kininase activity appears to be due to kininase II. In rat duodenum, an almost complete blockade of kininase activity was achieved when bacitracin and mergetpa were used together with enalaprilat. Enalaprilat and BPP9a potentiated bradykinin effects in guinea-pig ileum and rat uterus. In contrast, bradykinin-induced relaxations and contractions in rat duodenum were not potentiated by enalaprilat, BPP9a, or by the enzyme inhibitor mixture (enalaprilat – bacitracin – mergetpa). The results suggest that inhibition of bradykinin enzymatic metabolism by kininases does not necessarily lead to the potentiation of bradykinin effects.Key words: bradykinin, kininase II, potentiation, smooth muscle.
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Gao, X. P., J. M. Conlon, J. K. Vishwanatha, R. A. Robbins, and I. Rubinstein. "Loop diuretics attenuate bradykinin-induced increase in clearance of macromolecules in the oral mucosa." Journal of Applied Physiology 80, no. 3 (March 1, 1996): 818–23. http://dx.doi.org/10.1152/jappl.1996.80.3.818.
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The purpose of this study was to determine whether loop diuretics attenuate bradykinin-induced increase in clearance of macromolecules in the oral mucosa in situ and, if so, to start to determine the mechanisms that mediated these responses. By using intravital microscopy, we found that bradykinin induced a significant concentration-dependent increase in fluorescein isothiocyanate-labeled dextran (mol mass 70 kDa) leaky site formation in the hamster cheek pouch. These responses were significantly attenuated by topical application of two structurally distinct loop diuretics, furosemide and ethacrynic acid, onto the cheek pouch (P < 0.05). Hydrochlorothiazide, a nonloop diuretic, had no significant effects on bradykinin-induced responses. Furosemide had no significant effects on adenosine-induced leaky site formation. Application of bradykinin after furosemide, but not after hydrochlorothiazide, was associated with a significant concentration-dependent decrease in bradykinin-like immunoreactivity in the cheek pouch suffusate (P < 0.05). Prostaglandins and changes in vasomotor tone did not modulate the effects of furosemide on bradykinin-induced responses. These data indicate that loop diuretics attenuate bradykinin-induced increase in clearance of macromolecules in the oral mucosa in a specific fashion, probably by amplifying local bradykinin catabolism. We suggest that topical loop diuretics could be useful in the treatment of oral mucosa inflammation elicited by bradykinin.
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Beierwaltes, W. H. "Prostaglandin independence of kinin-stimulated renin release." American Journal of Physiology-Renal Physiology 252, no. 5 (May 1, 1987): F794—F799. http://dx.doi.org/10.1152/ajprenal.1987.252.5.f794.
Full textAbstract:
Bradykinin can increase prostaglandin synthesis and also stimulate renin release in vitro. Because prostaglandins also stimulate renin, studies were performed to determine whether bradykinin stimulation of renin is a function of prostaglandin synthesis. Isolated glomeruli with attendant arteriolar attachments were harvested from rat kidneys and superfused. The effluent was analyzed for renin, prostaglandins E2 and I2 (6-keto-PGF1 alpha). Bradykinin (10(-5) M) increased renin by 50% with a concomitant increase in prostacyclin (PGI2) but not in prostaglandin E2 (PGE2). The cyclooxygenase inhibitor meclofenamate (1.6 X 10(-5) M) inhibited bradykinin-induced PGI2 synthesis but not the concurrent increase in renin release. Additionally, neither the phospholipase inhibitor quinacrine (10(-2) M) nor the prostacyclin synthetase inhibitor 9,11-azoprosta-5,13-dienoic acid (Azo analogue-1) (5.67 X 10(-6) M) eliminated bradykinin-induced renin release. Superfusion with calcium-free media and EDTA increased basal renin release 2.5-fold, and bradykinin stimulated a twofold increase in renin release. Neither a high (10(-2) M) media calcium nor the calcium channel blocker nifedipine (10(-6) M) eliminated bradykinin stimulation of renin. These results suggest that bradykinin stimulation of renin is at least partially independent of prostaglandin synthesis and that bradykinin must act by some prostaglandin-independent pathway to induce renin release from isolated glomeruli.
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Jones, T. H., B. L. Brown, and P. R. M. Dobson. "Bradykinin stimulates phosphoinositide metabolism and prolactin secretion in rat anterior pituitary cells." Journal of Molecular Endocrinology 2, no. 1 (January 1989): 47–53. http://dx.doi.org/10.1677/jme.0.0020047.
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ABSTRACT Bradykinin stimulated prolactin secretion from monolayer cultures of rat anterior pituitary cells, the stimulation being greater from the cells of male rats. This stimulated secretion was accompanied by a rise in total inositol phosphate accumulation, suggesting that the action of bradykinin is mediated by phosphoinositide hydrolysis. The increase in inositol phosphate accumulation was biphasic; a further sharp rise occurred when the concentration of bradykinin exceeded 1 μmol/l. This may indicate that bradykinin acts on other cell types in the pituitary gland. Bradykinin had no effect on growth hormone secretion from cells of normal pituitary glands, or on prolactin secretion and phosphoinositide metabolism in GH3 rat pituitary tumour cells. Bradykinin receptor antagonists (both B1 and B2) had no effect on either bradykinin-stimulated inositol phosphate accumulation or prolactin secretion. Kallikreins, the enzymes responsible for the generation of kinins, are known to be present in the adenohypophysis. Therefore, the results presented here would suggest that kinins may have a role as paracrine agents in the pituitary gland.
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Brown, Nancy J., John H. Nadeau, and Douglas E. Vaughan. "Selective Stimulation of Tissue-Type Plasminogen Activator (t-PA) In Vivo by Infusion of Bradykinin." Thrombosis and Haemostasis 77, no. 03 (1997): 522–25. http://dx.doi.org/10.1055/s-0038-1656000.
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SummaryAngiotensin converting inhibitors (ACEI) not only decrease angiotensin II (Ang II) but also potentiate the effects of bradykinin. Bradykinin is a potent stimulus to tissue type plasminogen activator (t-PA) secretion in animal models. In this study, we tested the hypothesis that bradykinin increases t-PA levels in humans.Bradykinin was infused in seventeen hypertensive patients randomized to treatment with the ACEIs captopril and quinapril or with placebo. Bradykinin caused a significant decrease in mean arterial pressure (MAP) (p = 0.014) and increase in pulse (p <0.001). ACEI significantly potentiated the hemodynamic effect of bradykinin (p <0.05). Although baseline t-PA antigen levels were similar in the ACEI-treated (6.85 ± 0.85 ng/ml) and placebo-treated (7.85 ± 0.68 ng/ml) subjects, bradykinin caused a significant (p <0.01) increase in t-PA antigen levels (to 19.3 ± 8.2) only in the ACEI-treated patients. This increase in t-PA was independent of activation of the sympathetic nervous system. Bradykinin had no effect on PAI-1 antigen levels.These in vivo data suggest that infusion of bradykinin results in an increase in circulating t-PA levels without an effect on PAI-1.
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Brew, E. C., M. B. Mitchell, T. F. Rehring, F. Gamboni-Robertson, R. C. McIntyre, A. H. Harken, and A. Banerjee. "Role of bradykinin in cardiac functional protection after global ischemia-reperfusion in rat heart." American Journal of Physiology-Heart and Circulatory Physiology 269, no. 4 (October 1, 1995): H1370—H1378. http://dx.doi.org/10.1152/ajpheart.1995.269.4.h1370.
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We have reported that cardiac preconditioning against ischemia-reperfusion (IR) can be induced by transient ischemia (TI) and alpha 1-adrenoreceptor stimulation, both mediated by protein kinase C (PKC) (Mitchell, M., X. Meng, C. Parker, E. Brew, A. Harken, and A. Banerjee. Circ. Res. 76: 73-81, 1995). Our study objective was to explore the mechanism of endogenous preconditioning and address the role of PKC activation in bradykinin-mediated cardiac functional protection. Isolated rat heart was used to assess the effects of exogenous bradykinin, TI, selective B2-receptor blocker, and PKC antagonism on cardiac functional recovery after a global IR injury. Final recovery of developed pressure was improved in hearts treated with bradykinin and TI compared with controls. Bradykinin- and TI-mediated preconditioning was eliminated with coinfusion of the B2-receptor antagonist. Further evaluation of bradykinin-mediated preconditioning revealed that PKC blockade also eliminated functional protection. Immunofluorescent stains of bradykinin-treated hearts demonstrated translocation and activation of specific PKC isoforms in the preconditioned heart. We conclude that TI-mediated preconditioning involves intrinsic cardiac bradykinin receptor stimulation. Bradykinin, through the B2 receptor, initiates a series of intracellular events culminating in the activation of PKC.
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Stebbins, C. L., R. C. Smith, and J. C. Longhurst. "Effect of prostaglandins on bradykinin-induced visceral-cardiac reflexes." American Journal of Physiology-Heart and Circulatory Physiology 249, no. 1 (July 1, 1985): H155—H163. http://dx.doi.org/10.1152/ajpheart.1985.249.1.h155.
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We examined the effect of prostaglandins on the reflex cardiovascular response to bradykinin applied to the abdominal organs of anesthetized cats. Bradykinin (10 micrograms/ml) was applied to the serosal surface of the stomach, gallbladder, or jejunum before and after injection of indomethacin (2-10 micrograms/ml iv) and after application of 1 microgram/ml of prostaglandins E1, E2, or F2 alpha (PGE1, PGE2, PGF2 alpha) or prostacyclin (PGI2). In six cats, stimulation of the stomach with bradykinin significantly increased mean arterial pressure (MAP) by 37 +/- 5 (SE) mmHg and maximal dP/dt by 633 +/- 101 mmHg/s. Following indomethacin the bradykinin-induced increases in MAP and dP/dt were significantly reduced to 19 +/- 4 mmHg and 191 +/- 58 mmHg/s, respectively. Treatment with PGE1, PGE2, or PGI2, but not PGF2 alpha, restored the initial bradykinin response. The gallbladder and jejunum responded similarly. Also application of exogenous prostaglandins, PGE2 or PGI2, to the stomach, gallbladder, or jejunum significantly augmented the cardiovascular response to bradykinin. Finally, PGE2 restored a portion of the cardiovascular response to bradykinin following the development of tachyphylaxis. We conclude that prostaglandins are necessary for the full manifestation of the cardiovascular response to bradykinin.