Stability of murine bradykinin type 2 receptor despite treatment with <scp>NO</scp>, bradykinin, icatibant, or <scp>C</scp>1‐<scp>INH</scp>

Khosravani, Farbod; Suvorava, Tatsiana; Dao, V T-V; Brockmann, Nicole; Kocgirli, O.; Herbst, F. F.; Valcaccia, S.; Kassack, Matthias U.; Baş, Murat; Kojda, Georg

doi:10.1111/all.12556

Cited by 6 publications

(13 citation statements)

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“…and suggests an additional reorganization of LEC tight junctions via B2R signaling.The levels of Ca +2 and cAMP, key second messengers downstream of B2R,34,54 were also affected by BK stimulation. A rapid increase in intracellular Ca 2+ levels was observed in a concentrationdependent manner as expected, congruent with results obtained by others in murine bEND.3 cells 55. Whereas a significant 15% reduction in intracellular cAMP was observed after 4 hours of BK treatment, this is similar to what other permeabilizing agents do 39,56.…”

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confidence: 91%

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

et al. 2019

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Objective Determine the effect of bradykinin on solute permeability and cellular junctional proteins in human dermis microvascular endothelial cells. Methods Cells were characterized by immunofluorescence and fluorescence‐activated cell sorting. Macromolecular transport of dextran and albumin was monitored. Junctional protein expression and phosphorylation were determined by immunoblot analyses. Intracellular calcium and cAMP levels were evaluated. Target gene expression at mRNA and protein levels was determined. Results Human dermis microvascular endothelial cells comprised 97% lymphatic endothelial cells. Bradykinin increased the permeability to dextran in a concentration‐dependent manner, while reduced the permeability to albumin. Bradykinin treatment down‐regulated VE‐cadherin expression and affected its phosphorylation status at Tyr731. It also down‐regulated claudin‐5 expression at the transcriptional level through bradykinin‐2‐receptor signaling. An increase in the intracellular calcium levels and a reduction in the cAMP concentration were associated effects. Finally, bradykinin induced the up‐regulation of vascular endothelial growth factor‐C protein which was found increased in BK‐induced human dermis microvascular endothelial cells culture supernates. Conclusions Human dermis microvascular endothelial cells represent a model of lymphatic endothelial cells, in which bradykinin‐2‐receptor is expressed. Bradykinin‐induced bradykinin‐2‐receptor signaling through intracellular calcium mobilization and reduction in cAMP levels, triggered changes in solute permeability and cellular junction expression. It further up‐regulated vascular endothelial growth factors‐C protein expression, which is a key modulator of lymphatic vessels function and lymphangiogenesis.

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confidence: 91%

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

et al. 2019

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“…Quantitative real‐time PCR with lung mRNA using primers specific for the human or the mouse B 2 receptor cDNA revealed a strong expression of human B 2 receptor in B2 tg mice, while no expression of human B 2 receptors was detectable in transgene negative littermates B n (Figure A). Furthermore, expression of the human B 2 receptor did not alter the expression of murine B 2 receptors in B2 tg mice indicating that activation of B 2 receptors by bradykinin has no effect on B 2 receptor expression as described previously (Khosravani et al ., ). Surprisingly, initial Western blot analysis of lung tissues showed no difference in signals between B2 tg and B2 n mice.…”

Section: Resultsmentioning

confidence: 97%

“…We have evaluated the specificity of several antibodies directed against the B 2 receptor and found that a rabbit monoclonal anti‐B 2 receptor antibody (Abcam, Cambridge, UK) appears to be reliable (Khosravani et al ., ), that is, there was just a faint staining in lung tissue of B 2 receptor −/− mice. Briefly, a total of 50–100 mg protein was loaded onto 10% SDS‐PAGE gels.…”

Section: Methodsmentioning

confidence: 96%

“…Aortic reactivity to bradykinin was studied in aortas of B2 tg and B2 n by cumulative application of bradykinin (0.01 nmol·L −1 to 0.1 mmol·L −1 ) after submaximal pre‐contraction with 0.2 μmol·L −1 phenylephrine as described previously (Khosravani et al ., ). To evaluate endothelium‐dependent part of the aortic reaction to BK, aortic responses to increasing concentrations of BK were assessed in the endothelium‐intact and endothelium‐denuded aortic segments.…”

Section: Methodsmentioning

confidence: 97%

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The role of bradykinin receptor type 2 in spontaneous extravasation in mice skin: implications for non‐allergic angio‐oedema

Bisha

Dao

Gholamreza-Fahimi

et al. 2018

British J Pharmacology

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“…ACE is not the only degrading enzyme of bradykinin: Dipeptidyl peptidase 4 (DPP4), carboxypeptidase N, aminopeptidase P, and neprilysin are also involved in the degradation process [2–5]. According to the present state of knowledge, ACE inhibitor induced angioedema (ACEI-AE) results from accumulation of bradykinin [6]. In the formation of bradykinin, C1-inhibitor (C1-INH) plays an important role in slowing down its formation – mutations affecting C1-INH are considered the reason for the occurrence of bradykinin mediated hereditary angioedema (HAE) [7].…”

Section: Introductionmentioning

confidence: 99%

Drug-Induced Inhibition of Angiotensin Converting Enzyme and Dipeptidyl Peptidase 4 Results in Nearly Therapy Resistant Bradykinin Induced Angioedema: A Case Report

et al. 2017

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Objective:Unusual clinical course Background:Bradykinin is an underestimated mediator of angioedema. One subgroup of bradykinin induced angioedema is angioedema triggered by treatment with angiotensin converting enzyme (ACE) inhibitors. Due to its localization in the head and neck region and its unpredictable course, it is a possibly life-threatening condition. There is not an officially approved treatment for ACE inhibitor induced angioedema. Case Report:We present a case of an 83-year-old woman, who presented to our ENT department because of acute swelling of the tongue. On admission, there was no pharyngeal or laryngeal edema and no dyspnea. Treatment with glucocorticoids and antihistamines had no response. The patient had ramipril as regular medication, so we assumed ACE inhibitor induced angioedema and treated consequently with C1-inhibitor (human) 1,500 IU. Nevertheless, swelling was progressive and required intubation. Even after the second specific treatment with icatibant, her angioedema subsided extremely slowly. The patient also had regular treatment with saxagliptin, a dipeptidyl peptidase 4 inhibitor, so we assumed that the simultaneous inhibition of two bradykinin degrading enzymes led to a treatment-refractory course of angioedema. Conclusions:General awareness for bradykinin induced angioedema due to regular medication is limited. Our case demonstrated the importance of improving awareness and knowledge about this side effect. We need a better understanding of the pathomechanism to aid in more precise clinical diagnosis. Securing the patient's airway as well as administration of an officially approved therapy is of utmost importance. As the number of patients simultaneously treated with antihypertensive and antidiabetic drugs is likely to increase, the incidence of bradykinin mediated drug induced angioedema is likely to increase as well.

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Stability of murine bradykinin type 2 receptor despite treatment with NO, bradykinin, icatibant, or C1‐INH

Abstract: These data suggest that alterations of B2R protein expression induced by NO, bradykinin, C1-INH, or icatibant unlikely contribute to bradykinin-induced angioedema. This finding does not rule out a role for NO in bradykinin-induced extravasation and/or angioedema.

Cited by 6 publications

References 33 publications

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells

The role of bradykinin receptor type 2 in spontaneous extravasation in mice skin: implications for non‐allergic angio‐oedema

Drug-Induced Inhibition of Angiotensin Converting Enzyme and Dipeptidyl Peptidase 4 Results in Nearly Therapy Resistant Bradykinin Induced Angioedema: A Case Report

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