Bradykinin—from snake poison to therapeutic options

Hillmeister, Philipp; Persson, Anja Bondke

doi:10.1111/apha.13445

Cited by 5 publications

(5 citation statements)

References 35 publications

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“…Accordingly, the release of metabolites and other local vasoactive compounds (such as kinins) is increased to control blood flow and meet the increasing energy demand in muscle. 15 This process is significantly regulated by autophagy. [16][17][18] An increased autophagic flux was detected in peripheral blood mononuclear cells (PBMC) immediately after acute exercise and persisted for 4 h during the recovery period.…”

Section: Exercise-mediated Autophagy In Cardiovascular Diseasesmentioning

confidence: 99%

“…During exercise, cardiac output and peripheral perfusion are increased to match the increased oxygen consumption of muscles. Accordingly, the release of metabolites and other local vasoactive compounds (such as kinins) is increased to control blood flow and meet the increasing energy demand in muscle 15 . This process is significantly regulated by autophagy 16–18 .…”

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confidence: 99%

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Exercise‐mediated autophagy in cardiovascular diseases

Dai

Hillmeister

2022

Acta Physiologica

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Section: Exercise-mediated Autophagy In Cardiovascular Diseasesmentioning

confidence: 99%

mentioning

confidence: 99%

Exercise‐mediated autophagy in cardiovascular diseases

Dai

Hillmeister

2022

Acta Physiologica

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“…Bradykinin (BK) is an endogenous peptidic hormone (a nonapeptide), and a key member of the kallikrein‐kinin system exerting potent and diverse biological activities through two receptors, B1R and B2R. [ 1–3 ] The former is the inducible form whose expression is triggered by inflammation and stress whereas the latter is constitutively expressed in almost every cell type and tissue. BK action has been shown to be implicated in inflammation, nociception, autoimmunity, vasculopathy, viral infections, diabetes, CNS disorders, and many cancers.…”

Section: Introductionmentioning

confidence: 99%

“…The aqueous phase was extracted with 20 mL of TBME and adjusted to pH 2-3 with aqueous HCl 1 M. Next, the aqueous phase was extracted with 40 mL of EtOAc. The organic phase was washed with The reaction mixture was diluted with 20 mL of DCM and was washed once with an aq solution of 5% NaHCO 3 (10 mL), twice with water (10 mL), once with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and the solvent was removed in vacuo to afford 3.27 g (96%) of 14-o-nosylamide as an orange solid 1. H-NMR J = 7.8 and 1.2 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.27 (m, 1H), 6.68 (s, 1H), 5.36 (s, 2H), 2.61 (s, 3H) ppm; 13 C-NMR (150 MHz, CDCl 3 ): δ 161.1, 159.4, 155.8, 149.4, 148.1, 139.5, 137.1, 133.6, 133.2, 132.4, 132.3, 131.3, 125.4, 124.8, 123.1, 121.3, 119.8, 117.1, 116.4, 102.8, 71.0, 25.6 ppm; HRMS (m/z) [M+H] + calcd for C 22 H 18 N 4 O 5 S = 451.1076, found = 451.1074.…”

mentioning

confidence: 99%

Development of a multigram synthesis of the bradykinin receptor 2 agonist FR‐190997 and analogs thereof

Vachlioti

Ferikoglou

Georgiou

et al. 2023

Archiv der Pharmazie

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Using Fujisawa's B2R agonist FR-190997, we recently demonstrated for the first time that agonism at the bradykinin receptor type 2 (B2R) produces substantial antiproliferative effects. FR-190997 elicited an EC 50 of 80 nM in the triple-negative breast cancer cell line MDA-MB-231, a much superior performance to that exhibited by most approved breast cancer drugs. Consequently, we initiated a program aiming primarily at synthesizing adequate quantities of FR-190997 to support further in vitro and in vivo studies toward its repurposing for various cancers and, in parallel, enable the generation of novel FR-190997 analogs for an SAR study. Prerequisite for this endeavor was to address the synthetic challenges associated with the FR-190997 scaffold, which the Fujisawa chemists had constructed in 20 steps, 13 of which required chromatographic purification. We succeeded in developing a 17-step synthesis amenable to late-stage diversification that eliminated all chromatography and enabled access to multigram quantities of FR-190997 and novel derivatives thereof, supporting further anticancer research based on B2R agonists.

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“…Bradykinin receptor BDKRB2 is constitutively expressed in various cell types, whereas bradykinin receptor BDKRB1 is only upregulated under the inflammatory conditions. BK and kallidin, derived from plasma and tissue kallikrein, respectively, are the corresponding ligands of BDKRB2, whereas the BK and kallidin derivatives des-Arg9-bradykinin and Lys-bradykinin are the corresponding ligands of BDKRB1 [13]. It was shown that BDKRB2 and BDKRB1 signaling induces nitric oxide (NO) production in endothelial cells and circulating immune cells [14].…”

Section: Introductionmentioning

confidence: 99%

Effect of ACEI and ARB treatment on nitric oxide-dependent endothelial function

Zemmrich

Bramlage

et al. 2021

Vasa

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Summary: Background: Angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are widely used as a first-line therapy for the treatment of cardiovascular disease. Here, ACEI modulate the bradykinin receptor (BDKRB1 and BDKRB2) system and NO-dependent endothelial function, thus determining cardiovascular health and regenerative arteriogenesis. The current study aims at evaluating nitric oxide-dependent endothelial function, and gene expression of bradykinin receptors in peripheral blood mononuclear cells (PBMC) from patients with ACEI or ARB treatment. Patients and methods: The WalkByLab has been established to screen cardiovascular patients for peripheral artery disease and coronary artery disease. In total 177 patients from WalkByLab with heterogenous disease and risk status were randomly selected, divided according to their medication history into the following groups: 1. ACEI group, 2. ARB group or 3. non-ACE/ARB group. Total plasma nitrite/nitrate (NO) levels were measured, endothelial function was evaluated by assessing flow meditated dilation (FMD). PBMC were isolated from peripheral whole blood, and gene expression (qRT-PCR) of bradykinin receptors and angiotensin converting enzyme were assessed. Results: Plasma total NO concentration in the ACEI group (24.66±16.28, µmol/l) was increased as compared to the ARB group (18.57±11.58, µmol/l, P=0.0046) and non-ACE/ARB group (16.83±8.64, µmol/l, P=0.0127) in patients between 40 to 90 years of age. However, FMD values (%) in the ACEI group (7.07±2.40, %) were similar as compared to the ARB (6.35±2.13, %) and non-ACE/ARB group (6.51±2.15, %), but significantly negatively correlated with age. Interestingly, BDKRB1 mRNA level was significantly higher and BDKRB2 mRNA level lower in the ACEI group (BDKRB1 3.88-fold±1.05, BDKRB2 0.22-fold±0.04) as compared to the non-ACE/ARB group (BDKRB1 1.00-fold±0.39, P<0.0001, BDKRB2 1.00-fold±0.45, P=0.0136). Conclusions: ACEI treatment enhances total nitrite/nitrate concentration, furthermore, upregulates BDKRB1 in PBMC, but downregulates BDKRB2 mRNA expression. FMD is a strong determinant of vascular aging and is sensitive to underlying heterogenous cardiovascular diseases.

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Bradykinin—from snake poison to therapeutic options

Cited by 5 publications

References 35 publications

Exercise‐mediated autophagy in cardiovascular diseases

Exercise‐mediated autophagy in cardiovascular diseases

Development of a multigram synthesis of the bradykinin receptor 2 agonist FR‐190997 and analogs thereof

Effect of ACEI and ARB treatment on nitric oxide-dependent endothelial function

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