Search results

1

Metabolism of bradykinin in aorta of hypertensive rats

100%

Bujak-Giżycka B., Olszanecki R., Madej J., Suski M., Gębska A., Korbut R.

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2011

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vol. 58

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issue 2

199-202

EN

Alterations in the formation and metabolism of bradykinin (Bk) are hypothesized to play a role in the pathophysiology of hypertension, atherosclerosis and vascular complications of diabetes. However, despite its prominent role in cardiovascular regulation, studies on bradykinin have been limited by various difficulties in accurate measurements of this peptide in biological samples. In this study, using the LC-ESI-MS method we estimated the conversion of exogenous Bk to its main metabolites - Bk-(1-5) and Bk-(1-7) - in endothelial cell culture and in fragments of aorta of normotensive (WKY) and hypertensive rats (SHR). The effects of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors were more pronounced in SHR: perindoprilat inhibited Bk-(1-5) formation by 49 % and 76 % in WKY and SHR rats, respectively, and tiorphan tended to decrease formation of Bk-(1-5) in both groups of animals. The degradation of bradykinin and generation of both metabolites were significantly higher in the aorta of SHR rats than in WKY controls. Our results show that even in relatively early hypertension (in 4-month old SHR rats) inactivation of Bk by aorta wall is enhanced.

2

New bradykinin analogues acylated on the N-terminus: effect on rat uterus and blood pressure

100%

Labudda O., Wierzba T., Sobolewski D., Śleszyńska M., Gawiński Ł., Plackova M., Slaninová J., Prahl A.

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2007

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vol. 54

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issue 1

193-198

EN

Our previous studies suggested that acylation of the N-terminus of several known B2 antagonists with various kinds of bulky acyl groups consistently improved their antagonistic potency in rat blood pressure assay. On the other hand, our earlier observations also seemed to suggest that the effects of acylation on the contractility of isolated rat uterus depended substantially on the chemical character of the acyl group, as we observed that this modification might either change the range of antagonism or even transform it into agonism. Bearing all this in mind, we decided to synthesize seven new analogues of bradykinin by N-terminal acylation with various acyl groups of a moderately potent B2 antagonist, previously synthesized by Stewart's group, D-Arg-Arg-Pro-Hyp-Gly-Thr-Ser-D-Phe-Thi-Arg. The analogues were tested in vitro for their blood pressure-lowering and uterotonic activities. The modifications either preserved or increased the antagonistic potency in the rat blood pressure test. On the other hand, all seven substituents negatively influenced the interaction with the rat uterine receptors. Our results may be helpful for designing new B2 agonists and antagonists.

3

Bradykinin B2 receptor and dopamine D2 receptor cooperatively contribute to the regulation of neutrophil adhesion to endothelial cells

88%

Niewiarowska-Sendo A., Łabędź-Masłowska A., Kozik A., Guevara-Lora I.

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2018

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vol. 65

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issue 3

367-375

EN

Leukocyte adhesion to the vascular endothelium contributes to many immunological and inflammatory disorders. These processes have been shown to be mediated by bradykinin receptor type 2 (B2R) and dopamine receptor type 2 (D2R). In a previous study, we reported the formation of a B2R-D2R heterodimer, possibly altering cellular functions. Hence, in the present study, we examined the effect of co-activation of endothelial cells with B2R and D2R agonists on the interaction of these cells with neutrophils. Bradykinin, the main B2R agonist, significantly increased cell adhesion, and this effect was reversed when the endothelial cells were additionally co-treated with a selective D2R agonist, sumanirole. These results were dependent on the incubation time, showing an opposite tendency after prolonged stimulation. Significant changes in the expression of adhesion proteins, such as E-selectin and intercellular adhesion molecule 1 in endothelial cells were observed. Additionally, the cells preincubated with tumor necrosis factor-α showed decreased cell adhesion and IL-8 release after long incubation with both agonists. The modulation of cell adhesion by D2R and B2R seem to be mediated via STAT3 phosphorylation. In summary, this study demonstrated a protective role of D2R in neutrophil-endothelial cell adhesion induced by bradykinin, especially in cytokine-stimulated endothelial cells.

4

New bradykinin B2 receptor antagonists - influence of C-terminal segment modifications on their pharmacological properties

88%

Śleszyńska M., Kwiatkowska A., Sobolewski D., Wierzba T., Katarzyńska J., Zabrocki J., Borovickova L., Slaninová J., Prahl A.

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EN

In the present study we describe the synthesis and some pharmacological properties of eight new analogues of bradykinin (BK). Two peptides were designed by substitution of position 7 or 8 of the known [d-Arg0,Hyp3,Thi5,8,d-Phe7]BK antagonist (Stewart's antagonist) with l-pipecolic acid (l-Pip). The next two analogues were obtained by replacement of the d-Phe residue in position 7 of the Stewart's peptide with l-β2-isoproline (l-β2-iPro) or l-β3-homoproline (l-β3-hPro). The four analogues mentioned above were also prepared in N-acylated form with 1-adamantaneacetic acid (Aaa). Biological activity of the compounds was assessed by isolated rat uterus and rat blood pressure tests. Our results showed that l-Pip in position 7 slightly increased antagonistic potency in the blood pressure test, but it turned the analogue into an agonist in the rat uterus test. Replacement of Thi by l-Pip in position 8 also enhanced antagonism in the rat pressure test but preserved the antagonism in the rat uterus test. l-β2-iPro or l-β3-hPro in position 7 decreased the potencies in both tests. We also demonstrated that acylation of the N-terminus did not increase, as was claimed previously, the antagonistic potencies of the resulting peptides. The results thus support the hypothesis about the existence of different types of BK receptors in the rat uterus and blood vessels. Our studies provide new information about the structure-activity relationship of BK antagonists which may help in designing more potent BK receptor blockers.

5

Properties of chemically oxidized kininogens.

75%

Niziołek M., Kot M., Pyka K., Mak P., Kozik A.

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2003

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vol. 50

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issue 3

753-763

EN

Kininogens are multifunctional proteins involved in a variety of regulatory processes including the kinin-formation cascade, blood coagulation, fibrynolysis, inhibition of cysteine proteinases etc. A working hypothesis of this work was that the properties of kininogens may be altered by oxidation of their methionine residues by reactive oxygen species that are released at the inflammatory foci during phagocytosis of pathogen particles by recruited neutrophil cells. Two methionine-specific oxidizing reagents, N-chlorosuccinimide (NCS) and chloramine-T (CT), were used to oxidize the high molecular mass (HK) and low molecular mass (LK) forms of human kininogen. A nearly complete conversion of methionine residues to methionine sulfoxide residues in the modified proteins was determined by amino acid analysis. Production of kinins from oxidized kininogens by plasma and tissue kallikreins was significantly lower (by at least 70%) than that from native kininogens. This quenching effect on kinin release could primarily be assigned to the modification of the critical Met-361 residue adjacent to the internal kinin sequence in kininogen. However, virtually no kinin could be formed by human plasma kallikrein from NCS-modified HK. This observation suggests involvement of other structural effects detrimental for kinin production. Indeed, NCS-oxidized HK was unable to bind (pre)kallikrein, probably due to the modification of methionine and/or tryptophan residues at the region on the kininogen molecule responsible for the (pro)enzyme binding. Tests on papain inhibition by native and oxidized kininogens indicated that the inhibitory activity of kininogens against cysteine proteinases is essentially insensitive to oxidation.

6

Diagnosis of hereditary angioedema

75%

Kőhalmi K. V., Cervenak L., Farkas H.

Alergia Astma Immunologia - przegląd kliniczny

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2018

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vol. 23

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issue 4

168-174

EN

Hereditary angioedema (HAE) is a rare disorder characterized by acute episodes of edema formation in the subcutis and/or the submucosa. The clinical picture of the disease resembles that of histamine-mediated angioedema, nevertheless bradykinin release is involved in the pathomechanism of HAE. The diagnosis of HAE can be established from the clinical manifestations, the family history, as well as the findings of complement and genetic tests. Currently, the six types of hereditary angioedema are distinguished: types I and II of hereditary angioedema with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) and the following types of hereditary angioedema with normal C1-INH levels: hereditary angioedema caused by a mutation in the Factor XII gene (FXII-HAE), the angiopoietin-1 gene (ANGPT1-HAE), and the plasminogen gene (PLG-HAE) – and hereditary angioedema of unknown origin (U-HAE). Current options for the laboratory diagnosis of angioedemas include means for identifying C1-INH-HAE, FXII-HAE, ANGPT1-HAE, PLG-HAE and acquired angioedema with C1-INH deficiency (C1-INH-AAE). No laboratory method is available currently for diagnosing the other types of angioedemas such as idiopathic histaminergic acquired angioedema (IH-AAE), idiopathic non-histaminergic acquired angioedema (InH-AAE), acquired angioedema related to angiotensin-converting enzyme inhibitor (ACEI-AAE), and U-HAE. These disease types can be identified only by indirect methods, i.e. by exploring medical and family history, observing the clinical manifestations and the therapeutic response, as well as by excluding the presence of C1-INH deficiency, FXII-HAE, ANGPT1-HAE, and PLG-HAE.

7

Potential role of bradykinin and its receptors in COVID-19

63%

Obtułowicz K., Dubiela P., Madaliński K., Dyga W., Obtułowicz P.

Alergia Astma Immunologia - przegląd kliniczny

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2021

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vol. 26

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issue 2-3

46-53

PL

Bradykinina (BK) jest nonapeptydem należącym do rodziny kinin. Jest aktywnym mediatorem stanu zapalnego, który wywiera wiele różnych efektów poprzez swoje receptory B1 i B2 (B1R i B2R), jednak jej rola nie została do tej pory w pełni wyjaśniona. Wiadomo, że B1R i B2R oddziałują z białkiem konwertazy angiotensyny (ACE)-2, która działa jako receptor dla koronawirusa 2 (SARS-CoV-2), wywołującego chorobę COVID-19. Poprzez degradację BK do jego metabolitu desARG9-BK, ACE2 prowadzi do aktywacji B1R, co wyzwala uwalnianie cytokin pro- i przeciwzapalnych w odpowiedzi immunologicznej na patogeny. Z drugiej strony, ACE2 poprzez aktywację osi ANG(1-7)-MasR, stymuluje ekspresję B2R, która jest niezbędna dla prawidłowej funkcji śródbłonka. Kontrolowany wzrost uwalniania cytokin indukowany przez B1R podczas wnikania SARS-CoV-2 do komórek może być uznany za normalną odpowiedź immunologiczną zapobiegającą zakażeniu. Jeśli jednak mechanizmy regulacyjne zawiodą, wzrost uwalniania cytokin prozapalnych może prowadzić do progresji zakażenia, aktywacji śródbłonka i nasilenia objawów, w tym zajęcia narządów. Dostępne dane jednoznacznie sugerują, że BK i jego receptory są zaangażowane w patomechanizm COVID-19 i powiązane na drodze różnych mechanizmów sprzężenia zwrotnego z ACE2, ACE1, a także angiotensyną II (ANGII) i jej receptorami. Ponieważ ekspresja tych szlaków prawdopodobnie zmienia się dynamicznie w różnych stadiach COVID-19, należy opracować nowe opcje terapeutyczne ukierunkowane na te szlaki, ściśle monitorując ich aktywność.

EN

Bradykinin (BK) is a nonapeptide that belongs to the kinin family. It is an active inflammatory mediator that exerts multiple different effects via its B1 and B2 receptors (B1R and B2R); however, its role has not been fully elucidated so far. It is known that B1R and B2R interact with angiotensin-converting enzyme (ACE)-2 protein, which acts as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). By degrading BK to its desARG9-BK metabolite, ACE2 leads to B1R activation, which triggers a release of pro- and anti-inflammatory cytokines in an immune response to infectious pathogens. On the other hand, ACE2 stimulates the expression of B2R by activating the ANG(1-7)–MasR axis which is essential for proper endothelial function. A controlled increase in B1R-mediated cytokine release during SARS-CoV-2 cell entry may be considered a normal immune response aiming to prevent infection. However, if regulatory mechanisms fail, the increase in proinflammatory cytokine release may lead to progression of infection, endothelial activation, and onset of symptoms, including organ involvement. Available data strongly suggest that BK and its receptors are involved in the pathomechanism of COVID-19 and linked by various feedback mechanisms to ACE2, ACE1, as well as angiotensin II (ANGII) and its receptors. As expression of these pathways is likely to change dynamically throughout different stages of COVID-19, novel treatment options that target these pathways along with close monitoring of their activity should be developed.