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Potential role of vasomotor effects of fibrinogen in bradykinin-induced angioedema  Murat Bas, MD, Nadine Kirchhartz, Jessica Hochfeld, Cornelia Tüllmann,

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Presentation on theme: "Potential role of vasomotor effects of fibrinogen in bradykinin-induced angioedema  Murat Bas, MD, Nadine Kirchhartz, Jessica Hochfeld, Cornelia Tüllmann,"— Presentation transcript:

1 Potential role of vasomotor effects of fibrinogen in bradykinin-induced angioedema 
Murat Bas, MD, Nadine Kirchhartz, Jessica Hochfeld, Cornelia Tüllmann, Stephanie Kumpf, Tatsiana Suvorava, PhD, Marc Oppermann, PharmD, Dieter Hafner, PhD, Henning Bier, MD, Thomas K. Hoffmann, MD, Vera Balz, PhD, Georg Kojda, PharmD, PhD  Journal of Allergy and Clinical Immunology  Volume 121, Issue 4, Pages e2 (April 2008) DOI: /j.jaci Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 A, Original recording of the vasodilator effect of analytic-grade and purified fibrinogen in ITA rings. B, The fibrinogen-dependent vasodilatation in human ITA segments was completely inhibited by abciximab (4 μg/mL), and similar results were obtained in SPCAs (see the Results section). Multiply by 0.03 to convert fibrinogen concentrations from milligrams per deciliter to micromoles. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 A, Binding of abciximab to the human smooth muscle cell vitronectin receptor (αIIbβ3 integrin), as shown by displacing a human β3 integrin antibody on blotted SDS gels of human ITA homogenates. The highest concentration of abciximab is identical to that used in the organ bath study (see Fig 3, B). B, Quantitative analysis of blots from 5 different ITA segments. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 The maximal vasodilator effect of fibrinogen in SPCAs (70.0% ± 4.7%) is dependent on removal of the endothelium (A; reduction to 42.2% ± 7.4%, n = 9, P < .0001), preincubation with 100 μmol/L L-NAME (B; reduction to 48.0% ± 4.8%, P < .0001), and pretreatment with the 100 μmol/L potassium-channel blocker glibenclamide (C; reduction to 42.2% ± 7.6%, P < .0001). Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Preincubation of SPCA segments with 15 μmol/L fibrinogen significantly increased the vasodilator potency of bradykinin. The maximal vasodilatation to 1 μmol/L bradykinin increased from 70.3% ± 7.4% (n = 11) to 96% ± 3.7% (n = 6, P = .025). Likewise, the half-maximal effective concentration in −logM values of bradykinin increased from 6.7 ± 0.09 to 7.6 ± 0.10 (P < .0001). Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Fibrinogen enhances the effects of bradykinin on the vascular nitric oxide (NO)–cGMP signal transduction. Bradykinin-induced NO-dependent activation of cGMP-dependent protein kinase, as measured by means of Ser239 VASP phosphorylation, is potentiated by fibrinogen (A), whereas fibrinogen had no effect on total VASP levels (B). Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 A, Protein concentrations in different fractions collected during purification by means of size-exclusion chromatography of analytic-grade bovine fibrinogen. B, Coomassie-stained SDS gel showing native fibrinogen fractions: lane 1, purified fibrinogen of fraction 24; lanes 2 to 4, less purified fibrinogen of fractions 30 to 33; lane 5, purified human fibrinogen. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions


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