- 作者：Murat Bas ; Nadine Kirchhartz ; Jessica Hochfeld ; Cornelia Tü ; llmann ; Stephanie Kumpf ; Tatsiana Suvorava ; Marc Oppermann ; Dieter Hafner ; Henning Bier ; Thomas K. Hoffmann ; Vera Balz ; Georg Kojda
- 关键词：Angioedema ; angiotensin converting enzyme inhibitor ; fibrinogen ; acute-phase-protein ; bradykinin
- 刊名：Journal of Allergy and Clinical Immunology
- 出版年：2008
- 出版时间：April 2008
- 年：2008
- 卷：121
- 期：4
- 页码：969-975.e2
- 全文大小：665 K
Background
Although bradykinin is known to play a major role in the pathophysiology of hereditary and angiotensin-converting enzyme inhibitor (ACEi)–induced angioedema, other factors acting as triggers or enhancers are likely important as well.Objective
We hypothesized that fibrinogen might contribute to ACEi-induced angioedema (eg, through direct actions on vascular tone).
Methods
Plasma levels of fibrinogen were determined in 59 patients with acute angioedema. Vascular activity of human and bovine fibrinogen and its effects on bradykinin-induced vasodilation and phosphorylation of vasodilator-stimulated phosphoprotein were investigated in small (0.8-1.4 mm in diameter) porcine coronary artery and human internal thoracic artery (ITA) segments.
Results
In patients with ACEi-induced angioedema, fibrinogen levels (481 ± 22 mg/dL, n = 39) were significantly higher than in patients with idiopathic angioedema (302 ± 15 mg/dL, P < .001). Fibrinogen (1-15 μmol/L) induced a concentration-dependent vasodilation in preconstricted small porcine coronary arteries (n = 13), reaching a maximum vasodilator effect of 70 % ± 4.7 % . Likewise, fibrinogen induced a 52.1 % ± 9.1 % (n = 7) vasodilation in ITA rings. Fibrinogen vasorelaxations were completely inhibited by abciximab and diminished by endothelial denudation and treatment with the nitric oxide synthase inhibitor L-nitroargininemethylester and glibenclamide (P < .01). Importantly, fibrinogen increased the vasodilator potency of bradykinin by 10-fold (P < .0001) and increased bradykinin-induced vasodilator-stimulated phosphoprotein phosphorylation (P < .01).
Conclusion
The increase of plasma fibrinogen levels, its vasodilator activity in human ITAs, and the potentiation of bradykinin-induced vasodilation suggest that fibrinogen might contribute to the pathophysiology of ACEi-induced angioedema. Thus acute-phase proteins, such as fibrinogen, might be viewed as risk factors for bradykinin-induced angioedema.