Potential role of vasomotor effects of fibrinogen in bradykinin-induced angioedema.
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 mumol/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).


CONCLUSIONS
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.
Bas
Murat
M
Hals-Nasen-Ohrenklinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
Kirchhartz
Nadine
N
Hochfeld
Jessica
J
Tüllmann
Cornelia
C
Kumpf
Stephanie
S
Suvorava
Tatsiana
T
Oppermann
Marc
M
Hafner
Dieter
D
Bier
Henning
H
Hoffmann
Thomas K
TK
Balz
Vera
V
Kojda
Georg
G
D000368:Aged; D000799:Angioedema / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D000818:Animals; D001920:Bradykinin / Q000097:blood / Q000633:toxicity*; D002417:Cattle; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D005260:Female; D005340:Fibrinogen / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D012008:Recurrence; D013552:Swine; D013895:Thoracic Arteries / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000097:blood / Q000633:toxicity*
D000806:Angiotensin-Converting Enzyme Inhibitors; D014665:Vasodilator Agents; D005340:Fibrinogen; D001920:Bradykinin