Bradykinin involvement in angioedema

In recent years, several lines of evidence indicate that the kinin system is involved in the pathogenesis of angioedema due to C1-inhibitor deficiency as well as that related to treatment with angiotensin-converting enzyme (ACE) inhibitors. C1-inhibitor is the main inhibiting protein of the contact system; therefore, when C-1 inhibitor is deficient, the contact system should be more active and the generation of bradykinin increased. On the other hand, ACE is the main enzyme that catabolizes bradykinin; thus when ACE is inhibited, bradykinin should be increased because less is catabolized. In order to demonstrate these views, we have studied patients with angioedema due to C1-inhibitor deficiency and ACE-inhibitor treatment. We measured bradykinin directly in plasma with a radioimmunoassay after liquid phase extraction and high-performance liquid chromatography, then indirectly studied the generation of bradykinin by evaluating with western blot analysis the cleavage of high-molecular-weight kininogen, the progenitor molecule of bradykinin. Plasma levels of bradykinin were high in both groups of angioedema patients, whereas high-molecular-weight kininogen was cleaved in patients with angioedema due to C1-inhibitor deficiency but normal in those with ACE-inhibitor–related angioedema. This indicates an increased bradykinin production in angioedema due to C1-inhibitor deficiency and a reduced bradykinin catabolism in ACE-inhibitor–related angioedema. Whatever the reason for the increased plasma levels of bradykinin (increased production or decreased catabolism), these data provide the rationale for the use of the recently developed bradykinin receptor antagonists in these two types of angioedema.