Elsevier

The Lancet

Volume 351, Issue 9117, 6 June 1998, Pages 1693-1697
The Lancet

Early Report
Plasma bradykinin in angio-oedema

https://doi.org/10.1016/S0140-6736(97)09137-XGet rights and content

Summary

Background

Bradykinin is believed to be the main mediator of symptoms in hereditary (HA) and acquired (AA) angio-oedema due to C1 esterase inhibitor deficiency, as well as in angio-oedema that complicates treatment with inhibitors of angiotensin-converting enzyme (ACE). Difficulties in the measurement of kinin concentrations, however, have so far precluded the demonstration of an incontrovertible change in plasma bradykinin concentrations in these disorders. By developing a reliable assay we have been able to follow bradykinin concentrations during attacks and during remission in HA and in AA, and also in a patient treated with an ACE-inhibitor.

Methods

Liquid-phase extraction, high-performance liquid chromatography, and RIA were used for specific measurement of plasma bradykinin concentrations in 22 patients with HA and in 22 healthy volunteers of similar age and sex distribution. Four patients with AA and one hypertensive patient treated with the ACE inhibitor captopril were also studied.

Findings

Among the healthy volunteers plasma bradykinin concentration was inversely proportional to age. The geometric mean plasma bradykinin concentration in the healthy volunteers was 2·2 fmol/mL (SD 2·2), compared with 3·9 fmol/mL (3·7) among patients with HA during remission (p=0·095). Bradykinin was also high in the patients with AA (10·4 fmol/mL [1·6]). During acute attacks of oedema, in both HA and AA, plasma bradykinin rose to two to 12 times the upper limit of normal. Infusion of C1-esterase inhibitor (the deficient factor in both HA and AA) immediately lowered bradykinin concentrations. In the patient receiving the ACE-inhibitor captopril, bradykinin concentration was very high at 47 fmol/mL during an acute attack of angio-oedema, but normal at 3·2 fmol/mL in remission after withdrawal of the drug.

Interpretation

A sensitive method for measurement of plasma bradykinin provided the means to show that concentrations of this peptide decrease with age in healthy people. Although the differences between patients in remission and healthy controls did not reach statistical significance, there were substantial rises in bradykinin during acute attacks of hereditary, acquired, or captopril-induced angio-oedema.

Introduction

Inadequate inhibition of the first component of human complement (C1-inhibitor) gives rise to hereditary angio-oedema (HA)1 and an acquired form of angio-oedema (AA).2, 3 HA is attributed to a genetic deficiency (type I) or dysfunction (type II) of C1-inhibitor,4 whereas AA presents with too rapid catabolism of C1-inhibitor due to a concomitant disease or autoantibodies.2, 5 Symptoms involve episodic swelling of subcutaneous tissues, bowel walls, and upper airways.6, 7 Histamine is not involved in the pathogenesis of acute attacks in this type of oedema,6 but possible mediators include bradykinin8, 9 and a kinin-like peptide.10 Bradykinin is released by the action of kallikrein on high-molecular-weight kininogen during contact-system activation.11 The kinin-like peptide is thought to be released from the second component of complement (C2) during complement activation.10

C1-inhibitor has a broad range of regulatory actions,12 which suggests that more than one substance causes the symptoms of angio-oedema.13, 14 Bradykinin, however, may well be the primary mediator: Curd and colleagues15 detected active kallikrein in induced blister fluid of HA patients; Shapira and colleagues16 found activation of prekallikrein and consumption of high-molecular-weight kininogen during attacks of angio-oedema. Further support for bradykinin as a mediator of symptoms comes from the finding that in a large kindred a mutant C1-inhibitor—which did not inhibit C1 but retained the inhibitory action on activated factor XII and on kallikrein—did not lead to angio-oedema.17 In addition, a polymorphism of the bradykinin receptor B2 influenced clinical status in HA.18

Bradykinin is also assumed to mediate the angio-oedema arising after treatment with inhibitors of angiotensin-converting enzyme (ACE).19 ACE is identical to kininase II, an enzyme that metabolises and inactivates bradykinin, the inhibition of which causes accumulation of plasma kinins.20 Kinin concentrations are difficult to measure, however, and no definitive change in bradykinin plasma concentrations during attacks of angio-oedema has been shown. Talamo and colleagues21 reported varied concentrations of immunoreactive kinins in HA patients, but the values measured—both in patients and controls—were several orders of magnitude higher than the plasma concentrations of kinins obtained by more recent assays.20

To counter this difficulty we have developed a reliable assay for specific measurement of plasma bradykinin, excluding other immunoreactive kinins, and applied it to investigate HA, AA, and one case of angio-oedema induced by ACE-inhibitor treatment, both in remission and during acute attacks.

Section snippets

Patients

22 healthy members of the hospital staff (nine men and 13 women; mean age 45 years [SD 16], range 21–70) served as normal controls. Plasma bradykinin concentrations were measured in 22 patients with confirmed HA (nine men and 13 women; mean age 41 years [15], range 18–60, 19 type I and three type II) during clinical remission. They were matched for distribution of sex and age with the normal controls. Seven of these patients were under long-term treatment with the lowest effective doses of

Results

The detection limit for a single HPLC fraction was 0·125 fmol bradykinin (defined by two SD from zero-binding on the standard curve). The overall recovery of unlabelled bradykinin (20 fmol) added to pooled plasma after ethanol extraction, HPLC, and RIA was 99·7% (SD 8·4; n=12, coefficient of variation 8·4%). We calculated from the detection limit (0·125 fmol), the volume correction factor (1·4), the extracted plasma volume (1 mL), and the overall recovery (0·997), that the lowest bradykinin

Discussion

Measurement of plasma bradykinin concentration is difficult, since this short-lived peptide circulates in very low concentrations (fmol/mL range) in the presence of substantial amounts of related precursor and metabolite peptides. Furthermore, extremely active kinin-generating and kinin-degrading processes tend to hamper accurate bradykinin estimation in plasma. The production of a very sensitive antiserum against bradykinin, and an optimised sampling and extraction procedure,20 together with

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