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Biomedical subjects

M Cugno

Publications and source records attributed to M Cugno.

At least 19 recordsLinked to original sources
PubMed2006

Antibodies to tissue-type plasminogen activator (t-PA) in patients with inflammatory bowel disease: high prevalence, interactions with functional domains of t-PA and possible implications in thrombosis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have an increased prevalence of thromboembolic events. The pathogenetic mechanisms of these events include reduced fibrinolysis, which may be caused by antibodies to tissue-type plasminogen activator (t-PA). OBJECTIVES: To evaluate anti-t-PA antibodies in patients with IBD, considering clinical, biochemical and functional characteristics. PATIENTS AND METHODS: We immunoenzymatically measured anti-t-PA antibodies in plasma from 97 consecutive IBD patients and 97 age- and sex-matched healthy controls. We also assessed the antibody interactions with different epitopes of t-PA, the antibody inhibition on t-PA activity and the correlations with clinical features and other serum antibodies. RESULTS: IBD patients had higher median anti-t-PA antibody levels (5.4 U mL(-1) vs. 4.0 U mL(-1); P < 0.0001): 18 patients were above the 95th percentile of the controls (OR 5.3; 95% CI 1.7-16.3; P < 0.003), and the six with a history of thrombosis tended to have high levels (6.9 U mL(-1)). Anti-t-PA antibody levels did not correlate with IBD type, activity, location or treatment, or with age, sex, acute-phase reactants or other antibodies. The anti-t-PA antibodies were frequently IgG1 and bound t-PA in fluid phase; they recognized the catalytic domain in 10 patients and the kringle-2 domain in six. The IgG fraction from the three patients with the highest anti-t-PA levels slightly reduced t-PA activity in vitro. CONCLUSIONS: The prevalence of anti-t-PA antibodies is high in IBD patients. By binding the catalytic or kringle-2 domains of t-PA, these antibodies could lead to hypofibrinolysis and contribute to the prothrombotic state of IBD.

Adult↗
PubMed2005

Kallikrein-kinin system in inflammatory bowel diseases: Intestinal involvement and correlation with the degree of tissue inflammation.

BACKGROUND: Tissue kallikrein and its natural inhibitor, kallistatin, play opposite roles in the generation of bradykinin, a potent mediator of inflammation. Observations on experimental models and humans with ulcerative colitis suggest a pathogenetic role of the kallikrein-kinin system in inflammatory bowel diseases. AIM: To evaluate tissue kallikrein and kallistatin in intestinal tissue samples from Crohn's disease and ulcerative colitis patients with different degrees of disease involvement. PATIENTS AND METHODS: Full-thickness surgical intestinal samples were obtained from 144 subjects (38 normal controls, 32 inflammatory controls, 38 Crohn's disease, 36 ulcerative colitis) and tested for kallikrein and kallistatin by immunoperoxidase techniques. RESULTS: Compared with controls, kallikrein immunoreactivity was significantly weaker in goblet cells (p=0.0001) and significantly stronger in interstitium (p=0.0001) of the Crohn's disease and ulcerative colitis samples. Kallistatin colocalised with kallikrein, with almost no reactivity in goblet cells but strong reactivity in interstitium of inflammatory bowel disease patients (p=0.0001 versus controls). The kallikrein and kallistatin depletion of goblet cells and the increased interstitial kallikrein and kallistatin reactivity correlated with the degree of tissue inflammation (p=0.0001). Disease-free samples had normal kallikrein and kallistatin patterns. CONCLUSIONS: Kallikrein-kinin system is actively involved in inflammatory bowel disease as a result of the release of kallikrein in the intestinal extracellular space; this involvement correlates with the degree of tissue inflammation. The normal pattern observed in the disease-free samples seems to rule out a genetic defect of kallikrein and kallistatin in inflammatory bowel diseases.

Adult↗
PubMed2001

In vitro interaction of C1-inhibitor with thrombin.

Previous observations of increased generation of thrombin during acute attacks of angioedema in plasma of patients with C1-inhibitor (C1-INH) deficiency prompted us to evaluate the interaction of C1-INH with thrombin in both purified systems and human plasma. For this purpose, we used several methods: (1) sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting analysis; (2) enzyme-linked immunosorbent assays to measure complexes between C1-INH and thrombin and inactivated C1-INH; and (3) kinetic studies using a chromogenic assay. We found that the interaction of purified C1-INH with thrombin is associated with the formation of bimolecular complexes of molecular weight (Mr) 130 000 and 120 000 as well as with the appearance of a cleaved form of C1-INH of Mr 97 000. The kinetic studies of inhibition of thrombin by C1-INH showed an average second-order rate constant of 19/s per mol/l, which was significantly increased in the presence of heparin. The addition of thrombin to human plasma was not associated with detectable C1-INH-thrombin complex formation or with cleavage of C1-INH. In conclusion, our data demonstrate that C1-INH upon interaction with thrombin, in part, forms enzyme-inhibitor complexes and, in part, is cleaved. The low second-order rate constant and the lack of a significant interaction in plasma suggest that the inhibition of thrombin by C1-INH has a minor role in circulating blood; however, its role might be important at the endothelial surface, where high concentrations of glycosaminoglycans occur.

Complement C1 Inactivator Proteins↗
PubMed2001

Bradykinin and des-Arg(9)-bradykinin metabolic pathways and kinetics of activation of human plasma.

In the serum of 116 healthy individuals, exogenous bradykinin (BK) half-life (27 +/- 10 s) was lower than that of des-Arg(9)-BK (643 +/- 436 s) and was statistically different in men compared with women. The potentiating effect of an angiotensin-converting enzyme (ACE) inhibitor was, however, more extensive for BK (9.0-fold) than for des-Arg(9)-BK (2.2- fold). The activities of ACE, aminopeptidase P (APP), and kininase I were respectively 44 +/- 12, 22 +/- 9, and 62 +/- 10 nmol x min(-1) x ml(-1). A mathematical model (y = kt(alpha)e(-beta t), t > 0), applied to the BK kinetically released from endogenous high-molecular-weight kininogen (HK) during plasma activation in the presence of an ACE inhibitor, revealed a significant difference in the rate of formation of BK between men and women. For des-Arg(9)-BK, the active metabolite of BK, the rate of degradation was higher in women compared with men, correlating significantly with serum APP activity (r(2) = 0.6485, P < 0.001). In conclusion, these results constitute a basis for future pathophysiological studies of inflammatory processes where activation of the contact system of plasma and the kinins is involved.

Adult↗
PubMed2001

Increase of bradykinin in plasma of patients undergoing cardiopulmonary bypass: the importance of lung exclusion.

STUDY OBJECTIVES: Hemodynamic complications including hypotensive episodes are frequently associated with cardiopulmonary bypass (CPB) and can be attributed to a generalized inflammatory response in which bradykinin may be a mediator. The purpose of this study was to determine the plasma levels of bradykinin-(1-9)nonapeptide in patients during CPB and the physiologic elimination of bradykinin by the lungs. DESIGN: Prospective, observational study. SETTING: University hospital, cardiac surgery unit. PATIENTS AND METHODS: Intra-arterial BP was monitored and serial blood samples were obtained from 27 patients undergoing CPB for cardiac surgery. We measured plasma bradykinin and parameters of coagulation, fibrinolysis, complement, contact system, and the cytokine tumor necrosis factor (TNF). RESULTS: Mean arterial pressure fell progressively until the end of CPB (- 18 mm Hg, p = 0.001) but returned to baseline by the end of surgery. The venous bradykinin level, normal in basal conditions (median, 1.90 fmol/mL), was increased (p = 0.001) from 15 min after the beginning of CPB (5.71 fmol/mL) to the end of the operation (7.07 fmol/mL), with a peak at the end of CPB (9.81 fmol/mL; p = 0.0001); it was normal at recovery 24 h later (2.81 fmol/mL). Bradykinin plasma levels fell 60% across the lung when the pulmonary circulation was fully restored while the patients were still receiving CPB. Activated-factor XII, thrombin-antithrombin complexes, prothrombin fragment F1 + 2, plasmin-antiplasmin complexes, C(3)a, and TNF increased significantly after the beginning of the surgical procedure, rising further during CPB, and remained elevated until the end of surgery, but they all returned to normal within 24 h. Changes in plasma bradykinin levels were not correlated with any of the other variables. CONCLUSIONS: During CPB, there is a progressive increase of plasma bradykinin that is at least partially due to reduced catabolism as a consequence of shunting the lungs. The increase in bradykinin may contribute to the fall in BP.

Aged↗
PubMed2001

Treatment of Raynaud's phenomenon with intravenous prostaglandin E1alpha-cyclodextrin improves endothelial cell injury in systemic sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of prostaglandin (PG) E1alpha-cyclodextrin for Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc) and its effect on variables of immune activation and endothelial injury in SSc such as tumor necrosis factor-alpha (TNF-alpha), soluble interleukin 2 receptor (sIL-2R), circulating intercellular adhesion molecule-1 (cICAM-1), von Willebrand factor (vWF), and tissue-type plasminogen activator (t-PA). METHODS: We studied 36 women with SSc, 24 of them given three 60 microg intravenous PGE1alpha-cyclodextrin infusions on 5 consecutive days at 6 week intervals during the winter. RP symptoms and healing of digital lesions were evaluated. Twenty age matched healthy women were the controls. TNF-alpha, sIL-2R, cICAM-1, vWF, and t-PA were measured after the first and last infusion of PGEE1alpha-cyclodextrin and correlated with clinical features. RESULTS: RP symptoms improved in 87% of the patients. The benefit of each 5 day cycle lasted 4 or more weeks in 75%. PGE1alpha-cyclodextrin reduced the daily frequency of RP symptoms by 20% (p < 0.05), 41% (p < 0.005), and 53% (p < 0.0005) from baseline after the 1st, 2nd, and 3rd infusions, respectively. The severity of the attacks was reduced to a limited degree. In 12 of the 14 patients with digital lesions, these healed completely. Ten patients had mild side effects during treatment (headache, increased intestinal motility, flushing). TNF-alpha, sIL-2R, cICAM-1, vWF, and t-PA plasma concentrations were significantly higher in patients with SSc than controls (p < 0.05, p < 0.001). TNF-alpha, sIL-2R, and cICAM-1 were higher in diffuse SSc and patients with lung involvement. The plasma levels of cICAM-1 and t-PA were significantly reduced after the 1st infusion of PGE1alpha-cyclodextrin (both p < 0.005) and further reduced after the last (p < 0.0005 and p < 0.005). CONCLUSION: PGE1alpha-cyclodextrin reduces RP symptoms and plasma levels of the markers of endothelial injury in SSc, suggesting that an improvement of endothelial dysfunction contributes to its prolonged therapeutic effect.

Adult↗
PubMed2001

Bradykinin in the ascitic fluid of patients with liver cirrhosis.

Bradykinin, a nonapeptide with vasodilatory and permeabilizing activity, is generated through the cleavage of high-M(r) ('high-molecular-weight') kininogen by kallikrein, and its generation is facilitated by plasmin. In the ascitic fluid of patients with cirrhosis, there is massive cleavage of high-M(r) kininogen and activation of fibrinolysis, but bradykinin has never been measured directly. In the ascitic fluid of 24 patients with cirrhosis, we measured bradykinin-(1-9)-nonapeptide levels by RIA after liquid-phase and subsequent HPLC extraction, and those of its catabolic product bradykininin-(1-5)-pentapeptide by ELISA after liquid-phase extraction. Cleaved high-M(r) kininogen, activated factor XII and plasmin-antiplasmin complexes were measured in ascitic fluid and plasma. Plasma renin activity (PRA) was also determined. As a control, we also analysed plasma from 24 healthy subjects matched for sex and age with the patients. In the ascitic fluid from patients with cirrhosis, the median bradykinin-(1-9) concentration was 3.3 fmol/ml (range 0.2-29.0 fmol/ml), and the median bradykinin-(1-5) concentration was 210 fmol/ml (range 58-7825 fmol/ml). The levels of bradykinin-(1-5) in ascitic fluid were higher in patients with refractory ascites [median 1091 fmol/ml (range 58-7825 fmol/ml)] than in patients with responsive ascites [134 fmol/ml (72-1084 fmol/ml)] (P=0.010). Ascitic fluid levels of bradykinin-(1-9) were not related to the severity of ascites. PRA was higher in patients with refractory ascites [23.0 ng x h(-1) x ml(-1) (7.9-80.0 ng.h(-1).ml(-1))] than in patients with responsive ascites [6.9 ng x h(-1) x ml(-1) (0.9-29.4 ng x h(-1) x ml(-1))] (P=0.002). In ascitic fluid, 48% (19-68%) of high-M(r) kininogen was cleaved, and plasmin-antiplasmin complexes were more concentrated than in plasma (P=0.0001). In conclusion, in the ascitic fluid of patients with cirrhosis, both bradykinin-(1-9) and bradykinin-(1-5) are present, with cleavage of high-M(r) kininogen and activation of fibrinolysis. The highest levels of the long-lived metabolite bradykinin-(1-5) were found in the ascitic fluid of patients with refractory ascites and high PRA. Activation of the kinin system may therefore be involved in decompensating cirrhosis, but a cause-effect relationship remains to be established.

Adult↗
PubMed2001

[The kinin system: biological mechanisms and clinical implications].

The discovery of the kinin system is not recent, but its study in clinical field has been done only in the last years. This system is composed by substrates (kininogens) and plasma and tissue kallikreins are the specific activators of these substrates producing two vasoactive peptides called bradykinin and kallidin. The biologic effects of kinins are mediated by specific receptors called B1 and B2. The activation of this system is particularly important in blood pressure regulation and in inflammatory reactions. The kinin system is involved in many clinical situations including respiratory allergic reactions, septic shock, hypertension and its treatment, hypotensive transfusion reactions, heart diseases, pancreatitis, hereditary and acquired angioedema, Alzheimer's disease and liver cirrhosis with ascites. The study of the kinin system in clinical field, which had been limited by methodological difficulties, has now received an important stimulus by the recent availability of specific and sensitive methods of dosage.

Alzheimer Disease↗
PubMed2000

Antibodies to tissue-type plasminogen activator in plasma from patients with primary antiphospholipid syndrome.

A reduction in fibrinolysis has been described in association with thrombosis in the primary antiphospholipid syndrome (PAPS). In this study, we measured anti-tissue-type plasminogen activator (t-PA) antibodies and anti-fibrin-bound t-PA antibodies as possible causes of hypofibrinolysis in 39 patients with PAPS. We also evaluated the differences in anti t-PA antibodies between patients without previous thrombosis (20 patients) and patients with previous episodes of thrombosis (19 patients: deep vein thrombosis in nine, ischaemic stroke in six, arterial leg thrombosis in one, hepatic vein thrombosis in one, thrombophlebitis in one and cerebral venous thrombosis in one). Anti-t-PA antibodies were measured by an enzyme-linked immunosorbent assay (ELISA), and anti-t-PA fibrin-bound antibodies were measured by a solid-phase fibrin immunoassay (SOFIA) in 39 patients with PAPS and in 39 controls matched for gender and age. High levels of IgG anti-t-PA were found in three out of 39 patients with PAPS, and all three patients had a history of thrombosis; four other patients, one of whom had a history of thrombotic events, had high titres of antibodies directed against fibrin-bound t-PA. In addition, patients with ischaemic stroke had significantly higher levels of IgG anti-t-PA than patients without thrombosis (P = 0.029). In conclusion, our data showed that, in patients with PAPS, the highest levels of anti-t-PA antibodies were present in subjects with previous thrombotic events. The discrepancy in the results obtained with two methods of detection of anti-t-PA antibodies, ELISA and SOFIA, indicates a different interaction of the antibodies with the t-PA molecules, which are directly bound to polystyrene plates in ELISA and bound to fibrin as a bridging molecule in SOFIA.

Adult↗
PubMed2000

Plasma bradykinin levels in human chronic congestive heart failure.

Induction of congestive heart failure by high-frequency pacing has been reported to increase plasma levels of immunoreactive kinins in dogs. In the present study, we evaluated plasma bradykinin levels in human heart failure. Utilizing a recently developed method, we specifically measured plasma levels of bradykinin-(1-9) nonapeptide in 21 patients with chronic congestive heart failure [New York Heart Association (NYHA) stages III and IV). At the same time, we measured plasma atrial natriuretic peptide levels and plasma renin activity, and, as a marker of inflammation, plasma levels of tumour necrosis factor. In addition, 18 healthy subjects matched for gender and age served as normal controls. Plasma bradykinin concentrations were not higher in patients with chronic congestive heart failure (median 2.1 fmol/ml) than in healthy subjects (2.6 fmol/ml). In contrast, plasma atrial natriuretic peptide levels were clearly higher (patients, 63 fmol/ml; controls, 24 fmol/ml; P<0.0001), despite diuretic treatment and in the presence of high plasma renin activity (patients, 13.0 ng x h(-1) x ml(-1); controls, 0.3 ng x h(-1) x ml(-1); P<0.0001). Tumour necrosis factor was elevated in heart failure patients in NYHA class IV only (27 pg/ml, compared with 21 pg/ml in controls; P=0.013). Bradykinin, atrial natriuretic peptide and plasma renin activity levels were not correlated with the severity of the disease, as assessed by NYHA classification. These results indicate that a rather selective cytokine activation, without concomitant stimulation of the kallikrein-kinin system, occurs in human chronic congestive heart failure.

Aged↗
PubMed2000

Homocysteine concentration in primary and systemic sclerosis associated Raynaud's phenomenon.

OBJECTIVE: To investigate whether patients with systemic sclerosis (SSc) have raised homocysteine (Hcy) plasma levels, thought to be an independent risk factor for vascular disease, and to study the relationship between Hcy and endothelial damage, and between Hcy and methylene-tetrahydrofolate reductase (MTHFR) genotypes, and patients' vitamin nutritional status, which are among the more frequent causes of hyperhomocysteinemia. METHODS: We measured Hcy, von Willebrand factor (vWF), folic acid, and vitamin B12 plasma levels and analyzed the frequencies of MTHFR mutations in 30 patients with SSc and 12 patients with primary Raynaud's phenomenon (RP); 29 healthy subjects served as controls. RESULTS: Patients with SSc had higher Hcy and vWF concentrations than those with RP (p < 0.01 and p < 0.02, respectively) or controls (p < 0.02 and p < 0.0001, respectively). Folic acid and vitamin B12 were lower in SSc than in RP (p < 0.01 and p < 0.02, respectively) or controls (p < 0.05). MTHFR genotype did not influence Hcy, folate, or vitamin B12 concentrations, but patients homozygous for the mutant gene had higher vWF levels. CONCLUSION: Patients with SSc, but not those with RP, had significantly higher Hcy and vWF plasma levels. Nutritional rather than inherited factors seem to have a pathogenic role in SSc hyperhomocysteinemia.

Adult↗
PubMed1999

Angioedema due to angiotensin-converting enzyme inhibitors.

Angiotensin-converting enzyme (ACE) inhibitor associated angioedema was detected in 39 subjects (17%) of 231 consecutive patients examined in the last 5 years at our out-patient clinic for symptoms of angioedema without urticaria. In these patients, angioedema was most commonly localized to the face. The duration of ACE-inhibitor treatment at the onset of angioedema ranged from 1 day to 8 years with a median of 6 months. The time elapsed between onset of angioedema and withdrawal of ACE-inhibitor ranged from 1 day to 10 years with a median of 10 months. Delayed diagnosis is explained by the unusual characteristics of this adverse reaction: angioedema may start years after beginning the treatment and then it recurs irregularly. In fact, ACE-inhibitors seem to facilitate angioedema in predisposed subjects, rather than causing it with an allergic or idiosyncratic mechanism. Thus, while Cl-inhibitor levels are usually normal in subjects developing ACE-inhibitor-dependent angioedema, we found that ACE-inhibitors caused angioedema in Cl-inhibitor-deficient patients. Because the main inactivator of bradykinin is kininase II, which is identical with ACE, it is believed that bradykinin mediates ACE-inhibitor-dependent angioedema. We had the possibility to examine the plasma bradykinin levels in one ACE-inhibitor-treated patient during an angioedema attack and we found very high levels, but we did not find an increase of break-down products of high-molecular-weight-kininogen as observed during acute attacks in hereditary angioedema. Bradykinin fell to normal levels during remission after withdrawal of the drug. These observations indicate that in ACE-inhibitor-induced angioedema, contrary to hereditary angioedema, the reduction of bradykinin catabolic rate plays a predominant role.

Adolescent↗
PubMed1999

Cardiopulmonary bypass increases plasma bradykinin concentrations.

An increase of bradykinin (BK) plasma levels together with the activation coagulation cascade, fibrinolysis, complement and cytokines was observed during cardiopulmonary bypass (CPB). Since the procedure of extracorporeal circulation completely excludes the lung, the major site of BK catabolism, our data suggest that a reduced catabolism could contribute to the increase of BK during CPB.

Blood Pressure↗
PubMed1999

Alzheimer's beta-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner.

beta-Amyloid (beta-A) accumulates in the brain of patients with Alzheimer's disease (AD) and is presumably involved in the pathogenesis of this disease, on account of its neurotoxicity and complement-activating ability. Although assembly of beta-A in particular aggregates seems to be crucial, soluble non-fibrillar beta-A may also be involved. Non-fibrillar beta-A does not bind C1q, so we investigated alternative mechanisms of beta-A-dependent complement activation in vitro. On incubation with normal human plasma, non-fibrillar beta-A 1-42, and truncated peptide 1-28, induced dose-dependent activation of C1s and C4, sparing C3, as assessed by densitometric analysis of immunostained membrane after SDS-PAGE and Western blotting. The mechanism of C4 activation was not dependent on C1q, because non-fibrillar beta-A can still activate C1s and C4 in plasma genetically deficient in C1q (C1qd). In Factor XII-deficient plasma (F.XIId) the amount of cleaved C4 was about 5-10% less that in C1qd and in normal EDTA plasma; the reconstitution of F.XIId plasma with physiologic concentrations of F.XII resulted in an increased (8-15%) beta-A-dependent cleavage of C4. Thus our results indicate that the C1q-independent activation of C1 and C4 can be partially mediated by the activation products of contact system. Since the activation of contact system and of C4 leads to generation of several humoral inflammatory peptides, non-fibrillar beta-A might play a role in initiating the early inflammatory reactions leading to a multistep cascade contributing to neuronal and clinical dysfunction of AD brain.

Alzheimer Disease↗
PubMed1999

Parallel reduction of plasma levels of high and low molecular weight kininogen in patients with cirrhosis.

Little is known about the regulation of high-molecular-weight-kininogen (HK) and low-molecular-weight-kininogen (LK) or the relationship of each to the degree of liver function impairment in patients with cirrhosis. In this study, we evaluated HK and LK quantitatively by a recently described particle concentration fluorescence immunoassay (PCFIA) and qualitatively by SDS PAGE and immunoblotting analyses in plasma from 33 patients with cirrhosis presenting various degrees of impairment of liver function. Thirty-three healthy subjects served as normal controls. Patients with cirrhosis had significantly lower plasma levels of HK (median 49 microg/ml [range 22-99 microg/ml]) and LK (58 microg/ml [15-100 microg/ml]) than normal subjects (HK 83 microg/ml [65-115 microg/ml]; LK 80 microg/ml [45-120 microg/ml]) (p<0.0001). The plasma concentrations of HK and LK were directly related to plasma levels of cholinesterase (P<0.0001) and albumin (P<0.0001 and P<0.001) and inversely to the Child-Pugh score (P<0.0001) and to prothrombin time ratio (P<0.0001) (reflecting the clinical and laboratory abnormalities in liver disease). Similar to normal individuals, in patients with cirrhosis, plasma HK and LK levels paralleled one another, suggesting that a coordinate regulation of those proteins persists in liver disease. SDS PAGE and immunoblotting analyses of kininogens in cirrhotic plasma showed a pattern similar to that observed in normal controls for LK (a single band at 66 kDa) with some lower molecular weight forms noted in cirrhotic plasma. A slight increase of cleavage of HK (a major band at 130 kDa and a faint but increased band at 107 kDa) was evident. The increased cleavage of HK was confirmed by the lower cleaved kininogen index (CKI), as compared to normal controls. These data suggest a defect in hepatic synthesis as well as increased destructive cleavage of both kininogens in plasma from patients with cirrhosis. The decrease of important regulatory proteins like kininogens may contribute to the imbalance in coagulation and fibrinolytic systems, which frequently occurs in cirrhotic patients.

Adult↗
PubMed1998

Plasma bradykinin in angio-oedema.

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.

Adult↗