| 2021 | Targeted LC-MS/MS platform for the comprehensive determination of peptides in the kallikrein-kinin system. | Anal Bioanal Chem | The kallikrein-kinin system (KKS) is involved in many physiological and pathophysiological processes and is assumed to be connected to the development of clinical symptoms of angioedema or COVID-19, among other diseases. However, despite its diverse role in the regulation of physiological and pathophysiological functions, knowledge about the KKS in vivo remains limited. The short half-lives of kinins, their low abundance and structural similarities and the artificial generation of the kinin bradykinin greatly hinder reliable and accurate determination of kinin levels in plasma. To address these issues, a sensitive LC-MS/MS platform for the comprehensive and simultaneous determination of the four active kinins bradykinin, kallidin, des-Arg(9)-bradykinin and des-Arg(10)-kallidin and their major metabolites bradykinin 2-9, bradykinin 1-7 and bradykinin 1-5 was developed. This platform was validated according to the bioanalytical guideline of the US Food and Drug Administration regarding linearity, accuracy, precision, sensitivity, carry-over, recovery, parallelism, matrix effects and stability in plasma of healthy volunteers. The validated platform encompassed a broad calibration curve range from 2.0-15.3 pg/mL (depending on the kinin) up to 1000 pg/mL, covering the expected concentrations in disease states. No source-dependent matrix effects were identified, and suitable stability of the analytes in plasma was observed. The applicability of the developed platform was proven by the determination of endogenous levels in healthy volunteers, whose plasma kinin levels were successfully detected in the low pg/mL range. The established platform facilitates the investigation of kinin-mediated diseases (e.g. angioedema, COVID-19) and enables the assessment of the impact of altered enzyme activities on the formation or degradation of kinins. |
| 2020 | The role of TRPA1 and TRPV4 channels in bronchoconstriction and plasma extravasation in airways of rats treated with captopril. | Pulm Pharmacol Ther | Angiotensin-converting enzyme inhibitors (ACEis) may cause adverse airway events, such as cough and angioedema, due to a reduction in bradykinin breakdown and consequent activation of bradykinin type 2 receptor (B receptor). Recent studies have shown that bradykinin can also sensitize pro-inflammatory receptors such as the transient receptor potential ankyrin 1 (TRPA1) and vanilloid 4 (TRPV4), which are implicated in several inflammatory airway diseases. Based on these considerations, the aim of this study was to understand the role of TRPA1 and TRPV4 channels in the bronchoconstrictive response and plasma extravasation in the trachea of rats pretreated with captopril. Using methods to detect alterations in airway resistance and plasma extravasation, we found that intravenous (i.v.) administration of bradykinin (0.03-0.3 μmol/kg, B receptor agonist), allyl isothiocyanate (100-1000 μmol/kg, TRPA1 agonist) or GSK1016790A (0.01-0.1 μmol/kg, TRPV4 agonist), but not des-arg-bradykinin (DABK; 100-300 μmol/kg, B receptor agonist), induced bronchoconstriction in anaesthetized rats. In doses that did not cause significant bronchoconstriction, bradykinin (0.03 μmol/kg) or allyl isothiocyanate (100 μmol/kg), but not GSK1016790A (0.01 μmol/kg) or DABK (300 μmol/kg) induced an increased bronchoconstrictive response in rats pretreated with captopril (2.5 mg/kg, i.v.). On the other hand, in rats pretreated with captopril (5 mg/kg, i.v.), an increased bronchoconstrictive response to GSK1016790A (0.01 μmol/kg) was observed. The bronchoconstrictive response induced by bradykinin in captopril-pretreated rats was inhibited by intratracheal treatment (i.t.) with HC030031 (300 μg/50 μl; 36 ± 9%) or HC067047 (300 μg/50 μl; 35.1 ± 16%), for TRPA1 and TRPV4 antagonists, respectively. However, the co-administration of both antagonists did not increase this inhibition. The bronchoconstriction induced by allyl isothiocyanate in captopril-pretreated rats (2.5 mg/kg) was inhibited (58.3 ± 8%) by the B receptor antagonist HOE140 (10 nmol/50 μl, i.t.). Similarly, the bronchoconstriction induced by GSK1016790A in captopril-pretreated rats (5 mg/kg) was also inhibited (84.2 ± 4%) by HOE140 (10 nmol/50 μl, i.t.). Furthermore, the plasma extravasation induced by captopril on the trachea of rats was inhibited by pretreatment with HC030031 (47.2 ± 8%) or HC067047 (38.9 ± 8%). Collectively, these findings support the hypothesis that TRPA1 and TRPV4, via a B receptor activation-dependent pathway, are involved in the plasma extravasation and bronchoconstriction induced by captopril, making them possible pharmacological targets to prevent or remediate ACEi-induced adverse respiratory reactions. |
| 2020 | Does hereditary angioedema make COVID-19 worse? | World Allergy Organ J | The coronavirus disease 2019 (COVID-19) pandemic has spread rapidly worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2) and depletes ACE2, which is necessary for bradykinin metabolism. The depletion of ACE2 results in the accumulation of des-Arg (9)-bradykinin and possible bradykinin, both of which bind to bradykinin receptors and induce vasodilation, lung injury, and inflammation. It is well known that an overactivated contact system and excessive production of bradykinin comprise the key mechanisms that drive the pathogenesis of hereditary angioedema (HAE). It is reasonable to speculate that COVID-19 may increase disease activity in patients with HAE and vice versa. In this review, we explore the potential interactions between COVID-19 and HAE in terms of the contact system, the complement system, cytokine release, increased T helper 17 cells, and hematologic abnormalities. We conclude with the hypothesis that comorbidity with HAE might favor COVID-19 progression and may worsen its outcomes, while COVID-19 might in turn aggravate pre-existing HAE and prompt the onset of HAE in asymptomatic carriers of HAE-related mutations. Based on the pathophysiologic links, we suggest that long-term prophylaxis should be considered in patients with HAE at risk of SARS-CoV-2 infection, especially the prophylactic use of C1 inhibitor and lanadelumab and that HAE patients must have medications for acute attacks of angioedema. Additionally, therapeutic strategies employed in HAE should be considered for the treatment of COVID-19, and clinical trials should be performed. |
| 2020 | Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. | Elife | COVID-19 patients can present with pulmonary edema early in disease. We propose that this is due to a local vascular problem because of activation of bradykinin 1 receptor (B1R) and B2R on endothelial cells in the lungs. SARS-CoV-2 enters the cell via ACE2 that next to its role in RAAS is needed to inactivate des-Arg9 bradykinin, the potent ligand of the B1R. Without ACE2 acting as a guardian to inactivate the ligands of B1R, the lung environment is prone for local vascular leakage leading to angioedema. Here, we hypothesize that a kinin-dependent local lung angioedema via B1R and eventually B2R is an important feature of COVID-19. We propose that blocking the B2R and inhibiting plasma kallikrein activity might have an ameliorating effect on early disease caused by COVID-19 and might prevent acute respiratory distress syndrome (ARDS). In addition, this pathway might indirectly be responsive to anti-inflammatory agents. |
| 2019 | Glucocorticoids for acute urticaria: study protocol for a double-blind non-inferiority randomised controlled trial. | BMJ Open | This study protocol describes a trial designed to investigate whether antihistamine alone in patients with acute urticaria does not increase the 7-day Urticaria Activity Score (UAS7) in comparison with an association of antihistamine and glucocorticoids and reduces short-term relapses and chronic-induced urticaria.This is a prospective, double-blind, parallel-group, multicentre non-inferiority randomised controlled trial. Two-hundred and forty patients with acute urticaria admitted to emergency department will be randomised in a 1:1 ratio to receive levocetirizine or an association of levocetirizine and prednisone. Randomisation will be stratified by centre. The primary outcome will be the UAS7 at day 7. The secondary outcomes will encompass recurrence of hives and/or itch at day 7; occurrence of spontaneous hives or itch for >6 weeks; patients with angioedema at day 7, and 2, 6, 12 and 24 weeks; new emergency visits for acute urticaria recurrences at days 7 and 14, and 3 months; Dermatology Life Quality Index at days 7 and 14, and 3 and 6 months; and Chronic Urticaria Quality of Life Questionnaire at 6 weeks.The protocol has been approved by the and will be carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. A steering committee will oversee the progress of the study. Findings will be disseminated through national and international scientific conferences and publication in peer-reviewed journals.NCT03545464. |
| 2019 | Angioedema: a rare and sometimes delayed side effect of angiotensin-converting enzyme inhibitors. | Acta Cardiol | The effects of angiotensin converting enzyme (ACE) inhibitors result from the inhibition of the ACE (kininase II) to ultimately influence both the renin-angiotensin system and the degradation of the bradykinin (BK) metabolism. ACE inhibitors block the degradation of BK and substance P by ACE. In addition, an active metabolite of BK (Des-Arg9-BK) is catalysed by kininase I and its degradation is controlled in part by the conversion enzyme. These molecules have been associated with increased plasma extravasation associated with ACE inhibitors. ACE inhibitors are the leading cause of drug-induced Angioedema (AE). Symptoms of AE mainly occur after the first month of treatment by ACE. However, very late onset cases, sometimes after several years of stable therapy, are also described in the literature. It has been observed that patients previously stable under ACE inhibitor will most likely develop AE soon after the addition of another medication, including the combination of aspirin or non-steroid anti-inflammatory drugs with ACE inhibitor which has proved to be the most common cause, accounting for close to 50% of all AE cases related to ACE inhibitors. This side effect of ACE inhibitors, sometimes very late and rare, deserves to be recalled. |
| 2018 | [A Rare Cause of an Angioedema-Like Habitus]. | Praxis (Bern 1994) | A Rare Cause of an Angioedema-Like Habitus Abstract. We report about a 69-year-old patient arriving at the emergency room with suspected allergic reaction grade III due to a pronounced facial swelling, dyspnea and dizziness. However, the cause was a bilateral pneumothorax with massive soft-tissue emphysema. On the one side it was due to a spontaneous secondary genesis in the context of a chronic pulmonary disease, on the other side it was due to a traumatic serial rib fracture. |
| 2018 | Angiotensin-Converting Enzyme Inhibitors vs. Angiotensin Receptor Blockers for the Treatment of Hypertension in Adults With Type 2 Diabetes: Why We Favour Angiotensin Receptor Blockers. | Can J Diabetes | Cardiovascular disease is the principal cause of morbidity and mortality in patients with diabetes mellitus. The incidence or progression of kidney disease is also common in these patients. Several clinical trials have established the efficacy of angiotensin receptor blockers for the prevention of adverse cardiovascular and renal outcomes in this population and are summarized in this review article. Head-to-head comparison of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors has shown similar cardioprotective and renoprotective properties of both medication classes. However, angiotensin receptor blockers have an improved safety profile with fewer episodes of cough and angioedema and may be the agent of choice in patients with diabetes and hypertension. Novel therapeutic strategies, such as those that include a mineralocorticoid receptor blocker or a selective sodium-glucose cotransporter type 2 inhibitor, may further protect patients with diabetes from cardiovascular and renal complications. |
| 2016 | Dedicated call center (SOS-HAE) for hereditary angioedema attacks: study protocol for a randomised controlled trial. | Trials | Despite the availability of guidelines for the specific treatment of hereditary angioedema (HAE) attacks, HAE morbidity and mortality rates remain substantial. HAE attacks are a major medical issue requiring specific treatment as well as a considerable socio-economic burden. We report a protocol designed to test whether a dedicated call centre is more effective than usual practice in the management of patients experiencing an HAE attack.This prospective, cluster-randomised, single-blind, parallel-group, multicentre trial evaluates the morbidity and consequent socio-economic costs of the management of patients experiencing an HAE attack by a dedicated call centre as compared to usual practice. The trial aims to recruit 200 patients. Patients in the intervention arm are provided with an SOS-HAE card with the call centre's freephone number that they can access in the case of an attack. The centre's mission is to provide recommended expert advice on early home treatment. The centre can route the call to a local emergency medical service with competency in HAE management or even arrange for the drugs needed for the specific treatment of an HAE attack to be sent to the emergency department of the local hospital. The primary outcome measure is the number of hospital admissions for an HAE attack. Each patient will be followed up every 2 months for 2 years. The study has been approved by the ethics committee (Comité de Protection des Personnes d'Ile de France 10; registration number: 2012-A00044-39; date of approval: 19 January 2012).The SOS-HAE protocol has been designed to address the handling of attacks experienced by patients with HAE in the home. The proposed trial will determine whether the setting up of a dedicated call centre is more effective than usual practice in terms of reducing morbidity as given by the numbers of hospital admissions. The results are also anticipated to have important implications in terms of socio-economic costs for both healthcare services and patients.ClinicalTrials.gov NCT01679912 . |
| 2015 | Adverse drug reaction reports for cardiometabolic drugs from sub-Saharan Africa: a study in VigiBase. | Trop Med Int Health | Identifying key features in individual case safety reports (ICSR) of suspected adverse drug reactions (ADRs) with cardiometabolic drugs from sub-Saharan Africa (SSA) compared with reports from the rest of the world (RoW).Reports on suspected ADRs of cardiometabolic drugs (ATC: A10[antidiabetic], B01[antithrombotics] and C[cardiovascular]) were extracted from WHO Global database, VigiBase(®) (1992-2013). We used vigiPoint, a logarithmic odds ratios (log2 OR)-based method to study disproportional reporting between SSA and RoW. Case-defining features were considered relevant if the lower limit of the 99% CI > 0.5.In SSA, 3773 (9%) of reported ADRs were for cardiometabolic drugs, in RoW for 18%. Of these, 79% originated from South Africa and 81% were received after 2007. Most reports were for drugs acting on the renin-angiotensin system (36% SSA & 14% RoW). Compared with RoW, reports were more often sent for patients 18-44 years old (log2 OR 0.95 [99 CI 0.80; 1.09]) or with non-fatal outcome (log2 OR 1.16 [99 CI 1.10; 1.22]). Eight ADRs (cough, angioedema, lip swelling, face oedema, swollen tongue, throat irritation, drug ineffective and blood glucose abnormal) and seven drugs (enalapril, rosuvastatin, perindopril, vildagliptin, insulin glulisine, nifedipine and insulin lispro) were disproportionally more reported in SSA than in the RoW.'In recent years, the number of adverse drug reactions (ADRs) reported in Sub-Saharan Africa (SSA) has sharply increased. The data showed the well-known population-based differential ADR profile of ACE inhibitors in the SSA population.' |
| 2011 | A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema. | Hum Mutat | Angiotensin I-converting enzyme inhibitors (ACEi) are widely used antihypertensive agents that are associated with a potentially life-threatening reaction, ACEi-angioedema. Impaired metabolism of bradykinin and des-Arg(9) -bradykinin by aminopeptidase P (APP) is a key contributor to ACEi-angioedema. This study aimed to characterize the genetic regulation of the XPNPEP2 gene and identify the genetic factors contributing to variance in plasma APP activity and ACEi-angioedema. Additive genetic factors accounted for 47.3% of variance in plasma APP activity in healthy individuals. Nested deletion analysis identified the minimal promoter (-338 bp to -147 bp) and an enhancer region (-2,502 bp to -2,238 bp). Three polymorphisms (c.-2399C>A, c.-1612G>T, and c.-393G>A) were significantly associated with plasma APP activity. Haplotype ATG was significantly associated with reduced reporter gene activity and with reduced plasma APP activity. The c.-2399C>A polymorphism was located in an enhancer region and was predicted to differentially bind hepatic nuclear factor 4 (HNF4). Over expression of HNF4 increased the activation of haplotype ATG compared with haplotype CGG. In a case control study of subjects with a history of ACEi-angioedema, haplotype ATG was significantly associated with ACEi-angioedema (OR 4.87 [1.78-13.35] P = 0.002). The ATG haplotype is functional and contributes to ACEi-angioedema through a reduction in APP. |
| 2010 | The plasma bradykinin-forming pathways and its interrelationships with complement. | Mol Immunol | The plasma bradykinin-forming cascade and the complement pathways share many elements, including cross-activation, common control mechanisms, and shared binding proteins. The C1 inhibitor (C1 INH) is not only the inhibitor of activated C1r and C1s, but it is the key control protein of the plasma bradykinin-forming cascade. It inhibits the autoactivation of Factor XII, the ability of Factor XIIa to activate prekallikrein and Factor XI, the activation of high molecular weight kininogen (HK) by kallikrein, and the feedback activation of Factor XII by kallikrein. Thus in the absence of C1 INH (hereditary angioedema or acquired C1 INH deficiency) there is unimpeded formation of bradykinin leading to angioedema. Activated Factor XII (Factor XIIa, 80,000 kDa) is further cleaved by kallikrein or plasmin to yield Factor XII fragment (Factor XIIf, 30,000 kDa) and Factor XIIf can activate the C1r subcomponent of C1, particularly when C1 INH (which inhibits Factor XIIf) is absent. Once bradykinin is formed, it causes vasodilatation and increased vascular permeability by interaction with constitutively expressed B-2 receptors. However degradation of bradykinin by carboxypeptidase N (in plasma) or carboxypeptidase M (on endothelial cells) yields des-arg-9 (Kerbiriou and Griffin, 1979) bradykinin which interacts with B-1 receptors. B-1 receptors are induced in inflammatory states by cytokines such as Interleukin 1 and its interaction with bradykinin may prolong or perpetuate the vascular response until bradykinin is completely inactivated by angiotensin converting enzyme or aminopeptidase P, or neutral endopeptidase. The entire bradykinin-forming cascade is assembled and can be activated along the surface of endothelial cells in zinc dependent reactions involving gC1qR, cytokeratin 1, and the urokinase plasminogen activated receptor (u-PAR). Although Factors XII and HK can be shown to bind to each one of these proteins, they exist in endothelial cells as two bimolecular complexes; gC1qR-cytokeratin 1, which preferentially binds HK, and cytokeratin 1-u-PAR which preferentially binds Factor XII. The gC1qR, which binds the globular heads of C1q is present in excess and can bind either Factor XII or HK however the binding sites for HK and C1q have been shown to reside at opposite ends of gC1qR. Activation of the bradykinin-forming pathway can be initiated at the cell surface by gC1qR-induced autoactivation of Factor XII or direct activation of the prekallikrein-HK complex by endothelial cell-derived heat-shock protein 90 (HSP 90) or prolylcarboxypeptidase with recruitment or Factor XII by the kallikrein produced. |
| 2007 | [Physiopathology of the acute adverse effects of angiotensin-converting-enzyme inhibitors]. | Bull Acad Natl Med | Angiotensin-I-converting-enzyme inhibitors are currently used to treat more than 40 million cardiovascular patients worldwide. These drugs have a variety of acute adverse effects, the nature of which depends on the clinical context, and which include angioedema, anaphylactoid reactions in hemodialysis patients, and severe hypotensive reactions during blood product transfusions. These adverse effects result from a combination of factors affecting the synthesis, metabolism and pharmacological activity of bradykinin and des-arginine9-bradykinin, two powerful vasodilatory and pro-inflammatory peptides. Experimental evidence obtained in our laboratory suggests that acquired, genetic and pharmacological factors can influence the risk of these rare but potentially life-threatening effects. |
| 2008 | Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P. | J Allergy Clin Immunol | Aminopeptidase P (APP) plays an important role in the catabolism of kinins in human plasma, mostly for des-Arg(9)-bradykinin. Impaired degradation of this active bradykinin metabolite was found to be associated with a decreased APP activity in hypertensive patients who experienced angioedema while being treated with angiotensin I-converting enzyme inhibitors. The pathophysiology of hereditary angioedema is presently attributed only to a quantitative/qualitative C1 inhibitor (CI-INH) defect with increased bradykinin release.In the context of androgen prophylaxis, increased CI-INH function cannot fully explain protection from angioedema attacks alone because of the limited reversion of the CI-INH defects. Therefore we hypothesized that androgen prophylaxis could enhance plasma APP activity.Patients with hereditary angioedema were investigated for plasma metallopeptidase activities responsible for kinin catabolism (APP, angiotensin I-converting enzyme, and carboxypeptidase N) and for CI-INH function in treated and untreated patients.APP activity was asymmetrically distributed in untreated patients (n = 147): the mean value was significantly lower than the value in a reference healthy and unmedicated population (n = 116; P < or = .001). Prophylaxis with androgen induced a significant increase in APP activity (P < or = .001), whereas it did not affect the other metallopeptidase activities. In both patient groups, APP activity showed a significant inverse relationship to disease severity (P < or = .001).In addition to the effect on circulating CI-INH levels, the increase in APP levels brought on by androgens could contribute to a more effective control of the kinin accumulation considered to be responsible for the symptoms of angioedema. |
| 2008 | Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. | Hypertension | Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular permeability and cause tissue edema in animals. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor-associated angioedema. This case-control study tested the hypothesis that dipeptidyl peptidase IV activity and antigen are decreased in sera of patients with a history of angiotensin-converting enzyme inhibitor-associated angioedema. Fifty subjects with a history of angiotensin-converting enzyme inhibitor-associated angioedema and 176 angiotensin-converting enzyme inhibitor-exposed control subjects were ascertained. Sera were assayed for angiotensin-converting enzyme activity, aminopeptidase P activity, aminopeptidase N activity, dipeptidyl peptidase IV activity, and antigen and the ex vivo degradation half-lives of bradykinin, des-Arg(9)-bradykinin, and substance P in a subset. The prevalence of smoking was increased and of diabetes decreased in case versus control subjects. Overall, dipeptidyl peptidase IV activity (26.6+/-7.8 versus 29.6+/-7.3 nmol/mL per minute; P=0.026) and antigen (465.8+/-260.8 versus 563.1+/-208.6 ng/mL; P=0.017) were decreased in sera from individuals with angiotensin-converting enzyme inhibitor-associated angioedema compared with angiotensin-converting enzyme inhibitor-exposed control subjects without angioedema. Dipeptidyl peptidase IV activity (21.5+/-4.9 versus 29.8+/-6.7 nmol/mL per minute; P=0.001) and antigen (354.4+/-124.7 versus 559.8+/-163.2 ng/mL; P=0.003) were decreased in sera from cases collected during angiotensin-converting enzyme inhibition but not in the absence of angiotensin-converting enzyme inhibition. The degradation half-life of substance P correlated inversely with dipeptidyl peptidase IV antigen during angiotensin-converting enzyme inhibition. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema. |
| 2006 | Kinin-dependent hypersensitivity reactions in hemodialysis: metabolic and genetic factors. | Kidney Int | Although the association of angiotensin I-converting enzyme inhibitors (ACEis) with a negatively charged membrane is thought to be responsible for hypersensitivity reactions (HSRs) during hemodialysis, we hypothesize that these complications are due to changes in plasma aminopeptidase P (APP) activity and genotype. To test this hypothesis, we measured plasma APP activity in 14 patients who suffered HSR (HSR+) while dialyzed with an AN69 membrane and simultaneously treated with an ACEi. APP activity was also studied in a control group (n=39) dialyzed under the same conditions, but who did not suffer any side effect (HSR-). We found significantly decreased plasma APP activity (P=0.013) in HSR+ subjects as well as altered degradation of endogenous des-Arginine(9)-bradykinin, with a significantly lower beta value (P<0.001). The same analytical approach was taken in 171 relatives of HSR+ patients. Variance component analysis suggested that genetic differences may explain 61% of the phenotypic variability of plasma APP activity (P<0.001) and the kinetic parameters that characterized kinin degradation. We also showed that the C-2399A single-nucleotide polymorphism at the XPNPEP2 locus was a significant predictor of APP activity in the 39 HSR- controls (P=0.029). Furthermore, a recessive genetic model for the A allele disclosed a significant difference in mean APP activity by genotype (P<0.001). Finally, our study defined the nonspecific inhibition of recombinant APP by some ACEis. In conclusion, this paper highlights the complexity of HSR in hemodialysis, suggesting, as with angioedema, that these rare, but life-threatening adverse events are governed by several metabolic and genetic factors. |
| 2005 | Expression of metallopeptidases and kinin receptors in swine oropharyngeal tissues: effects of angiotensin I-converting enzyme inhibition and inflammation. | J Pharmacol Exp Ther | Angiotensin I-converting enzyme inhibitors (ACEi) cause both chronic and acute side effects, including rare but potentially life-threatening angioedema (AE). The main hypothesis to be tested in this study was that metallopeptidases and kinin receptors are present in oropharyngeal tissues and that their expression is modulated by ACEi and inflammation. Novel real-time polymerase chain reaction analysis was developed and allowed the relative quantification of tissue's gene expression for neprilysin, membrane-bound aminopeptidase P (mAPP), and both B1 and B2 kinin receptor subtypes in tongue, parotid gland, and laryngeal tissue (areas especially involved in the gravest clinical forms of AE) and in kidney in a porcine model (single injection or 7-day ACEi oral treatments applied or lipopolysaccharide injected as a positive inflammatory control). The results provide evidence of the expression and activities of kininases in oropharyngeal tissues in the swine. ACEi treatment modulated the expression of neutral endopeptidase and mAPP mRNA, but the corresponding enzyme activities and that of angiotensin I-converting enzyme (ACE) were generally stable in tissues. The 7-day ACEi treatment up-regulated both kinin receptor mRNAs in the oropharynx and the B1 receptor mRNA in the lingual vascular endothelium (immunohistochemistry). The inhibition of ACE in plasma is responsible for an accumulation of bradykinin and des-arginine9-bradykinin generated during activation of the contact system with glass beads. The expression of critical components of the kallikrein-kinin system in the oropharyngeal tissues supports the role of kinins in ACEi-induced AE. |
| 2002 | Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin. | J Pharmacol Exp Ther | Angioedema (AE) is a rare but potentially life-threatening side effect of therapy with inhibitors of angiotensin-converting enzyme (ACE), the main bradykinin (BK)- inactivating metallopeptidase in humans. The pathogenesis of ACE inhibitor (ACEi)- associated AE (AE+) is presently unknown, although there is increasing evidence of a kinin role. We analyzed the metabolism of endogenous BK (B(2) receptor agonist) and its active metabolite, des-Arg(9)-BK (B(1) receptor agonist), in the presence of an ACEi during in vitro contact activation of plasma from hypertensive patients (n = 39) who presented AE+. Kinetic parameters were compared with those measured in a control group (AE-) of hypertensive patients (n = 39) who never manifested any acute or chronic side effects while treated with an ACEi. The different kinetic parameters were analyzed using a mathematical model (y = k t(alpha) e(-beta t)) previously applied to a normal, healthy population. The slope of BK degradation, but not its formation from high-molecular-weight kininogen, was lower in AE+ patients when compared with the AE- controls. des-Arg(9)-BK accumulation during the kinetic measurements was significantly higher in AE+ plasma. This accumulation of the B(1) agonist in AE+ patients paralleled its half-life of degradation. In conclusion, our results show, for the first time, that an abnormality of endogenous des-Arg(9)-BK degradation exists in the plasma of patients with ACEi-associated AE, suggesting that its pathogenetic mechanism lies in the catabolic site of kinin metabolism. |
| 2002 | Biochemical basis of angioedema associated with recombinant tissue plasminogen activator treatment: an in vitro experimental approach. | Stroke | Angioedema has been reported during recombinant tissue plasminogen activator (rtPA) treatment of acute ischemic stroke, often with concomitant use of angiotensin I-converting enzyme inhibitor treatment. Angioedema has been partly attributed to the nonapeptide bradykinin (BK), although its precise role has been poorly documented until now. The purposes of this report are 2-fold. First, we sought to define and characterize the in vitro kinin-forming capacity of rtPA when incubated with human plasma at a concentration within the therapeutic concentration range of rtPA attained in blood in vivo during fibrinolysis. Second, we sought to define the mechanism by which rtPA liberates BK from purified human single-chain high-molecular-weight kininogen, a key constituent of the contact system of plasma and the precursor of BK.When incubated with human plasma, in the presence of an angiotensin I-converting enzyme inhibitor, rtPA generates BK, which is further metabolized to des-Arg9-BK. The quantity of kinins generated by rtPA is similar to that observed during the activation of the contact system of plasma with a negatively charged surface, suggesting that it is physiologically relevant. The total amount of des-Arg9-BK liberated during the incubation period depends on the aminopeptidase P activity, its main degrading peptidase. Additionally, incubations using purified proteins of the fibrinolytic and the contact system pathways show that the rtPA kinin-forming capacity is mediated by plasmin.We conclude that rtPA used in vitro at a therapeutic concentration has the capacity to generate significant quantities of kinins from human plasma. This kinin-forming activity depends on the activation of the fibrinolytic pathway. These data suggest that angioedema associated with rtPA treatment of ischemic stroke results directly from plasmin-mediated release of BK. |
| 1999 | Serum metabolism of bradykinin and des-Arg9-bradykinin in patients with angiotensin-converting enzyme inhibitor-associated angioedema. | Immunopharmacology | Angioedema (AE) associated with angiotensin-converting enzyme inhibitors (ACEi) is a rare, but potentially life-threatening adverse reaction. Several studies have suggested that bradykinin (BK) is responsible for ACEi-induced AE, but the mechanism remains unclear. We investigated the metabolism of BK and des-Arg9-BK in the serum of 20 patients with a history of ACEi-associated AE and 21 control (C) subjects. Synthetic BK was incubated with the sera for various periods of time and residual BK and generated des-Arg9-BK were quantified by specific and sensitive enzyme immunoassays. No significant difference of half-life (t1/2) of both BK and des-Arg9-BK could be measured between C subjects and patients with AE (AE) in absence of ACEi. However, an analysis according to the prolonged (+) or not (-) t1/2 of des-Arg9-BK allowed a new stratification of C subjects and AE patients in four subgroups. The preincubation of sera with enalaprilat at a concentration inhibiting ACE significantly prevented the rapid degradation of BK and des-Arg9-BK in these four subgroups. In presence of ACEi, a subgroup (50%) of AE patients (AE + ) had a particularly significant rise of the t1/2 of des-Arg9-BK. Once ACE was inhibited, the concentration or the nature of the ACEi had no significant effect on the t1/2 of des-Arg9-BK. However, a test dilution of AE + sera with a control (C) serum showed that an enzyme defect rather than a circulating inhibitor could be responsible for the abnormal metabolism of des-Arg9-BK when ACE is inhibited. In conclusion, half of the patients with ACEi-associated AE present in serum had an enzyme defect involved in the des-Arg9-BK metabolism leading to its accumulation. The B1 agonist could be responsible, at least in part, for the local inflammatory reaction associated with the AE. |
| 1987 | The properties of human C5a anaphylatoxin. The significance of C5a formation during hemodialysis. | Contrib Nephrol | Human C5a anaphylatoxin is a potent bioactive molecule that possesses both spasmogenic and leukocyte-related properties. As such, it normally serves as a local mediator of the acute inflammatory response. Additionally, C5a, through its actions of mononuclear phagocytes, may act to bridge the gap in the acute-chronic inflammatory continuum. While these properties are critical to normal host defense mechanisms, it is now apparent that this anaphylatoxin and/or its des-Arg74 derivative, may exert significant systemic effects that are manifest as cardiopulmonary abnormalities and intravascular activation of granulocytes. Knowledge of these properties is critically important for understanding the clinical sequelae exhibited by patients undergoing extracorporeal circulation since we now know that both hemodialysis and cardiopulmonary bypass [28-30] procedures promote intravascular complement activation and C5a formation. Viewed in this context, it seems reasonable to postulate that many of the immediate and delayed responses to extracorporeal circulation might be mediated by C5a formed in the extracorporeal circuit (table IV). For example, it is now recognized that a few particularly susceptible patients display adverse reactions during the initial phases of hemodialysis. The symptoms of this so-called 'first-use syndrome' may range from severe urticaria and angioedema to life-threatening bronchospasm, hypotension, and cardiopulmonary collapse. Some investigators have presented data which suggest that complement-derived products may be causative of these symptoms in some patients [31]. While this hypothesis remains to be confirmed, present evidence clearly demonstrates that C5a alone may produce many of the observed phenomena. In addition to the acute effects produced by C5a, both our own basic studies and the clinical investigations presented by others at this conference suggest that the long-term effects of repeated C5a exposure in the dialyzed patient may be considerable. Thus, there has been a great deal of interest in the role of complement-derived mediators as initiators of leukocyte degranulation and toxic oxygen radical production and an exploration of the significance of these events in the eventual development of chronic pulmonary fibrosis in the dialyzed patient. Similarly, the effects of repeated exposure to IL-1 that has been postulated to occur as a result of C5a triggering of monocytes during dialysis is currently an active area of investigation.(ABSTRACT TRUNCATED AT 400 WORDS) |