Multiple pathways have been proposed to generate bradykinin (BK)-related peptides from blood. We applied various forms of activation to fresh blood obtained from 10 healthy subjects or 10 patients with hereditary angioedema (HAE-1 or -2 only) to investigate kinin formation. An enzyme immunoassay for BK was applied to extracts of citrated blood incubated at 37°C under gentle agitation for 0-2 h in the presence of activators and/or inhibitory agents. Biologically active kinins in extracts were corroborated by c-Fos accumulation in HEK 293a cells that express either recombinant human B2 or B1 receptors (B2R, B1R). Biological evidence of HAE diagnostic and blood cell activation was also obtained. The angiotensin converting enzyme inhibitor enalaprilat, without any effect per se, increased immunoreactive BK (iBK) concentration under active stimulation of blood. Tissue kallikrein (KLK-1) and Kontact-APTT, a particulate material that activates the contact system, rapidly (5 min) and intensely (>100 ng/mL) induced similar iBK generation in the blood of control or HAE subjects. Tissue plasminogen activator (tPA) slowly (≥1 h) induced iBK generation in control blood, but more rapidly and intensely so in that of HAE patients. Effects of biotechnological inhibitors indicate that tPA recruits factor XIIa (FXIIa) and plasma kallikrein to generate iBK. KLK-1, independent of the contact system, is the only stimulus leading to an inconsistent B1R stimulation. Stimulating neutrophils or platelets did not generate iBK. In the HAE patients observed during remission, iBK formation capability coupled to B2R stimulation appears largely intact. However, a selective hypersensitivity to tPA in the blood of HAE patients suggests a role of plasmin-activated FXIIa in the development of attacks. Proposed pathways of kinin formation dependent on blood cell activation were not corroborated.

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.

Angioedema (AE) is a sudden localized, subcutaneous or submucosal, swelling due to one of two major possible mechanisms: mast cell induced (MC-AE) or bradykinin mediated (BkAE). MC-AE may be allergic or non-allergic (mast cell degranulation non-specific to the antigen). BkAE may be hereditary, with (C1-INH-HAE) or without C1 inhibitor (C1-INH) deficiency. BkAE may also be acquired with C1-INH deficiency (C1-INH-AAE), complicating some blood diseases, dysimmunities or be iatrogenic, mainly due to angiotensin converting enzyme inhibitors (ACEi). This article is protected by copyright. All rights reserved.

Angiotensin-converting enzyme inhibitors (ACEI) are widely used to treat hypertension and congestive heart failure. A rare side effect of ACEI therapy is angioedema, which in very rare cases may present as gastrointestinal angioedema (GA). A 45-year-old female presented with suddenly occurring diffuse abdominal pain. Imaging studies revealed small bowel wall edema. The patient had been on ACEI therapy for the last 6 months. The therapy was withdrawn, and the patient recovered quickly. There is no specific diagnostic test to confirm ACEI-induced GA, but symptoms usually regress completely after therapy discontinuation. An early diagnosis of ACEI-induced GA is important to avoid invasive diagnostic investigations and even laparotomy.

It has been demonstrated that certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT1 receptor antagonists can possess anticonvulsant activity. The purpose of the current study was to examine the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, against pentylenetetrazole (PTZ)-induced clonic seizures in mice and on the protective activity of conventional antiepileptic drugs (AEDs) in this seizure model. Effects of aliskiren on the PTZ threshold and the protective efficacy of AEDs such as clonazepam (CLO), phenobarbital (PB), valproate (VPA) and ethosuximide (ETX) in the PTZ test, were evaluated in adult Swiss mice. Aliskiren and AEDs were administered intraperitoneally (i.p.) while PTZ (50 - 100 mg/kg) was injected subcutaneously (s.c.). The rota-rod and passive avoidance test were used to assess the adverse effects of the combined treatment with aliskiren and AEDs. Aliskiren, at the dose of 75 mg/kg, significantly raised the PTZ threshold (P < 0.05). Furthermore, aliskiren, at the subthreshold dose of 50 mg/kg, significantly enhanced the protective action of CLO (P < 0.01), PB (P < 0.01) and VPA (P < 0.05) but not ETX (P > 0.05) in the s.c. PTZ test. Motor coordination in the rota-rod test and long-term memory in the passive avoidance task were not impaired by the combined treatment of the drugs. This study suggests that treatment with aliskiren can be useful in hypertensive patients with myoclonic seizures. Certainly, a clinical verification of using aliskiren in such patients would be necessary. This article is protected by copyright. All rights reserved.