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Background SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. Methods This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. Discussion Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. Trial registration Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.

Thirty patients with ACE-inhibitor–induced angioedema were assigned to receive icatibant or standard therapy with intravenous prednisolone plus clemastine. The median time to complete resolution of edema was 8.0 hours with icatibant and 27.1 hours with standard therapy. Angioedema induced by treatment with angiotensin-converting–enzyme (ACE) inhibitors is estimated to occur in up to 0.68% of patients who receive ACE inhibitors, 1 – 5 although the true incidence is difficult to estimate because symptoms can take years to appear. 6 Although the risk of ACE-inhibitor–induced angioedema is low, the increasing use of ACE inhibitors is resulting in a comparatively large number of patients at risk for this condition, 7 which accounts for one third of all cases of angioedema treated in the emergency room. 8 ACE-inhibitor–induced angioedema affects almost exclusively the upper aerodigestive tract but can, in rare cases, affect the gut. Obstruction of . . .

Two randomized trials evaluated the effect of the bradykinin-receptor antagonist icatibant in patients with hereditary angioedema presenting with acute attacks. The primary end point in each trial was the median time to clinically significant relief of symptoms. In one trial, the primary end point was reached significantly faster with icatibant than with tranexamic acid. In the other trial, the primary end point was not reached significantly faster with icatibant than with placebo. Hereditary angioedema is an autosomal dominant disorder caused by a deficiency of C1 esterase inhibitor, which has a regulatory role in the classic complement pathway and in the coagulation, fibrinolytic, and kallikrein–kinin (contact-system) cascades. Reduced activity of C1 esterase inhibitor may result in an elevated plasma level of bradykinin, 1 , 2 the key mediator of symptoms in hereditary angioedema. 3 , 4 Patients with hereditary angioedema present with acute attacks of subcutaneous and submucosal edema that can affect the upper airways, face, extremities, genitals, and gastrointestinal tract. 5 – 7 Pharyngolaryngeal edema, which is potentially life-threatening because of the risk of upper-airway obstruction, can also . . .

Background: In randomized, controlled, double-blind, multicenter phase 3 studies, one icatibant injection was efficacious and generally well tolerated in patients with a single hereditary angioedema (HAE) attack. Here, the efficacy and safety of icatibant for multiple HAE attacks was evaluated across the controlled and open-label extension phases of the For Angioedema Subcutaneous Treatment (FAST)-3 study (NCT00912093). Methods: In the controlled phase, adults with HAE type I or II were randomized (1:1) to receive a single subcutaneous injection of icatibant 30 mg or placebo within 6 h of an attack becoming mild (laryngeal) or moderate (cutaneous/abdominal). Open-label icatibant was administered for severe laryngeal symptoms. In the open-label extension phase, patients could receive up to three icatibant injections per attack. Efficacy and safety were analyzed for the first five icatibant-treated attacks at any location (prospective analysis) and laryngeal attacks (post hoc analysis) across both phases. Efficacy outcomes were based on patient-reported symptom severity (visual analog scale). Results: In groups of patients with one to five icatibant-treated attacks at any location (n = 88), the median times to onset of symptom relief, onset of primary symptom relief and almost complete symptom relief were 1.9-2.1, 1.5-2.0 and 3.5-19.7 h, respectively. The same outcomes for laryngeal attacks (n = 25) were 1.0-2.0, 1.0-2.0 and 1.5-8.1 h, respectively. The most frequently reported adverse events were a worsening or recurrence of HAE attack, headache and nasopharyngitis. Two serious adverse events (arrhythmia and noncardiac chest pain) were considered to be related to icatibant. Conclusions: Icatibant was efficacious and generally well tolerated across multiple HAE attacks, including laryngeal attacks.

Gliomas are the most common malignant brain tumors in adults. Bradykinin (BK) displays an important role in cancer, although the exact role of kinin receptors in the glioma biology remains unclear. This study investigated the role of kinin B 1 and B 2 receptors (B 1 R and B 2 R) on cell proliferation in human glioblastoma cell lineages. The mRNA expression of B 1 R and B 2 R was verified by RT-qPCR, whereas the effects of kinin agonists (des-Arg 9 -BK and BK) were analyzed by cell counting, MTT assay and annexin-V/PI determination. The PI3K/Akt and ERK1/2 signaling activation was assessed by flow cytometry. Our results demonstrated that both human glioblastoma cell lines U-138MG and U-251MG express functional B 1 R and B 2 R. The proliferative effects induced by the incubation of des-Arg 9 -BK and BK are likely related to the activation of PI3K/Akt and ERK 1/2 pathways. Moreover, the pre-incubation of the selective PI3Kγ blocker AS252424 markedly prevented kinin-induced AKT phosphorylation. Noteworthy, the selective B 1 R and B 2 R antagonists SSR240612 and HOE-140 were able to induce cell death of either lineages, with mixed apoptosis/necrosis characteristics. Taken together, the present results show that activation of B 1 R and B 2 R might contribute to glioblastoma progression in vitro. Furthermore, PI3K/Akt and ERK 1/2 signaling may be a target for adjuvant treatment of glioblastoma with a possible impact on tumor proliferation.

Pharmacological research in mice and human genetic analyses suggest that the kallikrein-kinin system (KKS) may regulate anxiety. We examined the role of the KKS in anxiety and stress in both species. In human genetic association analysis, variants in genes for the bradykinin precursor ( KNG1 ) and the bradykinin receptors ( BDKRB1 and BDKRB2 ) were associated with anxiety disorders (p < 0.05). In mice, however, neither acute nor chronic stress affected B1 receptor gene or protein expression, and B1 receptor antagonists had no effect on anxiety tests measuring approach-avoidance conflict. We thus focused on the B2 receptor and found that mice injected with the B2 antagonist WIN 64338 had lowered levels of a physiological anxiety measure, the stress-induced hyperthermia (SIH), vs controls. In the brown adipose tissue, a major thermoregulator, WIN 64338 increased expression of the mitochondrial regulator Pgc1a and the bradykinin precursor gene Kng2 was upregulated after cold stress. Our data suggests that the bradykinin system modulates a variety of stress responses through B2 receptor-mediated effects, but systemic antagonists of the B2 receptor were not anxiolytic in mice. Genetic variants in the bradykinin receptor genes may predispose to anxiety disorders in humans by affecting their function.

We used the data from a successful therapeutic assay that used icatibant in patients with hypoxemic COVID-19 pneumonia (the ICAT·COVID trial) to explore pathophysiological mechanisms. We performed concurrent-type, criterion-related validity analyses to assess the discriminative ability of a panel of nine potential serum markers (interleukin 6, ferritin, lactate dehydrogenase, C reactive protein, fibrin fragment D (D-dimer), complement 1 esterase inhibitor (antigenic and functional), complement 4 factor, and lymphocyte count) to predict the clinical milestones. Consistent with previous research, we evidenced a significant relationship between interleukin 6, lactate dehydrogenase and the lymphocyte count, and the clinical events. Furthermore, exposure to icatibant, a bradykinin B2 receptor antagonist (which improved pneumonia and mortality in the aforementioned randomised trial), attenuated this relationship, although this effect faded over time. The results reinforce the key role that the angiotensin-converting enzyme 2 has on COVID-19 pathophysiology as a point of convergence between the renin–angiotensin and kallikrein–kinin systems. This was shown clinically by the successful blocking of inflammatory pathways by icatibant at the bradykinin effector loop level early during the acute hyperinflammatory stage of the disease.

Kinin B1 (B1R) and B2 receptors (B2R) and the transient receptor potential vanilloid 4 (TRPV4) channel are known to play a critical role in the peripheral neuropathy induced by paclitaxel (PTX) in rodents. However, the downstream pathways activated by kinin receptors as well as the sensitizers of the TRPV4 channel involved in this process remain unknown. Herein, we investigated whether kinins sensitize TRPV4 channels in order to maintain PTX-induced peripheral neuropathy in mice. The mechanical hyperalgesia induced by bradykinin (BK, a B2R agonist) or des-Arg9-BK (DABK, a B1R agonist) was inhibited by the selective TRPV4 antagonist HC-067047. Additionally, BK was able to sensitize TRPV4, thus contributing to mechanical hyperalgesia. This response was dependent on phospholipase C/protein kinase C (PKC) activation. The selective kinin B1R (des-Arg9-[Leu8]-bradykinin) and B2R (HOE 140) antagonists reduced the mechanical hyperalgesia induced by PTX, with efficacies and time response profiles similar to those observed for the TRPV4 antagonist (HC-067047). Additionally, both kinin receptor antagonists inhibited the overt nociception induced by hypotonic solution in PTX-injected animals. The same animals presented lower PKCε levels in skin and dorsal root ganglion samples. The selective PKCε inhibitor (εV1–2) reduced the hypotonicity-induced overt nociception in PTX-treated mice with the same magnitude observed for the kinin receptor antagonists. These findings suggest that B1R or B2R agonists sensitize TRPV4 channels to induce mechanical hyperalgesia in mice. This mechanism of interaction may contribute to PTX-induced peripheral neuropathy through the activation of PKCε. We suggest these targets represent new opportunities for the development of effective analgesics to treat chronic pain.

We recently observed a bradykinin-induced increase in the cytosolic Ca super(2+) concentration in submucosal neurons of rat colon, an increase inhibited by blockers of voltage-dependent Ca super(2+) (Ca sub(v)) channels. As the types of Ca sub(v) channels used by this part of the enteric nervous system are unknown, the expression of various Ca sub(v) subunits has been investigated in whole-mount submucosal preparations by immunohistochemistry. Submucosal neurons, identified by a neuronal marker (microtubule-associated protein 2), are immunoreactive for Ca sub(v)1.2, Ca sub(v)1.3 and Ca sub(v)2.2, expression being confirmed by reverse transcription plus the polymerase chain reaction. These data agree with previous observations that the inhibition of L- and N-type Ca super(2+) currents strongly inhibits the response to bradykinin. However, whole-cell patch-clamp experiments have revealed that bradykinin does not enhance Ca super(2+) inward currents under voltage-clamp conditions. Consequently, bradykinin does not directly interact with Ca sub(v) channels. Instead, the kinin-induced Ca super(2+) influx is caused indirectly by the membrane depolarization evoked by this peptide. As intracellular Ca super(2+) channels on Ca super(2+)-storing organelles can also contribute to Ca super(2+) signaling, their expression has been investigated by imaging experiments and immunohistochemistry. Inositol 1,4,5-trisphosphate (IP sub(3)) receptors (IP sub(3)R) have been functionally demonstrated in submucosal neurons loaded with the Ca super(2+)-sensitive fluorescent dye, fura-2. Histamine, a typical agonist coupled to the phospholipase C pathway, induces an increase in the fura-2 signal ratio, which is suppressed by 2-aminophenylborate, a blocker of IP sub(3) receptors. The expression of IP sub(3)R1 has been confirmed by immunohistochemistry. In contrast, ryanodine, tested over a wide concentration range, evokes no increase in the cytosolic Ca super(2+) concentration nor is there immunohistochemical evidence for the expression of ryanodine receptors in these neurons. Thus, rat submucosal neurons are equipped with various types of high-voltage activated Ca sub(v) channels and with IP sub(3) receptors for intracellular Ca super(2+) signaling.

One of the major challenges in diagnosing various diseases, including neurological and neurodegenerative disorders, as well as carcinogenesis, is detecting unlabeled neurotransmitters. Surface-enhanced Raman spectroscopy (SERS) and surface-enhanced infrared spectroscopy (SEIRA) are promising methods for neurotransmitter biosensing and bioimaging. These methods are unique in that they are non-destructive and can identify molecular fingerprints. In this study, these methods were used to detect the following potent bradykinin (BK) antagonists: [D-Arg0,Hyp3,Thi5,D-Tic7,Oic8]BK, [D-Arg0,Hyp3,Thi5,D-Phe7,Thi8]BK, [D-Arg0,Hyp3,Igl5,D-Phe(5F)7,Oic8]BK, and [D-Arg0,Hyp3,Igl5,D-Igl7,Oic8]BK. The peptides were immobilized on a sensor surface consisting of silver (AgNPs) and gold (AuNPs) nanoparticles. These sensors have uniform particle sizes and small size distributions. Thanks to fast synthesis, easy handling, and reproducible results, these sensors enable routine testing. The vibrational structure of these peptides could not be determined using classical vibrational methods (Raman and IR) or surface-enhanced methods (SERS and SEIRA). This work presents the results of that research. Additionally, the SEIRA spectrum for BK or its analogs has not yet been published. This study presents research using SERS and SEIRA that shows that AgNP and AuNP sensors can detect the peptides under investigation. SERS is a more selective method than SEIRA because it allows for the differentiation of peptides based on the enhancement of certain bands in the SERS spectra. Furthermore, each peptide uniquely interacts with AuNPs, whereas all peptides bind to AgNPs via the C-terminus in different orientations. Consequently, the AuNP sensor is more selective than the AgNP sensor. Some bands were selected as markers for the sensing of specific peptides.