B2 Receptor Antagonist Research Articles

Interplay between on-demand treatment trials for hereditary angioedema and treatment guidelines.

Over the past two decades, guidelines for the on-demand treatment of hereditary angioedema (HAE) attacks have undergone significant evolution. Early treatment guidelines, such as the Canadian 2003 International Consensus Algorithm, often gated on-demand treatment by attack location and/or severity. Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor [C1INH], icatibant, ecallantide [US only], recombinant C1INH), which were approved in the US and EU between 2008-2014, were designed accordingly. Subsequent post hoc analyses of clinical trial data alongside real-world evidence led to a paradigm shift. In 2013, the US HAE Association guidelines recommended that all attacks, irrespective of location or severity, be considered for treatment as early as possible after onset to minimize morbidity and mortality. This approach remains the cornerstone of current treatment guidelines and has shaped the design of recent clinical trials, such as those for the investigational agents, oral plasma kallikrein inhibitor sebetralstat and oral bradykinin B2 receptor antagonist deucrictibant. This narrative review discusses the evolution of on-demand treatment guidelines, the clinical trial and real-world data that prompted significant revisions, and the subsequent changes to trial designs introduced to facilitate guideline compliance.

Activation of Bradykinin B2 Receptors in Astrocytes Stimulates the Release of Leukemia Inhibitory Factor for Autocrine and Paracrine Signaling.

Communications between different cell types within a tissue are often critical for the proper functioning of an organ. In the central nervous system, interactions among neurons and glial cells are known to modulate neurotransmission, energy metabolism, extracellular ion homeostasis, and neuroprotection. Here we showed that bradykinin, a proinflammatory neuropeptide, can be detected by astrocytes, resulting in the secretion of cytokines that act on neurons. In astrocytic cell lines and primary astrocytes, bradykinin and several other ligands acting on Gq-coupled receptors stimulated Ca2+ mobilization, which subsequently led to the release of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). The bradykinin B2 receptor antagonist, HOE-140, effectively blocked the ability of bradykinin to mobilize Ca2+ and stimulate mitogen-activated protein kinases (MAPKs) in astrocytes. Interestingly, incubation of neuronal cell lines and primary cortical neurons with conditioned media from bradykinin-treated astrocytes resulted in the activation of STAT3, a key component downstream of LIF and IL-6 receptors. LIF was apparently the major active factor in the conditioned media as the STAT3 response was almost completely neutralized by an anti-LIF antiserum. The presence of kininogen and kallikrein transcripts in neuronal cells but not in astrocytic cells indicates that neurons can produce bradykinin. Correspondingly, conditioned media from neuronal cells stimulated MAPKs in astrocytes in a HOE-140-sensitive manner. These studies demonstrate that paracrine signaling between neurons and astrocytes may involve ligands of Gq-coupled receptors and cytokines such as LIF.

Kinin B1- and B2-Receptor Subtypes Contract Isolated Bovine Ciliary Muscle: Their Role in Ocular Lens Function and Intraocular Pressure Reduction.

Background: Bradykinin is an endogenously produced nonapeptide with many physiological and pathological functions that are mediated by two pharmacologically defined receptor subtypes, B1- and B2-receptors. Current studies sought to characterize the functional bradykinin (BK) receptors present in freshly isolated bovine ciliary muscle (BCM) using an organ-bath tissue contraction system. Methods: Cumulative longitudinal isometric tension responses of BCM strips (4-5 mm) were recorded before and after the addition of test compounds to BCM strips hooked up to an isometric strain gauge transducer system. Results: BK and its analogs (7-11 concentrations) contracted BCM in a biphasic concentration-dependent manner. The first high affinity/potency phase accounted for 40-60% of the maximal contraction by each of BK (potency, EC50 = 0.9 ± 0.3 nM), Lys-BK (EC50 = 0.7 ± 0.1 nM), Met-Lys-BK (EC50 = 1 ± 0.1 nM), Hyp3-BK (EC50 = 1 ± 0.2 nM), RMP-7 (EC50 = 3.5 ± 0.5 nM), and Des-Arg9-BK (EC50 = 10 ± 0.4nM) (mean ± SEM, n = 3-8). The second lower activity phase of contraction potency values for these peptides ranged between 100 nM and 3 µM. In the presence of a selective B1-receptor antagonist (R715; 0.1-10 µM), the concentration-response curves to Des-Arg9-BK (B1-receptor agonist) were still observed, indicating activation of B2-receptors by this kinin. Likewise, when B2-receptors were completely blocked by using a B2-selective antagonist (WIN-64338; 1-10 µM), BK still induced BCM contraction, now by stimulating B1-receptors. Conclusions: This agonist/antagonist profile of BCM receptors indicated the presence of both B1- and B2-receptor subtypes, both being responsible for contracting this smooth muscle. The BCM kinin receptors may be involved in changing the shape of the ocular lens to influence accommodation, and since the ciliary muscle is attached to the trabecular meshwork through which aqueous humor drains, endogenously released kinins may regulate intraocular pressure.

R-954, a bradykinin B1 receptor antagonist, as a potential therapy in a preclinical endometriosis model

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues outside of the uterine cavity. Currently available drugs are efficacious in treating endometriosis-related pain, however it’s not a targeted treatment. The aim of this work is to evaluate the effects of R-954, a bradykinin B1 receptor antagonist, in a murine model of endometriosis. The model was induced in animals through autologous transplantation of part of the uterine horn. After 51 days, it was observed that implants developed into endometriotic lesions. The administration of R-954 or progesterone, for 15 consecutive days, prevented the progression of cyst development, reduced the size and weight of the cysts. Both treatments also reduced cellular infiltrate and production of inflammatory mediators (interleukin-1β, interleukin-6, tumor necrosis factor). However, only R-954 decreased angiogenic factors (VEGF and VEGF receptor). In addition, treatment with the antagonist did not interfere in the females’ estrous cycle, as well as prevented gestational losses (reduction in the number of intermediate resorptions in pregnant females with endometriosis). Data suggested that R-954 has anti-inflammatory and anti-angiogenic effects; does not influence the estrous cycle; and prevents the number of gestational losses suggesting it as a good candidate for endometriosis treatment.

Advent of oral medications for the treatment of hereditary angioedema.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable, debilitating episodes of submucosal and/or subcutaneous tissue swelling, which may be life-threatening depending on anatomic location. The two primary management strategies for HAE are ready access to effective on-demand treatment in all patients and the prevention of attacks (short-term prophylaxis [STP] and long-term prophylaxis [LTP]) in appropriate patients. All approved on-demand and most LTP medications require subcutaneous or intravenous administration. Injection-related challenges include trypanophobia (fear of needles), difficulty with self-administration, injection-site reactions (e.g., pain, erythema, bleeding, bruising), and anxiety-all contributing to poor compliance and administration delays. Oral HAE treatments may improve outcomes by reducing treatment barriers. To review oral therapies, approved or in development, for on-demand treatment and/or prevention of HAE attacks. To provide a comprehensive review, data was obtained from publicly available resources through a targeted PubMed literature review and supplemented by information provided on company websites (search cutoff of May 31, 2024). Berotralstat, an oral plasma kallikrein (PKa) inhibitor, is approved for LTP. Sebetralstat, another PKa inhibitor, is the investigational first oral on-demand HAE treatment to complete a phase 3 trial. Deucrictibant, an oral bradykinin B2 receptor antagonist, has completed phase 2 trials for on-demand therapy and LTP. Several other oral PKa inhibitors (ATN249, VE-4666, and VE-4062) are in early development for LTP. Substantial advances have been made in the development of oral treatments for HAE. These treatments have the potential to improve and optimize clinical outcomes, satisfaction, and quality of life among patients with HAE.

Kinin B1 receptor deficiency promotes enhanced adipose tissue thermogenic response to β3-adrenergic stimulation.

Kinin B1 receptor (B1R) has a key role in adipocytes to protect against obesity and glycemic metabolism, thus becoming a potential target for regulation of energy metabolism and adipose tissue thermogenesis. Kinin B1 knockout mice (B1KO) were subjected to acute induction with CL 316,243 and chronic cold exposure. Metabolic and histological analyses, gene and protein expression and RNA-seq were performed on interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) of mice. B1KO mice, under acute effect of CL 316,243, exhibited increased energy expenditure and upregulated thermogenic genes in iWAT. They were also protected from chronic cold, showing enhanced non-shivering thermogenesis with increased iBAT mass (~ 90%) and recruitment of beige adipocytes in iWAT (~ 50%). Positive modulation of thermogenic and electron transport chain genes, reaching a 14.5-fold increase for Ucp1 in iWAT. RNA-seq revealed activation of the insulin signaling pathways for iBAT and oxidative phosphorylation, tricarboxylic acid cycle, and browning pathways for iWAT. B1R deficiency induced metabolic and gene expression alterations in adipose tissue, activating thermogenic pathways and increasing energy metabolism. B1R antagonists emerge as promising therapeutic targets for regulating obesity and associated metabolic disorders, such as inflammation and diabetes.

ADPORT-601: First-in-human study of adenosine 2A (A2A) and adenosine 2B (A2B) receptor antagonists in patients with select advanced solid tumors.

e14681 Background: Hypoxic tumors possess high levels of extracellular adenosine within the tumor microenvironment (TME) which suppresses both innate and adaptive immune responses by binding the adenosine receptors A2AR and A2BR. TT-10 (PORT-6) and TT-4 (PORT-7) are potent and selective antagonists of A2AR and A2BR, respectively. Both agents have shown monotherapy activity in both non-immunogenic (4T-1) and immunogenic (CT-26) tumor mouse models. Optimizing inhibition of A2AR and A2BR separately and in combination provides an opportunity to dissect the role of each signaling pathway within the TME. Methods: ADPORT-601 is a multi-center, open-label Phase 1 study, evaluating the safety, efficacy, PK and pharmacodynamics of PORT-6 in participants with mCRPC, RCC, or other selected solid tumors which are refractory to standard therapy. A subsequent arm will similarly test PORT-7 in participants with selected solid tumors. The Phase 1a cohorts utilize a standard 3+3 design. Phase 1b will be initiated once recommended doses have been established and will consist of monotherapy expansion cohorts for each drug, as well as both drugs combined at the optimal doses, and with other immunotherapy agents. A novel IHC-based assay will be implemented to select for patients with high A2AR expression. Metabolomic and gene expression profiling were performed on previously acquired bone biopsy and blood samples, respectively, to characterize the role of adenosine in CRPC. Results: 10 patients with mCRPC (n=6), RCC (n=3) or NSCLC (n=1) have been enrolled at escalating doses. Treatment-related AEs have been G1-2, with fatigue (29%), nausea (29%) and vomiting (14%) being the most reported. No related SAEs or dose limiting toxicities (DLTs) have been observed. Higher adenosine precursor metabolite (e.g., AMP, ADP, ATP, ADPR, inosine) levels were observed in image-guide bone metastatic lesions relative to non-tumor bearing bone controls (P<0.05; n=10/group). A2AR and A2BR mRNA levels were enriched (1.3 and 1.4 log2 fold change, p<0.05, respectively) in the plasma of mCRPC patients compared to those with localized disease. Updated safety, efficacy, PK and adenosine expression data will be reported at the meeting. Conclusions: PORT-6 is well tolerated to date. The TME within mCRPC bone metastases provides a unique target for A2AR and A2BR antagonism. Longitudinal blood and tissue samples, including bone biopsies, are being collected to enable biomarker analyses, allowing for elucidation of the relative contribution of A2AR and A2BR in suppressing anti-tumor immunity. Multi-omic translational analyses of tissue are planned to determine whether potent adenosine receptor antagonism will have an anti-tumor effect and convert the TME from immunosuppressive to proinflammatory. Clinical trial information: NCT04969315 .

Interaction of Angiotensin-(1−7) with kinins in the kidney circulation: Role of B1 receptors

Changes in renal hemodynamics impact renal function during physiological and pathological conditions. In this context, renal vascular resistance (RVR) is regulated by components of the Renin-Angiotensin System (RAS) and the Kallikrein-Kinin System (KKS). However, the interaction between these vasoactive peptides on RVR is still poorly understood. Here, we studied the crosstalk between angiotensin-(1−7) and kinins on RVR. The right kidneys of Wistar rats were isolated and perfused in a closed-circuit system. The perfusion pressure and renal perfusate flow were continuously monitored. Ang-(1−7) (1.0–25.0 nM) caused a sustained, dose-dependent reduction of relative RVR (rRVR). This phenomenon was sensitive to 10 nM A-779, a specific Mas receptor (MasR) antagonist. Bradykinin (BK) promoted a sustained and transient reduction in rRVR at 1.25 nM and 125 nM, respectively. The transient effect was abolished by 4 μM des-Arg9-Leu8-bradykinin (DALBK), a specific kinin B1 receptor (B1R) antagonist. Accordingly, des-Arg9-bradykinin (DABK) 1 μM (a B1R agonist) increased rRVR. Interestingly, pre-perfusion of Ang-(1−7) changed the sustained reduction of rRVR triggered by 1.25 nM BK into a transient effect. On the other hand, pre-perfusion of Ang-(1−7) primed and potentiated the DABK response, this mechanism being sensitive to A-779 and DALBK. Binding studies performed with CHO cells stably transfected with MasR, B1R, and kinin B2 receptor (B2R) showed no direct interaction between Ang-(1−7) with B1R or B2R. In conclusion, our findings suggest that Ang-(1−7) differentially modulates kinin's effect on RVR in isolated rat kidneys. These results help to expand the current knowledge regarding the crosstalk between the RAS and KKS complex network in RVR.

Microglia Mediate Hypertension and Autonomic Dysfunction through Kinin B1 Receptor Activation

Reactive oxygen species and proinflammatory cytokines in the central nervous system can induce or exacerbate hypertension (HTN) and result in autonomic dysfunction. During HTN, activated microglia modulates autonomic neural activity in the paraventricular nucleus of the hypothalamus (PVN) by regulating neuroinflammation and blood pressure. We previously reported that enhanced kinin B1 receptor (B1R) expression in the brain is associated with increased neuroinflammation and autonomic dysfunction leading to the development of HTN. However, the functional role of B1R within microglia and signaling mechanisms during HTN have yet to be investigated. In this study, we tested the hypothesis that B1R blockade will reduce oxidative stress and mitochondrial dysfunction in microglia, resulting in an attenuation of hypertension and improved autonomic function. Male and female C57BL/6NJ wild-type (WT) and B1R global gene deficient mice (B1RKO) were administered angiotensin II (Ang II) (600 ng/kg/min; SC, 2 weeks) or saline (vehicle) via osmotic minipumps. Ang II infusion significantly increased mean arterial pressure (radiotelemetry) in WT mice (145 ±13 mmHg vs. 103 ±6, n=6, p<0.01), which was attenuated in B1RKO mice. Ang II induced HTN resulted in dysautonomia as indicated by significantly increased plasma norepinephrine levels (p<0.05, n=6) and decreased spontaneous baroreceptor reflex sensitivity (p<0.05, n=6). This further suggests that B1R contributes to impaired autonomic and baroreflex functions in HTN. In addition, CX3CR1 expression in the PVN revealed that microglia-neuron interactions may be increased during HTN. TMEM119 immunofluorescence revealed significant morphological changes in microglia in the PVN of Ang II infused mice compared to saline controls (p<0.05, n=3). To further define the role of microglia, we cultured primary microglia from neonatal mice and found that Ang II induces mitochondrial oxidative stress (MitoSOX) and decreases mitochondrial membrane potential (TMRE) (p<0.01, n=4), however use of B1R specific antagonist SSR240612 was able to reduce these responses. This data coincides with previous data published in primary hypothalamic neurons. To then explore the role of neuron-microglia interactions following Ang II stimulation, we established a direct co-culturing method and through immunocytochemistry, confirmed that levels of oxidative stress and inflammation were significantly increased in our co-culture model compared to when cultured individually (p<0.05, n=3). Pretreatment with B1R antagonist was able to attenuate these effects. This data indicates that autonomic and mitochondrial dysfunction may be regulated, in part, through the kinin B1 receptor in microglia and that neuron-microglia interactions can enhance these effects. This allows us to believe that B1R blockade may serve as a potential therapeutic target for HTN induced mitochondrial and autonomic dysfunction. This study was supported by the NHLBI/NIH 5R01HL153115 (S. Sriramula). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Bradykinin attenuates endothelial-mesenchymal transition following cardiac ischemia-reperfusion injury

AimsEndothelial-mesenchymal transition (EndMT) is a crucial pathological process contributing to cardiac fibrosis. Bradykinin has been found to protect the heart against fibrosis. Whether bradykinin regulates EndMT has not been determined. Materials and methodsRats were subjected to ligation of the left anterior descending coronary artery for 1 h and subsequent reperfusion to induce cardiac ischemia-reperfusion (IR) injury. Bradykinin (0.5 μg/h) was infused by an osmotic pump implanted subcutaneously at the onset of reperfusion. Fourteen days later, the functional, histological, and molecular analyses were performed to investigate the changes in cardiac fibrosis and EndMT. Human coronary artery endothelial cells were utilized to determine the molecular mechanisms in vitro. ResultsBradykinin treatment improved cardiac function and decreased fibrosis following cardiac IR injury, accompanied by ameliorated EndMT and increased nitric oxide (NO) production. In vitro experiments found that bradykinin mitigated transforming growth factor β1 (TGFβ1)-induced EndMT. Significantly, the bradykinin B2 receptor antagonist or endothelial nitric oxide synthase inhibitor abolished the effects of bradykinin on EndMT inhibition, indicating that the bradykinin B2 receptor and NO might mediate the effects of bradykinin on EndMT inhibition. ConclusionBradykinin plays an essential role in the process of cardiac fibrosis. Bradykinin preserves the cellular signature of endothelial cells, preventing them from EndMT following cardiac IR injury, possibly mediated by bradykinin B2 receptor activation and NO production.

Deucrictibant for angioedema due to acquired C1-inhibitor deficiency: A randomized-controlled trial

BackgroundAngioedema due to acquired C1-inhibitor deficiency is a very rare but serious disease, with an estimated prevalence of 1 per 500,000 persons. There are no approved therapies to treat or prevent angioedema swellings in patients with this condition. Deucrictibant is a specific, orally bioavailable, competitive antagonist of the bradykinin B2 receptor currently under investigation for hereditary angioedema. ObjectiveTo assess the efficacy and safety of deucrictibant as acute and prophylactic treatment for angioedema due to acquired C1-inhibitor deficiency. MethodsA two-part, randomized, double-blind, placebo-controlled crossover study was conducted. In Part 1, four consecutive angioedema attacks were treated with three doses of deucrictibant (10 mg, 20 mg, and 30 mg) or placebo. In Part 2, deucricibant 20 mg or placebo was administered bidaily for two treatment periods of eight weeks. ResultsThree patients were enrolled of which one completed both study parts and two completed only Part 2. In Part 1, a reduction in attack severity was observed in the three attacks treated with deucrictibant as opposed to an increase in severity of the attack treated with placebo. In Part 2, the individual mean monthly attack rates were 2.0, 0.6 and 1.0 during the placebo period and 0.0 across all patients during treatment with deucrictibant. There were no severe adverse events, and one self-limiting treatment-emergent adverse event (abdominal pain). ConclusionsDeucrictibant has the potential to effectively and safely treat and prevent angioedema attacks due to acquired C1-inhibitor deficiency.

Prevention of Inflammation, Neovascularization, and Retinal Dysfunction by Kinin B1 Receptor Antagonism in a Mouse Model of Age-Related Macular Degeneration.

The kallikrein-kinin system (KKS) contributes to vascular inflammation and neovascularization in age-related macular degeneration (AMD), particularly via the kinin B1 receptor (B1R). The aim of the present study was to determine the protective effects of the topical administration of the B1R antagonist (R-954) on inflammation, neovascularization, and retinal dysfunction in a murine model of neovascular AMD. Choroidal neovascularization (CNV) was induced in C57BL6 mice using an argon laser. A treatment with ocular drops of R-954 (100 μg/15 μL, twice daily in both eyes), or vehicle, was started immediately on day 0, for 7, 14, or 21 days. CNV, invasive microglia, and B1R immunoreactive glial cells, as well as electroretinography alterations, were observed within the retina and choroid of the CNV group but not in the control group. The staining of B1R was abolished by R-954 treatment as well as the proliferation of microglia. R-954 treatment prevented the CNV development (volume: 20 ± 2 vs. 152 ± 5 × 104 µm3 in R-954 vs. saline treatment). R-954 also significantly decreased photoreceptor and bipolar cell dysfunction (a-wave amplitude: -47 ± 20 vs. -34 ± 14 µV and b-wave amplitude: 101 ± 27 vs. 64 ± 17 µV in R-954 vs. saline treatment, day 7) as well as angiogenesis tufts in the retina. These results suggest that self-administration of R-954 by eye-drop treatment could be a promising therapy in AMD to preserve retinal health and vision.

Abstract 081: Transactivation Of Brain ADAM17 In Angiotensin II-Induced Hypertension Can Be Prevented By Kinin B1 Receptor Blockade

A disintegrin and metalloprotease 17 (ADAM17) has been implicated in mediating inflammation in several cardiovascular diseases. Targeting brain ADAM17 using siRNA revealed a reduction in blood pressure, confirming its role in hypertension. Previously, we reported that kinin B1 receptor (B1R) activation increases ADAM17 activity in primary hypothalamic neurons, while pretreatment with a B1R antagonist mitigated this effect. However, whether there is a direct interaction between ADAM17 and B1R in hypertension is unknown. In this study, we tested the hypothesis that B1R blockade will prevent the transactivation of ADAM17, thereby, preventing the development of angiotensin II-induced hypertension. Male and female C57BL/6NJ wild-type (WT) and B1R knockout mice (B1RKO) were administered Ang II (600 ng/kg/min; SC, 2 weeks) or saline via osmotic minipumps. Ang II infusion significantly increased mean arterial pressure (radiotelemetry) in WT mice (145 ±13 mmHg vs. 103 ±6, n=6, p<0.01), which was attenuated in B1RKO mice. Both male and female B1RKO mice showed similar attenuation of Ang II-induced hypertension. Ang II-infusion led to a significant upregulation of ADAM17 in the PVN of WT mice and was blunted in B1RKO mice (p<0.05, n=3). Proximity ligation assay (PLA) was used to examine close proximity (<40nm) interactions between two receptors. ADAM17-B1R interactions in the PVN of hypertensive mice were significantly increased (p<0.05, n=3). To further understand this correlation, primary neurons and microglia from the hypothalamus of neonatal WT mice were cultured and treated with Ang II (300 nM) for 24 hours. Ang II increased B1R and ADAM17 protein expression in both cell types and was prevented by a B1R antagonist SSR240612 (10 uM) (p<0.05, n=5). To supplement these findings, PLA was used on primary neurons and microglia and revealed an increase in ADAM17-B1R interactions following Ang II. Furthermore, B1R antagonism attenuated this ADAM17-B1R interaction in both neurons and microglia (p<0.05, n=5). Our data provides novel evidence that B1R blockade can attenuate Ang II-induced hypertension in the brain, possibly through a reduction in B1R-ADAM17 interactions, suggesting that B1R blockade may serve as a potential antihypertensive therapeutic agent.

Kinin B1 Receptor Antagonism Prevents Acute Kidney Injury to Chronic Kidney Disease Transition in Renal Ischemia-Reperfusion by Increasing the M2 Macrophages Population in C57BL6J Mice.

Chronic kidney disease (CKD) is a multifactorial, world public health problem that often develops as a consequence of acute kidney injury (AKI) and inflammation. Strategies are constantly sought to avoid and mitigate the irreversibility of this disease. One of these strategies is to decrease the inflammation features of AKI and, consequently, the transition to CKD. C57Bl6J mice were anesthetized, and surgery was performed to induce unilateral ischemia/reperfusion as a model of AKI to CKD transition. For acute studies, the animals received the Kinin B1 receptor (B1R) antagonist before the surgery, and for the chronic model, the animals received one additional dose after the surgery. In addition, B1R genetically deficient mice were also challenged with ischemia/reperfusion. The absence and antagonism of B1R improved the kidney function following AKI and prevented CKD transition, as evidenced by the preserved renal function and prevention of fibrosis. The protective effect of B1R antagonism or deficiency was associated with increased levels of macrophage type 2 markers in the kidney. The B1R is pivotal to the evolution of AKI to CKD, and its antagonism shows potential as a therapeutic tool in the prevention of CKD following AKI.

Kinin B2 Receptor Mediates Cisplatin-Induced Painful Peripheral Neuropathy by Intracellular Kinase Pathways and TRPA1 Channel Sensitisation.

Chemotherapy-induced peripheral neuropathy is a severe clinical problem frequently associated with cisplatin use. Although its pathophysiology is poorly understood, it is known that kinin receptors and the transient receptor potential ankyrin 1 (TRPA1) channel play a significant role in the peripheral neuropathy induced by cisplatin in rodents. However, the role of signalling pathways downstream from B2 kinin receptors activation and sensitisation of the TRPA1 channel remains unknown in this model. The cisplatin-induced neuropathy model caused mechanical and cold allodynia in male Swiss mice. Antagonists for kinin B2 and B1 receptors and the TRPA1 channel attenuated the painful parameters. Local sub-nociceptive doses of kinin B2 receptor (bradykinin) and TRPA1 channel (allyl isothiocyanate; AITC) agonists enhanced the painful parameters in cisplatin-treated mice, which their respective antagonists attenuated. Furthermore, we demonstrated the interaction between the kinin B2 receptor and the TRPA1 channel in cisplatin-induced peripheral neuropathy since phospholipase C (PLC) and protein kinase C epsilon (PKCε) inhibitors attenuated the increase in mechanical and cold allodynia evoked by bradykinin and AITC in cisplatin-treated mice. Therefore, regulating the activation of signalling pathways downstream from the kinin B2 receptors activation and TRPA1 channel sensitisation can mitigate the painful peripheral neuropathy decurrent of the oncology treatment with cisplatin.

Kinins' Contribution to Postoperative Pain in an Experimental Animal Model and Its Implications.

Postoperative pain causes discomfort and disability, besides high medical costs. The search for better treatments for this pain is essential to improve recovery and reduce morbidity and risk of chronic postoperative pain. Kinins and their receptors contribute to different painful conditions and are among the main painful inflammatory mediators. We investigated the kinin's role in a postoperative pain model in mice and reviewed data associating kinins with this painful condition. The postoperative pain model was induced by an incision in the mice's paw's skin and fascia with the underlying muscle's elevation. Kinin levels were evaluated by enzyme immunoassays in sham or operated animals. Kinin's role in surgical procedure-associated mechanical allodynia was investigated using systemic or local administration of antagonists of the kinin B1 receptor (DALBk or SSR240612) or B2 receptor (Icatibant or FR173657) and a kallikrein inhibitor (aprotinin). Kinin levels increased in mice's serum and plantar tissue after the surgical procedure. All kinin B1 or B2 receptor antagonists and aprotinin reduced incision-induced mechanical allodynia. Although controversial, kinins contribute mainly to the initial phase of postoperative pain. The kallikrein-kinin system can be targeted to relieve this pain, but more investigations are necessary, especially associations with other pharmacologic targets.

Bradykinin receptors in GtoPdb v.2023.1

Bradykinin (or kinin) receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Bradykinin (kinin) Receptors [92]) are activated by the endogenous peptides bradykinin (BK), [des-Arg9]bradykinin, Lys-BK (kallidin), [des-Arg10]kallidin, [Phospho-Ser6]-Bradykinin, T-kinin (Ile-Ser-BK), [Hyp3]bradykinin and Lys-[Hyp3]-bradykinin. Variation in pharmacology and activity of B1 and B2 receptor antagonists at species orthologs has been documented. icatibant (Hoe140, Firazir) is approved in North America and Europe for the treatment of acute attacks of hereditary angioedema. Inhibition of bradykinin with icatibant in COVID-19 infection is under clinical evaluation, with trial NCT05407597 expected to complete in mid 2023.

Kinin B1 and B2 receptors mediate cancer pain associated with both the tumor and oncology therapy using aromatase inhibitors

Pain caused by the tumor or aromatase inhibitors (AIs) is a disabling symptom in breast cancer survivors. Their mechanisms are unclear, but pro-algesic and inflammatory mediators seem to be involved. Kinins are endogenous algogenic mediators associated with various painful conditions via B1 and B2 receptor activation, including chemotherapy-induced pain and breast cancer proliferation. We investigate the involvement of the kinin B1 and B2 receptors in metastatic breast tumor (4T1 breast cancer cells)-caused pain and in aromatase inhibitors (anastrozole or letrozole) therapy-associated pain. A protocol associating the tumor and antineoplastic therapy was also performed. Kinin receptors’ role was investigated via pharmacological antagonism, receptors protein expression, and kinin levels. Mechanical and cold allodynia and muscle strength were evaluated. AIs and breast tumor increased kinin receptors expression, and tumor also increased kinin levels. AIs caused mechanical allodynia and reduced the muscle strength of mice. Kinin B1 (DALBk) and B2 (Icatibant) receptor antagonists attenuated these effects and reduced breast tumor-induced mechanical and cold allodynia. AIs or paclitaxel enhanced breast tumor-induced mechanical hypersensitivity, while DALBk and Icatibant prevented this increase. Antagonists did not interfere with paclitaxel's cytotoxic action in vitro. Thus, kinin B1 or B2 receptors can be a potential target for treating the pain caused by metastatic breast tumor and their antineoplastic therapy.

Kinin B1 and B2 Receptors Contribute to Cisplatin-Induced Painful Peripheral Neuropathy in Male Mice

Cisplatin is the preferential chemotherapeutic drug for highly prevalent solid tumours. However, its clinical efficacy is frequently limited due to neurotoxic effects such as peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a dose-dependent adverse condition that negatively impacts quality of life, and it may determine dosage limitations or even cancer treatment cessation. Thus, it is urgently necessary to identify pathophysiological mechanisms underlying these painful symptoms. As kinins and their B1 and B2 receptors contribute to the development of chronic painful conditions, including those induced by chemotherapy, the contribution of these receptors to cisplatin-induced peripheral neuropathy was evaluated via pharmacological antagonism and genetic manipulation in male Swiss mice. Cisplatin causes painful symptoms and impaired working and spatial memory. Kinin B1 (DALBK) and B2 (Icatibant) receptor antagonists attenuated some painful parameters. Local administration of kinin B1 and B2 receptor agonists (in sub-nociceptive doses) intensified the cisplatin-induced mechanical nociception attenuated by DALBK and Icatibant, respectively. In addition, antisense oligonucleotides to kinin B1 and B2 receptors reduced cisplatin-induced mechanical allodynia. Thus, kinin B1 and B2 receptors appear to be potential targets for the treatment of cisplatin-induced painful symptoms and may improve patients' adherence to treatment and their quality of life.

An Update of Carbazole Treatment Strategies for COVID-19 Infection

The Coronavirus disease 2019 (COVID-19) outbreak was declared by the World Health Organization (WHO) in March 2020 to be a pandemic and many drugs used at the beginning proved useless in fighting the infection. Lately, there has been approval of some new generation drugs for the clinical treatment of severe or critical COVID-19 infections. Nevertheless, more drugs are required to reduce the pandemic’s impact. Several treatment approaches for COVID-19 were employed since the beginning of the pandemic, such as immunomodulatory, antiviral, anti-inflammatory, antimicrobial agents, and again corticosteroids, angiotensin II receptor blockers, and bradykinin B2 receptor antagonists, but many of them were proven ineffective in targeting the virus. So, the identification of drugs to be used effectively for treatment of COVID-19 is strongly needed. It is aimed in this review to collect the information so far known about the COVID-19 studies and treatments. Moreover, the observations reported in this review about carbazoles as a treatment can signify a potentially useful clinical application; various drugs that can be introduced into the therapeutic equipment to fight COVID-19 or their molecules can be used as the basis for designing new antivirals.