RESUMEN

The factors that contribute to pain after nerve injury remain incompletely understood. Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are common surgical techniques to correct refractive errors. After LASIK or PRK, a subset of patients suffers intense and persistent pain, of unknown origin, described by patients as feeling like shards of glass in their eye. Here, we evaluated a TRPV1 variant, p.V527M, found in a 49-y-old woman who developed corneal pain after LASIK and subsequent PRK enhancement, reporting an Ocular Surface Disease Index score of 100. Using patch-clamp and Ca2+ imaging, we found that the V527M mutation enhances the response to acidic pH. Increasing proton concentration induced a stronger leftward shift in the activation curve of V527M compared to WT, resulting in channel activity of the mutant in acidic pH at more physiological membrane potentials. Finally, comparing the responses to consecutive applications of different agonists, we found in V527M channels a reduced capsaicin-induced desensitization and increased sensitization by the arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). We hypothesize that the increased response in V527M channels to protons and enhanced sensitization by 12-HETE, two inflammatory mediators released in the cornea after tissue damage, may contribute to the pathogenesis of corneal neuralgia after refractive surgery.

Asunto(s)

Bradiquinina , Capsaicina , Mutación , Neuralgia , Canales Catiónicos TRPV , Animales , Humanos , Ratas , Bradiquinina/metabolismo , Bradiquinina/farmacología , Capsaicina/farmacología , Córnea/metabolismo , Córnea/patología , Células HEK293 , Concentración de Iones de Hidrógeno , Neuralgia/genética , Neuralgia/metabolismo , Neuralgia/etiología , Queratectomía Fotorrefractiva/efectos adversos , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/metabolismo

RESUMEN

Sepsis and atherosclerotic cardiovascular disease (ASCVD) are major health challenges involving complex processes like inflammation, renin-angiotensin system (RAS) dysregulation, and thrombosis. Despite distinct clinical symptoms, both conditions share mechanisms mediated by bradykinin. This review explores bradykinin's role in inflammation, RAS modulation, and thrombosis in sepsis and ASCVD. In sepsis, variable kininogen-bradykinin levels may correlate with disease severity and progression, though the effect of bradykinin receptor modulation on inflammation remains uncertain. RAS activation is present in both diseases, with sepsis showing variable or low levels of Ang II, ACE, and ACE2, while ASCVD consistently exhibits elevated levels. Bradykinin may act as a mediator for ACE2 and AT2 receptor effects in RAS regulation. It may influence clotting and fibrinolysis in sepsis-associated coagulopathy, but evidence for an antithrombotic effect in ASCVD is insufficient. Understanding bradykinin's role in these shared pathologies could guide therapeutic and monitoring strategies and inform future research.

Asunto(s)

Aterosclerosis , Coagulación Sanguínea , Bradiquinina , Sistema Renina-Angiotensina , Sepsis , Transducción de Señal , Humanos , Bradiquinina/metabolismo , Sepsis/fisiopatología , Sepsis/metabolismo , Sepsis/sangre , Aterosclerosis/fisiopatología , Aterosclerosis/metabolismo , Aterosclerosis/sangre , Animales , Coagulación Sanguínea/efectos de los fármacos , Receptores de Bradiquinina/metabolismo , Trombosis/fisiopatología , Trombosis/sangre , Trombosis/metabolismo

RESUMEN

A zinc metallopeptidase neurolysin (Nln) processes diverse bioactive peptides to regulate signaling in the mammalian nervous system. To understand how Nln interacts with various peptides with dissimilar sequences, we determined crystal structures of Nln in complex with diverse peptides including dynorphins, angiotensin, neurotensin, and bradykinin. The structures show that Nln binds these peptides in a large dumbbell-shaped interior cavity constricted at the active site, making minimal structural changes to accommodate different peptide sequences. The structures also show that Nln readily binds similar peptides with distinct registers, which can determine whether the peptide serves as a substrate or a competitive inhibitor. We analyzed the activities and binding of Nln toward various forms of dynorphin A peptides, which highlights the promiscuous nature of peptide binding and shows how dynorphin A (1-13) potently inhibits the Nln activity while dynorphin A (1-8) is efficiently cleaved. Our work provides insights into the broad substrate specificity of Nln and may aid in the future design of small molecule modulators for Nln.

Asunto(s)

Dinorfinas , Neurotensina , Humanos , Especificidad por Sustrato , Dinorfinas/química , Dinorfinas/metabolismo , Neurotensina/química , Neurotensina/metabolismo , Metaloendopeptidasas/metabolismo , Metaloendopeptidasas/química , Metaloendopeptidasas/antagonistas & inhibidores , Unión Proteica , Cristalografía por Rayos X , Modelos Moleculares , Dominio Catalítico , Bradiquinina/química , Bradiquinina/metabolismo , Angiotensinas/metabolismo , Angiotensinas/química , Secuencia de Aminoácidos

RESUMEN

OBJECTIVE: We aimed to broaden our understanding of a potential interaction between B1R and TLR4, considering earlier studies suggesting that lipopolysaccharide (LPS) may trigger B1R stimulation. METHODS: We assessed the impact of DBK and LPS on the membrane potential of thoracic aortas from C57BL/6, B1R, or TLR4 knockout mice. Additionally, we examined the staining patterns of these receptors in the thoracic aortas of C57BL/6 and in endothelial cells (HBMEC). RESULTS: DBK does not affect the resting membrane potential of aortic rings in C57BL/6 mice, but it hyperpolarizes preparations in B1KO and TLR4KO mice. The hyperpolarization mechanism in B1KO mice involves B2R, and the TLR4KO response is independent of cytoplasmic calcium influx but relies on potassium channels. Conversely, LPS hyperpolarizes thoracic aorta rings in both C57BL/6 and B1KO mice, with the response unaffected by a B1R antagonist. Interestingly, the absence of B1R alters the LPS response to potassium channels. These activities are independent of nitric oxide synthase (NOS). While exposure to DBK and LPS does not alter B1R and TLR4 mRNA expression, treatment with these agonists increases B1R staining in endothelial cells of thoracic aortic rings and modifies the staining pattern of B1R and TLR4 in endothelial cells. Proximity ligation assay suggests a interaction between the receptors. CONCLUSION: Our findings provide additional support for a putative connection between B1R and TLR4 signaling. Given the involvement of these receptors and their agonists in inflammation, it suggests that drugs and therapies targeting their effects could be promising therapeutic avenues worth exploring.

Asunto(s)

Aorta Torácica , Células Endoteliales , Lipopolisacáridos , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Bradiquinina B1 , Receptor Toll-Like 4 , Animales , Masculino , Ratones , Aorta Torácica/metabolismo , Bradiquinina/farmacología , Bradiquinina/metabolismo , Células Cultivadas , Células Endoteliales/metabolismo , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Potenciales de la Membrana/efectos de los fármacos , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B1/genética , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Femenino

RESUMEN

Irritant contact dermatitis (ICD) is a nonspecific skin inflammation caused by irritants, leading to itch and pain. We tested whether differential responses to histamine-dependent and -independent pruritogens can be evoked in ICD induced by sodium lauryl sulfate (SLS). An ICD mouse model was established with 5% SLS in acetone versus a vehicle topically applied for 24 h to the cheek. Site-directed itch- and pain-like behaviors, occurring spontaneously and in response to mechanical, thermal, and chemical stimuli (histamine, ß-alanine, BAM8-22, and bradykinin) applied to the cheek, were recorded before (day 0) and after irritant removal (days 1, 2, 3, and 4). Skin inflammation was assessed through visual scoring, ultrasound, and measurements of skin thickness. SLS-treated mice exhibited hyperalgesia-like behavior in response to mechanical and heat stimuli on day 1 compared to the controls. SLS mice exhibited more spontaneous wipes (pain) but not scratching bouts (itch) on day 1. Pruritogen injections caused more scratching but not wiping in SLS-treated mice compared to the controls. Only bradykinin increased wiping behavior compared to saline. SLS-treated mice developed noticeable erythema, scaling, and increased skin thickness on days 1 and 2. SLS induced cutaneous inflammation and behavioral signs of spontaneous pain and itching, hyperalgesia to mechanical and heat stimuli and a chemical algogen, and enhanced itch response to pruritogens. These sensory reactions preceded the inflammation peak and lasted up to two days.

Asunto(s)

Dermatitis Irritante , Modelos Animales de Enfermedad , Dolor , Prurito , Dodecil Sulfato de Sodio , Animales , Dodecil Sulfato de Sodio/efectos adversos , Prurito/inducido químicamente , Ratones , Dermatitis Irritante/etiología , Dermatitis Irritante/patología , Dermatitis Irritante/fisiopatología , Dolor/inducido químicamente , Dolor/fisiopatología , Masculino , Hiperalgesia/inducido químicamente , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Histamina , Irritantes/toxicidad , Bradiquinina/farmacología , Conducta Animal/efectos de los fármacos

RESUMEN

Although TRPV1 receptors play an essential role in the adverse effects on the airways following captopril treatment, there is no available evidence of their involvement in treatment regimens involving repeated doses of captopril. Comparing the difference in these two treatment regimens is essential since captopril is a continuous-use medication. Thus, this study explored the role of the transient receptor potential vanilloid 1 (TRPV1) in the effects of captopril on rat airways using two treatment regimens. Airway resistance, bronchoalveolar lavage (BAL), and histological and immunohistochemical analyses were conducted in rats administered with single or repeated doses of captopril. This study showed that the hyperresponsiveness to bradykinin and capsaicin in captopril-treated rats was acute. Treatment with the selective B2 antagonist, HOE140 reduced bradykinin hyperresponsiveness and abolished capsaicin exacerbation in single-dose captopril-treated rats. Likewise, degeneration of TRPV1-positive neurones also reduced hyperresponsiveness to bradykinin. Single-dose captopril treatment increased leukocyte infiltration in the BAL when compared with the vehicle and this increase was reduced by TRPV1-positive neurone degeneration. However, when compared with the vehicle treatment, animals treated with repeated doses of captopril showed an increase in leukocyte influx as early as 1 h after the last captopril treatment, but this effect disappeared after 24 h. Additionally, an increase in TRPV1 expression occurred only in animals who received repeated captopril doses and the degeneration of TRPV1-positive neurones attenuated TRPV1 upregulation. In conclusion, these data strongly indicate that a treatment regimen involving multiple doses of captopril not only enhances sensitisation but also upregulates TRPV1 expression. Consequently, targeting TRPV1 could serve as a promising strategy to reduce the negative impact of captopril on the airways.

Asunto(s)

Bradiquinina , Líquido del Lavado Bronquioalveolar , Capsaicina , Captopril , Canales Catiónicos TRPV , Animales , Captopril/farmacología , Canales Catiónicos TRPV/metabolismo , Ratas , Masculino , Bradiquinina/farmacología , Capsaicina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Ratas Sprague-Dawley , Resistencia de las Vías Respiratorias/efectos de los fármacos , Antagonistas del Receptor de Bradiquinina B2/farmacología , Relación Dosis-Respuesta a Droga , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/tratamiento farmacológico , Neuronas/efectos de los fármacos , Neuronas/metabolismo

RESUMEN

BACKGROUND AND PURPOSE: Psoriasis is an autoimmune inflammatory skin disease, featuring microvascular abnormalities and elevated levels of bradykinin. Contact activation of Factor XII can initiate the plasma kallikrein-kinin cascade, producing inflammation and angioedema. The role of Factor XII in psoriasis is unknown. EXPERIMENTAL APPROACH: The effects of deficiency of Factor XII or its enzymatic substrate, prekallikrein, were examined in the imiquimod-induced mouse model of psoriasis. Skin microcirculation was assessed using intravital confocal microscopy and laser Doppler flowmeter. A novel antibody blocking Factor XII activation was evaluated for psoriasis prevention. KEY RESULTS: Expression of Factor XII was markedly up-regulated in human and mouse psoriatic skin. Genetic deletion of Factor XII or prekallikrein, attenuated imiquimod-induced psoriatic lesions in mice. Psoriatic induction increased skin microvascular blood perfusion, causing vasodilation, hyperpermeability and angiogenesis. It also promoted neutrophil-vascular interaction, inflammatory cytokine release and enhanced Factor XII / prekallikrein enzymatic activity with elevated bradykinin. Factor XII or prekallikrein deficiency ameliorated these microvascular abnormalities and abolished bradykinin increase. Antagonism of bradykinin B2 receptors reproduced the microvascular protection of Factor XII / prekallikrein deficiency, attenuated psoriatic lesions, and prevented protection by Factor XII / prekallikrein deficiency against psoriasis. Furthermore, treatment of mice with Factor XII antibody alleviated experimentally induced psoriasis and suppressed microvascular inflammation. CONCLUSION AND IMPLICATIONS: Activation of Factor XII promoted psoriasis via prekallikrein-dependent formation of bradykinin, which critically mediated psoriatic microvascular inflammation. Inhibition of contact activation represents a novel therapeutic strategy for psoriasis.

Asunto(s)

Factor XII , Precalicreína , Psoriasis , Animales , Femenino , Humanos , Masculino , Ratones , Aminoquinolinas/farmacología , Bradiquinina/farmacología , Modelos Animales de Enfermedad , Factor XII/metabolismo , Factor XII/antagonistas & inhibidores , Factor XII/genética , Imiquimod , Inflamación/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Microvasos/efectos de los fármacos , Microvasos/metabolismo , Precalicreína/metabolismo , Psoriasis/metabolismo , Psoriasis/inducido químicamente , Psoriasis/patología , Piel/irrigación sanguínea , Piel/metabolismo , Piel/patología , Piel/efectos de los fármacos

RESUMEN

A clear disease classification schema coupled with an understanding of the specific mechanisms involved in the different types of angioedema without hives informs the diagnostic assessment. The recommended approach involves several key steps. Foremost is the recognizing of the clinical clues which allow for the differentiation of mast cell-mediated disorders from bradykinin-mediated angioedema. Enhanced vascular permeability related to bradykinin is of critical importance to identify given the implications for disease morbidity and risk of mortality. The ability to efficiently categorize and diagnose all forms of angioedema results in improved patient outcomes.

Asunto(s)

Angioedema , Humanos , Angioedema/diagnóstico , Angioedema/etiología , Mastocitos/inmunología , Mastocitos/metabolismo , Bradiquinina/metabolismo , Diagnóstico Diferencial , Permeabilidad Capilar

RESUMEN

Angioedema is characterized by transient movement of fluid from the vasculature into the interstitial space leading to subcutaneous or submucosal non-pitting edema. Current evidence suggests that most angioedema conditions can be grouped into 2 categories: mast cell-mediated (previously termed histaminergic) or bradykinin-mediated angioedema. Although effective therapies for mast cell-mediated angioedema have existed for decades, specific therapies for bradykinin-mediated angioedema have more recently been developed. In recent years, rigorous studies of these therapies in treating hereditary angioedema (HAE) have led to regulatory approvals of medication for HAE management thereby greatly expanding HAE treatment options.

Asunto(s)

Angioedemas Hereditarios , Bradiquinina , Humanos , Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/terapia , Angioedemas Hereditarios/tratamiento farmacológico , Bradiquinina/metabolismo , Bradiquinina/análogos & derivados , Mastocitos/inmunología , Mastocitos/metabolismo , Proteína Inhibidora del Complemento C1/uso terapéutico , Animales

RESUMEN

Electrospray ionization (ESI) mass spectrometry is widely used for interrogating peptides, proteins, and other biomolecular analytes. A growing number of laboratories use molecular dynamics (MD) simulations for uncovering ESI mechanisms by modeling the behavior of highly charged nanodroplets. The outcome of any MD simulation depends on certain assumptions and parameter settings, and it is desirable to optimize these factors by benchmarking computational data against experiments. Unfortunately, benchmarking of ESI simulations is difficult because experimentally generated gaseous ions do not generally retain any features that would reveal their formation pathway [e.g., the charged residue mechanism (CRM) or the ion evaporation mechanism (IEM)]. Here, we tackle this problem by examining the effects of various MD settings on the ESI behavior of the 9-residue peptide bradykinin in acidic aqueous droplets. Several parameters were found to significantly affect the kinetic competition between peptide IEM and CRM. By systematically probing the droplet behavior, we uncovered problems associated with certain settings, including peptide/solvent temperature imbalances, unexpected peptide deceleration during IEM, and a dependence of the ESI mechanism on the water model. We also noted different simulation outcomes for different force fields. On the basis of comprehensive tests, we propose a set of "best practice" parameter settings for MD simulations of ESI droplets. The strategies used here should be transferable to other types of droplet simulations, paving the way toward a more solid understanding of ESI mechanisms.

Asunto(s)

Gases , Simulación de Dinámica Molecular , Espectrometría de Masa por Ionización de Electrospray , Gases/química , Péptidos/química , Iones/química , Bradiquinina/química , Agua/química

RESUMEN

Host proteins released by the activated endothelial cells during SARS-CoV-2 infection are implicated to be involved in coagulation and endothelial dysfunction. However, the underlying mechanism that governs the vascular dysfunction and disease severity in COVID-19 remains obscure. The study evaluated the serum levels of Bradykinin, Kallikrein, SERPIN A, and IL-18 in COVID-19 (N-42 with 20 moderate and 22 severe) patients compared to healthy controls (HC: N-10) using ELISA at the day of admission (DOA) and day 7 post-admission. The efficacy of the protein levels in predicting disease severity was further determined using machine learning models. The levels of bradykinins and SERPIN A were higher (P ≤ 0.001) in both severe and moderate cases on day 7 post-admission compared to DOA. All the soluble proteins studied were found to elevated (P ≤ 0.01) in severe compared to moderate in day 7 and were positively correlated (P ≤ 0.001) with D-dimer, a marker for coagulation. ROC analysis identified that SERPIN A, IL-18, and bradykinin could predict the clinical condition of COVID-19 with AUC values of 1, 0.979, and 1, respectively. Among the models trained using univariate model analysis, SERPIN A emerged as a strong prognostic biomarker for COVID-19 disease severity. The serum levels of SERPIN A in conjunction with the coagulation marker D-dimer, serve as a predictive indicator for COVID-19 clinical outcomes. However, studies are required to ascertain the role of these markers in disease virulence.

Asunto(s)

Biomarcadores , Bradiquinina , COVID-19 , Interleucina-18 , SARS-CoV-2 , Humanos , COVID-19/sangre , COVID-19/diagnóstico , Biomarcadores/sangre , Femenino , Masculino , Persona de Mediana Edad , Pronóstico , Interleucina-18/sangre , Bradiquinina/sangre , Adulto , Anciano , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Índice de Severidad de la Enfermedad , Endotelio Vascular/metabolismo , Calicreínas/sangre , alfa 1-Antitripsina/sangre

RESUMEN

The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor (C1INH)-protease complexes, levels of functional C1INH, plasma kallikrein activation, and cleavage of high-molecular-weight kininogen have each been associated with disease activity. More recently, HAE with normal levels of C1INH (HAE-nl-C1INH) has been recognized. Six genetic mutations have been identified which are linked to HAE-nl-C1INH phenotypes. The majority of individuals with HAE-nl-C1INH fall into the unknown category. There is substantial evidence that bradykinin generation underlies the recurrent attacks of swelling in some of these cohorts.

Asunto(s)

Biomarcadores , Bradiquinina , Proteína Inhibidora del Complemento C1 , Humanos , Bradiquinina/metabolismo , Proteína Inhibidora del Complemento C1/metabolismo , Angioedema/diagnóstico , Angioedema/metabolismo , Angioedema/etiología , Angioedemas Hereditarios/diagnóstico , Angioedemas Hereditarios/metabolismo , Angioedemas Hereditarios/etiología , Mutación

RESUMEN

The intestinal barrier plays a crucial role in homeostasis by both facilitating the absorption of nutrients and fluids and providing a tight shield to prevent the invasion by either pathogen or commensal microorganisms. Intestinal barrier malfunction is associated with systemic inflammation, oxidative stress, and decreased insulin sensitivity, which may lead to the dysregulation of other tissues. Therefore, a deeper understanding of physiological aspects related to an enhanced barrier function is of significant scientific and clinical relevance. The naked mole-rat has many unusual biological features, including attenuated colonic neuron sensitivity to acid and bradykinin and resistance to chemical-induced intestinal damage. However, insight into their intestinal barrier physiology is scarce. Here, we observed notable macroscopic and microscopic differences in intestinal tissue structure between naked mole-rats and mice. Moreover, naked mole-rats showed increased number of larger goblet cells and elevated mucus content. In measuring gut permeability, naked mole-rats showed reduced permeability compared with mice, measured as transepithelial electrical resistance, especially in ileum. Furthermore, intestinal ion secretion induced by serotonin, bradykinin, histamine, and capsaicin was significantly reduced in naked mole-rats compared with mice, despite the expression of receptors for all these agonists. In addition, naked mole-rats exhibited reduced prosecretory responses to the nonselective adenylate cyclase activator forskolin. Collectively, these findings indicate that naked mole-rats possess a robust and hard-to-penetrate gastrointestinal barrier that is resistant to environmental and endogenous irritants. Naked mole-rats may therefore provide valuable insights into the physiology of the intestinal barrier and set the stage for the development of innovative and effective therapies.NEW & NOTEWORTHY This is the first study to characterize the intestinal function of naked mole-rats. We found that these animals show a robust gut tissue structure, displaying thicker intestinal layers, longer villi, and larger crypts. Naked mole-rats showed more and larger goblet cells, with increased mucus content. Intestinal permeability, especially in the ileum, was substantially lower than that of mice. Finally, naked mole-rats showed reduced intestinal anion secretion in response to serotonin, bradykinin, histamine, capsaicin, and forskolin.

Asunto(s)

Mucosa Intestinal , Ratas Topo , Permeabilidad , Animales , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Ratones , Masculino , Células Caliciformes/metabolismo , Células Caliciformes/efectos de los fármacos , Capsaicina/farmacología , Bradiquinina/farmacología , Bradiquinina/metabolismo , Serotonina/metabolismo , Ratones Endogámicos C57BL , Funcion de la Barrera Intestinal

RESUMEN

Angioedema without concomitant urticaria is a well-known complication of treatment with the recombinant tissue-type plasminogen activator (r-tPA) alteplase and its genetically modified variant tenecteplase. It is potentially lethal when causing airway obstruction and can require intubation. The latest guideline for the early management of patients with acute ischemic stroke from the American Heart Association/American Stroke Association advises to treat this complication initially by interfering with the histamine pathway. This article aims to clarify the pathophysiological mechanism of r-tPA-induced angioedema and provides several arguments that this condition is primarily bradykinin-mediated and hence should be treated initially by intervening with the bradykinin pathway. Second, other-less frequently reported-adverse symptoms after r-tPA therapy and their proposed pathophysiological mechanisms leading to specific treatment are described. This manuscript describes the need for an update of the section "3.5 IV alteplase" from the American Heart Association/American Stroke Association guideline to treat this r-tPA-induced angioedema adequately and prevent potentially fatal outcomes.

Asunto(s)

Angioedema , Fibrinolíticos , Accidente Cerebrovascular , Activador de Tejido Plasminógeno , Humanos , Angioedema/inducido químicamente , Activador de Tejido Plasminógeno/efectos adversos , Activador de Tejido Plasminógeno/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Fibrinolíticos/efectos adversos , Fibrinolíticos/uso terapéutico , Bradiquinina/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico

RESUMEN

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.

Asunto(s)

Angiotensina I , Bradiquinina , Fragmentos de Péptidos , Receptor de Bradiquinina B1 , Resistencia Vascular , Animales , Cricetinae , Masculino , Ratas , Angiotensina I/farmacología , Angiotensina I/metabolismo , Angiotensina II/análogos & derivados , Bradiquinina/farmacología , Bradiquinina/análogos & derivados , Células CHO , Cricetulus , Sistema Calicreína-Quinina/fisiología , Sistema Calicreína-Quinina/efectos de los fármacos , Riñón/metabolismo , Riñón/efectos de los fármacos , Cininas/metabolismo , Fragmentos de Péptidos/farmacología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Ratas Wistar , Receptor de Bradiquinina B1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Circulación Renal/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Resistencia Vascular/efectos de los fármacos

RESUMEN

OBJECTIVE: Reno-renal reflexes are disturbed in cardiovascular and hypertensive conditions when elevated levels of pro-inflammatory mediators/cytokines are present within the kidney. We hypothesised that exogenously administered inflammatory cytokines tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1ß modulate the renal sympatho-excitatory response to chemical stimulation of renal pelvic sensory nerves. METHODS: In anaesthetised rats, intrarenal pelvic infusions of vehicle [0.9% sodium chloride (NaCl)], TNF-α (500 and 1000 ng/kg) and IL-1ß (1000 ng/kg) were maintained for 30 min before chemical activation of renal pelvic sensory receptors was performed using randomized intrarenal pelvic infusions of hypertonic NaCl, potassium chloride (KCl), bradykinin, adenosine and capsaicin. RESULTS: The increase in renal sympathetic nerve activity (RSNA) in response to intrarenal pelvic hypertonic NaCl was enhanced during intrapelvic TNF-α (1000 ng/kg) and IL-1ß infusions by almost 800% above vehicle with minimal changes in mean arterial pressure (MAP) and heart rate (HR). Similarly, the RSNA response to intrarenal pelvic adenosine in the presence of TNF-α (500 ng/kg), but not IL-1ß, was almost 200% above vehicle but neither MAP nor HR were changed. There was a blunted sympatho-excitatory response to intrapelvic bradykinin in the presence of TNF-α (1000 ng/kg), but not IL-1ß, by almost 80% below vehicle, again without effect on either MAP or HR. CONCLUSION: The renal sympatho-excitatory response to renal pelvic chemoreceptor stimulation is modulated by exogenous TNF-α and IL-1ß. This suggests that inflammatory mediators within the kidney can play a significant role in modulating the renal afferent nerve-mediated sympatho-excitatory response.

Asunto(s)

Interleucina-1beta , Riñón , Sistema Nervioso Simpático , Factor de Necrosis Tumoral alfa , Animales , Interleucina-1beta/farmacología , Ratas , Riñón/inervación , Riñón/efectos de los fármacos , Masculino , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Ratas Sprague-Dawley , Frecuencia Cardíaca/efectos de los fármacos , Bradiquinina/farmacología , Reflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Adenosina/administración & dosificación , Adenosina/farmacología , Solución Salina Hipertónica/administración & dosificación , Solución Salina Hipertónica/farmacología

RESUMEN

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.

Asunto(s)

Bradiquinina , Degranulación de la Célula , Mastocitos , Receptores Acoplados a Proteínas G , Receptores de Neuropéptido , Humanos , Mastocitos/inmunología , Mastocitos/metabolismo , Bradiquinina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Animales , Angioedema/metabolismo , Angioedema/inmunología , Angioedema/etiología , Proteínas del Tejido Nervioso/metabolismo , Sistema Calicreína-Quinina/fisiología

RESUMEN

We studied the inhibitory actions of docosahexaenoic acid (DHA) on the contractions induced by carbachol (CCh), angiotensin II (Ang II), and bradykinin (BK) in guinea pig (GP) gastric fundus smooth muscle (GFSM), particularly focusing on the possible inhibition of store-operated Ca2+ channels (SOCCs). DHA significantly suppressed the contractions induced by CCh, Ang II, and BK; the inhibition of BK-induced contractions was the strongest. Although all contractions were greatly dependent on external Ca2+, more than 80% of BK-induced contractions remained even in the presence of verapamil, a voltage-dependent Ca2+ channel inhibitor. BK-induced contractions in the presence of verapamil were not suppressed by LOE-908 (a receptor-operated Ca2+ channel (ROCC) inhibitor) but were suppressed by SKF-96365 (an SOCC and ROCC inhibitor). BK-induced contractions in the presence of verapamil plus LOE-908 were strongly inhibited by DHA. Furthermore, DHA inhibited GFSM contractions induced by cyclopiazonic acid (CPA) in the presence of verapamil plus LOE-908 and inhibited the intracellular Ca2+ increase due to Ca2+ addition in CPA-treated 293T cells. These findings indicate that Ca2+ influx through SOCCs plays a crucial role in BK-induced contraction in GP GFSM and that this inhibition by DHA is a new mechanism by which this fatty acid inhibits GFSM contractions.

Asunto(s)

Angiotensina II , Bradiquinina , Carbacol , Ácidos Docosahexaenoicos , Fundus Gástrico , Contracción Muscular , Músculo Liso , Animales , Cobayas , Ácidos Docosahexaenoicos/farmacología , Bradiquinina/farmacología , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Músculo Liso/metabolismo , Carbacol/farmacología , Contracción Muscular/efectos de los fármacos , Angiotensina II/farmacología , Fundus Gástrico/efectos de los fármacos , Fundus Gástrico/fisiología , Fundus Gástrico/metabolismo , Verapamilo/farmacología , Calcio/metabolismo , Masculino , Humanos , Canales de Calcio/metabolismo , Células HEK293 , Bloqueadores de los Canales de Calcio/farmacología , Imidazoles/farmacología

RESUMEN

Intervertebral disc degeneration (IVDD) is a leading cause of degenerative spinal disorders, involving complex biological processes. This study investigates the role of the kallikrein-kinin system (KKS) in IVDD, focusing on the protective effects of bradykinin (BK) on nucleus pulposus cells (NPCs) under oxidative stress. Clinical specimens were collected, and experiments were conducted using human and rat primary NPCs to elucidate BK's impact on tert-butyl hydroperoxide (TBHP)-induced oxidative stress and damage. The results demonstrate that BK significantly inhibits TBHP-induced NPC apoptosis and restores mitochondrial function. Further analysis reveals that this protective effect is mediated through the BK receptor 2 (B2R) and its downstream PI3K/AKT pathway. Additionally, BK/PLGA sustained-release microspheres were developed and validated in a rat model, highlighting their potential therapeutic efficacy for IVDD. Overall, this study sheds light on the crucial role of the KKS in IVDD pathogenesis and suggests targeting the B2R as a promising therapeutic strategy to delay IVDD progression and promote disc regeneration.

Asunto(s)

Apoptosis , Bradiquinina , Degeneración del Disco Intervertebral , Núcleo Pulposo , Estrés Oxidativo , Ratas Sprague-Dawley , terc-Butilhidroperóxido , Animales , Núcleo Pulposo/efectos de los fármacos , Núcleo Pulposo/patología , Núcleo Pulposo/metabolismo , terc-Butilhidroperóxido/toxicidad , Degeneración del Disco Intervertebral/tratamiento farmacológico , Degeneración del Disco Intervertebral/patología , Humanos , Masculino , Bradiquinina/farmacología , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Células Cultivadas , Receptor de Bradiquinina B2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Femenino , Microesferas , Transducción de Señal/efectos de los fármacos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Fosfatidilinositol 3-Quinasas/metabolismo , Modelos Animales de Enfermedad

RESUMEN

A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice.

Asunto(s)

Analgésicos , Animales , Ratones , Ratas , Masculino , Analgésicos/farmacología , Diclofenaco/farmacología , Tramadol/farmacología , Psicotrópicos/farmacología , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Ansiolíticos/farmacología , Antagonistas del Receptor de Bradiquinina B1/farmacología , Ratas Wistar , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos