RESUMEN
Kinins are a set of peptides present in tissues and involved in cardiovascular regulation, inflammation, and pain. Here, we briefly comment on recent key findings on the use of kinins in regenerative medicine.
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Inflamación , Cininas , Humanos , Cininas/fisiología , Péptidos/uso terapéutico , Dolor , Bradiquinina/fisiologíaRESUMEN
Vasoactive peptides are key early mediators of inflammation released through activation of different enzymatic systems. The mammalian kinin-kallikrein (K-KLK) system produces bradykinin (BK) through proteolytic cleavage of a kininogen precursor by enzymes named kallikreins. BK acts through specific ubiquitous G-protein coupled receptors (B1R and B2R) to participate in physiological processes and inflammatory responses, such as activation of mononuclear phagocytes. In chickens, the BK-like nonapeptide ornithokinin (OK) has been shown to promote intracellular calcium increase in embryonic fibroblasts and to be vasodilatory in vivo. Also, one of its receptors (B2R) was already cloned. However, the participation of chicken K-KLK system components in the inflammatory response remains unknown and was therefore investigated. We first showed that B1R, B2R and kininogen 1 (KNG1) are expressed in unstimulated chicken tissues and macrophages. We next showed that chicken B1R and B2R are expressed at transcript and protein levels in chicken macrophages and are upregulated by E. coli LPS or avian pathogenic E. coli (APEC) infection. Interestingly, exogenous OK induced internalization and degradation of OK receptors protein, notably B2R. Also, OK induced intracellular calcium increase and potentiated zymosan-induced ROS production and Dextran-FITC endocytosis by chicken macrophages. Exogenous OK itself did not promote APEC killing and had no pro-inflammatory effect. However, when combined with LPS or APEC, OK upregulated cytokine/chemokine gene expression and NO production by chicken macrophages. This effect was not blocked by canonical non-peptide B1R or B2R receptor antagonists but was GPCR- and PI3K/Akt-dependent. In vivo, pulmonary colibacillosis led to upregulation of OK receptors expression in chicken lungs and liver. Also, colibacillosis led to significant upregulation of OK precursor KNG1 expression in liver and in cultured hepatocytes (LMH). We therefore provide hitherto unknown information on how OK and its receptors are involved in inflammation and infection in chickens.
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Bradiquinina/análogos & derivados , Inflamación/veterinaria , Cininas/fisiología , Enfermedades de las Aves de Corral/inmunología , Receptores de Neuropéptido/fisiología , Animales , Bradiquinina/fisiología , Pollos/inmunología , Escherichia coli/inmunología , Inflamación/inmunología , Inflamación/metabolismo , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Enfermedades de las Aves de Corral/metabolismoRESUMEN
The blood coagulation balance in the organism is achieved by the interaction of the blood platelets (PLTs) with the plasma coagulation system (PCS) and the vascular endothelial cells. In healthy organism, these systems prevent thrombosis and, in events of vascular damage, enable blood clotting to stop bleeding. The dysregulation of hemostasis may cause serious thrombotic and/or hemorrhagic pathologies. Numerous engineered nanomaterials are being investigated for biomedical purposes and are unavoidably exposed to the blood. Also, nanomaterials may access vascular system after occupational, environmental, or other types of exposure. Thus, it is essential to evaluate the effects of engineered nanomaterials on hemostasis. This review focuses on investigations of nanomaterial interactions with the blood components involved in blood coagulation: the PCS and PLTs. Particular emphases include the pathophysiology of effects of nanomaterials on the PCS, including the kallikrein-kinin system, and on PLTs. Methods for investigating these interactions are briefly described, and a review of the most important studies on the interactions of nanomaterials with plasma coagulation and platelets is provided. WIREs Nanomed Nanobiotechnol 2017, 9:e1448. doi: 10.1002/wnan.1448 For further resources related to this article, please visit the WIREs website.
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Coagulación Sanguínea , Hemostasis , Nanoestructuras/uso terapéutico , Trombosis , Plaquetas/efectos de los fármacos , Humanos , Calicreínas/fisiología , Cininas/fisiología , Agregación PlaquetariaRESUMEN
In this work, we examined some mechanisms involved in the hypotension caused by Lachesis muta (South American bushmaster) venom in anesthetized rats. Venom (1.5 mg/kg, i.v.) caused immediate hypotension that was maximal after 5 min and gradually returned to baseline over 60 min. Pretreatment of rats with the non-selective nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) did not attenuate the early phase of venom-induced hypotension, but abolished the recovery phase and resulted in rapid death; a similar effect was observed with the soluble guanylate cyclase (sGC) inhibitor ODQ. In contrast, the hemodynamic responses to venom were not attenuated by the non-selective NOS inhibitor NG-monomethyl-L-arginine, the inducible NOS inhibitor aminoguanidine, the phosphodiesterase 5 inhibitor sildenafil, the adenylate cyclase (AC) inhibitor SQ-22.536, the non-selective muscarinic receptor antagonist atropine, the bradykinin B2 receptor antagonist HOE-140 and the non-selective cyclooxygenase inhibitor indomethacin. Preincubation of venom with the PLA2 inhibitor pBPB had no effect on the immediate hypotension but tended to improve the recovery phase. Neither AEBSF (a serine proteinase inhibitor) nor EDTA (a metalloproteinase inhibitor) prevented the venom-induced hypotension, but AEBSF and not EDTA protected against the lethality of a high dose (3.0 mg/kg, i.v.). There were no marked changes in the ECG parameters with the various treatments, except with L-NAME and ODQ that increased the RR interval. Pulmonary thrombus formation was markedly enhanced by L-NAME and ODQ, and to a lesser extent by pBPB, especially in small vessels, whereas AEBSF and EDTA inhibited thrombus formation. Venom relaxed phenylephrine-precontracted thoracic aorta and pulmonary artery in vitro, with the latter being more sensitive. The relaxation was endothelium-dependent and was inhibited by ODQ but not by H-89, a protein kinase A (PKA) inhibitor. Together, these findings indicate involvement of the NO/sGC/cGMP, but not the AC/cAMP/PKA signaling pathway, in the hemodynamic responses to L. muta venom in rats. Muscarinic mechanisms, kinins and arachidonic acid metabolites are apparently not involved.
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Hemodinámica/efectos de los fármacos , Venenos de Víboras/toxicidad , Viperidae , Animales , Aorta Torácica/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Hipotensión/inducido químicamente , Técnicas In Vitro , Cininas/metabolismo , Cininas/fisiología , Masculino , NG-Nitroarginina Metil Éster/uso terapéutico , Sistema Nervioso Parasimpático/efectos de los fármacos , Arteria Pulmonar/efectos de los fármacos , Ratas Wistar , Transducción de Señal , Mordeduras de Serpientes/tratamiento farmacológico , Mordeduras de Serpientes/patología , Mordeduras de Serpientes/fisiopatologíaRESUMEN
The G protein-coupled receptors (GPCRs), one of the largest protein families, are essential components of the most commonly used signal-transduction systems in cells. These receptors, often using common pathways, may cooperate in the regulation of signal transmission to the cell nucleus. Recent scientific interests increasingly focus on the cooperation between these receptors, particularly in a context of their oligomerization, e.g. the formation of dimers that are able to change characteristic signaling of each receptor. Numerous studies on kinin and dopamine receptors which belong to this family of receptors have shown new facts demonstrating their direct interactions with other GPCRs. In this review, current knowledge on signaling pathways and oligomerization of these receptors has been summarized. Owing to the fact that kinin and dopamine receptors are widely expressed in cell membranes where they act as mediators of numerous common physiological processes, the information presented here sheds new light on a putative crosstalk of these receptors and provides more comprehensive understanding of possible direct interactions that may change their functions. The determination of such interactions may be useful for the development of new targeted therapeutic strategies against many disorders in which kinin and dopamine receptors are involved.
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Receptores Dopaminérgicos/fisiología , Animales , Dopamina/fisiología , Humanos , Cininas/fisiología , Multimerización de Proteína , Transducción de SeñalRESUMEN
Kinin-mediated angioedema results from accumulation of kinins, vasoactive and vasopermeant peptides, on the vascular endothelium. The disease is characterized by sudden episodes of swelling in the subcutaneous and submucosal tissues; the edema may occur spontaneously or it may be precipitated by triggering factors such as physical or emotional stress, or certain medicines. The characterization of kinin formation and catabolism systems helps improve knowledge of the aetiopathogenic mechanisms involved and provides the basis for classification of kinin-mediated angioedema conditions; thus, we may distinguish between angioedema with C1 inhibitor deficiency, whether inherited or acquired, and angioedema with normal C1 inhibitor activity, associated with increased kinin-forming activity or deficiency in kinin catabolism enzymes. In support of the clinical diagnosis, the physician may request laboratory investigation for a functional and molecular definition of the disease. Laboratory diagnosis is based on the characterization of: (1) kinin production control by C1 inhibitor investigation (function, antigen levels and circulating species); (2) kinin production (kininogenase activity, kininogen cleavage species); and (3) kinin catabolism enzymes (aminopeptidase P, carboxypeptidase N, angiotensin-I converting enzyme and dipeptidyl peptidase IV). An abnormal biological phenotype is supported by examination of susceptibility genes (SERPING1, F12 and XPNPEP2) and mutation segregation in the families.
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Angioedema/sangre , Angioedema/diagnóstico , Cininas/sangre , Angioedema/clasificación , Angioedema/etiología , Proteínas Inactivadoras del Complemento 1/análisis , Proteína Inhibidora del Complemento C1 , Árboles de Decisión , Humanos , Cininas/fisiologíaRESUMEN
Epithelia frequently segregate transport processes to specific cell types, presumably for improved efficiency and control. The molecular players underlying this functional specialization are of particular interest. In Drosophila, the renal (Malpighian) tubule displays the highest per-cell transport rates known and has two main secretory cell types, principal and stellate. Electrogenic cation transport is known to reside in the principal cells, whereas stellate cells control the anion conductance, but by an as-yet-undefined route. Here, we resolve this issue by showing that a plasma membrane chloride channel, encoded by ClC-a, is exclusively expressed in the stellate cell and is required for Drosophila kinin-mediated induction of diuresis and chloride shunt conductance, evidenced by chloride ion movement through the stellate cells, leading to depolarization of the transepithelial potential. By contrast, ClC-a knockdown had no impact on resting secretion levels. Knockdown of a second CLC gene showing highly abundant expression in adult Malpighian tubules, ClC-c, did not impact depolarization of transepithelial potential after kinin stimulation. Therefore, the diuretic action of kinin in Drosophila can be explained by an increase in ClC-a-mediated chloride conductance, over and above a resting fluid transport level that relies on other (ClC-a-independent) mechanisms or routes. This key segregation of cation and anion transport could explain the extraordinary fluid transport rates displayed by some epithelia.
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Canales de Cloruro/fisiología , Diuresis/fisiología , Proteínas de Drosophila/fisiología , Drosophila melanogaster/fisiología , Neuropéptidos/fisiología , Animales , Animales Modificados Genéticamente , Canales de Cloruro/deficiencia , Canales de Cloruro/genética , Diuresis/genética , Proteínas de Drosophila/deficiencia , Proteínas de Drosophila/genética , Drosophila melanogaster/citología , Drosophila melanogaster/genética , Femenino , Técnicas de Silenciamiento del Gen , Genes de Insecto , Cininas/fisiología , Masculino , Túbulos de Malpighi/citología , Túbulos de Malpighi/fisiología , Modelos BiológicosRESUMEN
Endogenous kinins are important vasoactive peptides whose effects are mediated by two G-Protein-coupled receptors (R), named B2R (constitutive) and B1R (inducible). They are involved in vascular homeostasis, ischemic pre- and post- conditioning, but also in cardiovascular diseases. They contribute to the therapeutic effects of angiotensin-1 converting enzyme inhibitors (ACEI) and angiotensin AT1 receptor blockers. Benefits derive primarily from vasodilatory, antiproliferative, antihypertrophic, antifibrotic, antithrombic and antioxidant properties, which are associated with the release of endothelial factors such as nitric oxide, prostacyclin and tissue plasminogen activator. Uncontrolled production of kinins or the inhibition of their metabolism may lead to unwanted pro-inflammatory side effects. Thus, B2R antagonism is salutary in angioedema, septic shock, stroke, and Chagas vasculopathy. B1R is virtually absent in healthy tissues, yet this receptor is induced by the cytokine pathway and the oxidative stress via the transcriptional nuclear factor NF-κB. The B1R may play a compensatory role for the lack of B2R, and its up-regulation during tissue damage may be a useful mechanism of host defense. Activation of both receptors may be beneficial, notably in neovascularisation, angiogenesis, heart ischemia and diabetic nephropathy. At the same time, B1R is a potent activator of inducible nitric oxide and NADPH oxidase, which are associated with vascular inflammation, increased permeability, insulin resistance, endothelial dysfunction and diabetic complications. The dual beneficial and deleterious effects of kinin receptors and, particularly B1R, raise an unsettled issue on the therapeutic value of B1R/B2R agonists versus antagonists in cardiovascular diseases. Hence, the Janus-face of kinin receptors needs to be seriously addressed in the upcoming clinical trials for each pathological setting.
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Receptores de Bradiquinina/fisiología , Enfermedades Vasculares/etiología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Apoptosis , Enfermedades Cardiovasculares/etiología , Homeostasis , Humanos , Cininas/fisiología , Óxido Nítrico Sintasa de Tipo III/fisiología , Sistema Renina-Angiotensina/fisiología , Enfermedades Vasculares/patología , Enfermedades Vasculares/fisiopatologíaRESUMEN
The study was aimed at assessing the degree of impairments of the kinin mechanisms by the level of antibodies to bradykinin in patients with ischaemic stroke in association with the indices of the vascular endothelium function. We examined people belonging to four various categories, i.e. 30 apparently healthy people (the control group), 30 high-risk patients with degree I-II arterial hypertension, 56 patients with degree II-III arterial hypertension running very high risk for cardiovascular disease, and 35 patients undergoing in-hospital treatment for acute stage of ischaemic stroke. We determined the content of natural antibodies to bradykinin (NABB) and the indices of endothelial function. We revealed alterations in the content of NABB in all groups of patients as compared with the control group. Their degree depended upon the disease and was highest in patients with stroke. Simultaneously we revealed impaired functioning of the vascular endothelium, the key manifestation of which was a pronounced decrease in the endothelium-dependent vasodilation in patients with stroke. Despite different directivity of alterations of certain indices of endothelial function in the groups of patients, we revealed statistically significant correlations of the alterations with the content of NABB.
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Isquemia Encefálica/sangre , Endotelio Vascular/fisiopatología , Cininas/fisiología , Vasodilatación/fisiología , Adulto , Anciano , Isquemia Encefálica/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
The albumin overload model induces proteinuria and tubulointersitial damage, followed by hypertension when rats are exposed to a hypersodic diet. To understand the effect of kinin system stimulation on salt-sensitive hypertension and to explore its potential renoprotective effects, the model was induced in Sprague-Dawley rats that had previously received a high-potassium diet to enhance activity of the kinin pathway, followed with/without administration of icatibant to block the kinin B2 receptor (B2R). A disease control group received albumin but not potassium or icatibant, and all groups were exposed to a hypersodic diet to induce salt-sensitive hypertension. Potassium treatment increased the synthesis and excretion of tissue kallikrein (Klk1/rKLK1) accompanied by a significant reduction in blood pressure and renal fibrosis and with downregulation of renal transforming growth factor-ß (TGF-ß) mRNA and protein compared with rats that did not receive potassium. Participation of the B2R was evidenced by the fact that all beneficial effects were lost in the presence of the B2R antagonist. In vitro experiments using the HK-2 proximal tubule cell line showed that treatment of tubular cells with 10 nM bradykinin reduced the epithelial-mesenchymal transdifferentiation and albumin-induced production of TGF-ß, and the effects produced by bradykinin were prevented by pretreatment with the B2R antagonist. These experiments support not only the pathogenic role of the kinin pathway in salt sensitivity but also sustain its role as a renoprotective, antifibrotic paracrine system that modulates renal levels of TGF-ß.
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Bradiquinina/análogos & derivados , Fibrosis/prevención & control , Hipertensión/tratamiento farmacológico , Enfermedades Renales/prevención & control , Cininas/fisiología , Potasio en la Dieta/farmacología , Proteinuria/fisiopatología , Factor de Crecimiento Transformador beta/fisiología , Animales , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B2 , Línea Celular , Femenino , Humanos , Hipertensión/fisiopatología , Enfermedades Renales/patología , Túbulos Renales/patología , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/fisiología , Proteinuria/inducido químicamente , Ratas , Ratas Sprague-Dawley , Albúmina Sérica Bovina , Cloruro de Sodio Dietético/efectos adversos , Calicreínas de Tejido/orina , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
INTRODUCTION: Kinins are bioactive peptide hormones that exert biological effects by activating two types of G protein-coupled receptors namely, B(1) (B(1)R) and B(2) (B(2)R). These modulate normal physiological cellular functions, inflammatory disorders and carcinogenesis. New and novel kinin receptor antagonists have been synthesized and their efficacy evaluated. AREAS COVERED: The authors provide a comprehensive review on the cellular and molecular biology of kinins and their receptors is delineated along with evolution and discovery of selective peptide and non-peptide antagonists. The authors describe the in vitro and in vivo methods used to understand the relative functional roles of B(1)R and B(2)R in physiology and pathohysiology. Furthermore, the authors translate the evaluation of kinin antagonists in selected preclinical models and associated clinical indications. Literature was surveyed from original publications, standard sources, SciFinder, patent applications and clinical trials. EXPERT OPINION: The authors suggest that several key areas of functional biology need consideration, namely: re-evaluation, particularly in vivo, of the mechanism of action and relative functional roles of the B(1)R and B(2)R in physiology and acute and chronic disease in animals and man; need for improved animal models with increased use of humanized and human systems; development of fluorescent probes for use in vivo in animals and man using advanced imaging techniques; combination of kinin receptor antagonists and traditional chemotherapy for various cancers.
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Antineoplásicos/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Antagonistas del Receptor de Bradiquinina B2 , Neoplasias/tratamiento farmacológico , Animales , Descubrimiento de Drogas , Humanos , Cininas/fisiología , Modelos AnimalesRESUMEN
The mediatory role of kinins in both acute and chronic inflammation within nervous tissues has been widely described. Bradykinin, the major representative of these bioactive peptides, is one of a few mediators of inflammation that directly stimulates afferent nerves due to the broad expression of specific kinin receptors in cell types in these tissues. Moreover, kinins may be delivered to a site of injury not only after their production at the endothelium surface but also following their local production through the enzymatic degradation of kininogens at the surface of nerve cells. A strong correlation between inflammatory processes and neurodegeneration has been established. The activation of nerve cells, particularly microglia, in response to injury, trauma or infection initiates a number of reactions in the neuronal neighborhood that can lead to cell death after the prolonged action of inflammatory substances. In recent years, there has been a growing interest in the effects of kinins on neuronal destruction. In these studies, the overexpression of proteins involved in kinin generation or of kinin receptors has been observed in several neurologic disorders including neurodegenerative diseases such Alzheimer's disease and multiple sclerosis as well as disorders associated with a deficiency in cell communication such as epilepsy. This review is focused on recent findings that provide reliable evidence of the mediatory role of kinins in the inflammatory responses associated with different neurological disorders. A deeper understanding of the role of kinins in neurodegenerative diseases is likely to promote the future development of new therapeutic strategies for the control of these disorders. An example of this could be the prospective use of kinin receptor antagonists.
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Inflamación/complicaciones , Cininas/fisiología , Enfermedades Neurodegenerativas/complicaciones , Animales , Humanos , Inflamación/fisiopatologíaRESUMEN
The kallikrein/kinin system uses two distinct serine proteases, plasma kallikrein and tissue kallikrein, to yield bradykinin and Lys-bradykinin (kallidin) from specific substrate kininogens. The kallikrein/kinin system is known to have a role in contact-activated coagulation mechanisms and in inflammatory responses, and recently has been shown to contribute to homeostatic and protective mechanisms in the cardiovascular and renal systems. This article reviews current knowledge of the ocular kallikrein/kinin system within the context of proposed roles for this system in other important organs and tissues. All components of the kallikrein/kinin system are present in the eye and are positioned to participate in key ocular functions. Plasma kallikrein binds to vascular endothelium and generates bradykinin, which may contribute to regulation of ocular blood flow, and, in excess, has been implicated in the pathogenesis of retinal edema in patients with proliferative diabetic retinopathy. Tissue kallikrein is expressed in retina, ciliary muscle, and trabecular meshwork cells and could be a significant factor in the protective mechanism of ischemic preconditioning, and in the modulation of aqueous dynamics. Improved understanding of the role of plasma and tissue kallikreins and kinins in such processes has the potential to identify significant new targets for the therapy of ocular dysfunction.
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Ojo/metabolismo , Calicreínas/metabolismo , Cininas/metabolismo , Fenómenos Fisiológicos Oculares , Animales , Humanos , Calicreínas/fisiología , Cininas/fisiología , Transducción de SeñalRESUMEN
UNLABELLED: Vasculitis is a systemic autoimmune inflammatory disease, characterized by inflammation in and around vessel walls leading to perturbed vessel patency and tissue damage. Many different organs may be involved. In this review, pathogenetic mechanisms of vasculitis are discussed, with special reference to activation of the kinin system. Mechanisms of kinin system activation are described, ultimately leading to release of kinins from high molecular weight kininogen. These vasoactive peptides promote inflammation. CONCLUSION: Kinin system activation during vasculitis promotes inflammation.
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Cininas/fisiología , Vasculitis/etiología , HumanosRESUMEN
Insect kinin neuropeptides share a common C-terminal pentapeptide sequence Phe1-Xaa1(2)-Xaa2(3)-Trp4-Gly5-NH2 (Xaa1(2) = His, Asn, Phe, Ser or Tyr; Xaa2(3) = Pro, Ser or Ala) and have been isolated from a number of insects, including species of Dictyoptera, Orthoptera and Lepidoptera. They have been associated with the regulation of such diverse processes as hindgut contraction, diuresis and the release of digestive enzymes. In this chapter, the chemical, conformational and stereochemical aspects of the activity ofthe insect kinins with expressed receptors and/or biological assays are reviewed. With this information, biostable analogs are designed that protect peptidase-susceptible sites in the insect kinin sequence and demonstrate significant retention of activity on both receptor and biological assays. The identification of the most critical residue of the insect kinins for receptor interaction is used to select a scaffold for a recombinant library that leads to identification ofa nonpeptide mimetic analog. C-terminal aldehyde insect kinin analogs modify the activity of the insect kinins leading to inhibition of weight gain and mortality in corn earworm larvae and selective inhibition ofdiuresis in the housefly. Strategies for the modification of insect neuropeptide structures for the enhancement ofthe topical and oral bioavailability of insect neuropeptides and the promotion of time-release from the cuticle and/or foregut are reviewed. Promising mimetic analog leads for the development of selective agents capable of disrupting insect kinin regulated processes are identified that may provide interesting tools for arthropod endocrinologists and new pest insect management strategies in the future.
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Artrópodos/fisiología , Insectos/fisiología , Cininas/fisiología , Neuropéptidos/fisiología , Receptores de Droga/fisiología , Células Receptoras Sensoriales/fisiología , Secuencia de Aminoácidos , Animales , Artrópodos/efectos de los fármacos , Glutamatos/farmacología , Cininas/química , Cininas/farmacología , Neuropéptidos/farmacología , Oligopéptidos/química , Receptores de Droga/química , Receptores de Droga/efectos de los fármacos , Células Receptoras Sensoriales/efectos de los fármacos , Tetrazoles/farmacología , Garrapatas/efectos de los fármacos , Garrapatas/fisiologíaRESUMEN
Cardiovascular responses elicited by the stimulation of kinin B2 receptors in the IV cerebral ventricle, paratrigeminal nucleus or in the thoracic spinal cord are similar to those observed during an exercise bout. Considering that the kalikrein-kinin system (KKS) could act on the cardiovascular modulation during behavioral responses as physical exercise or stress, this study evaluated the central B2 receptor densities of Wistar (W) and spontaneously hypertensive rats (SHR) after chronic moderate exercise. Animals were exercise-trained for ten weeks on a treadmill. Afterwards, systolic blood pressure decreased in both trained strains. Animals were killed and the medulla and spinal cord extracted for B2 receptor autoradiography. Trained animals were compared to their sedentary controls. Sedentary groups showed specific binding sites for Hoe-140 (fmol/mg of tissue) in laminas 1 and 2 of the spinal cord, nucleus of the solitary tract (NTS), area postrema (AP), spinal trigeminal tract (sp5) and paratrigeminal nucleus (Pa5). In trained W a significant increase (p<0.05) in specific binding was observed in the Pa5 (31.3%) and NTS (28.2%). Trained SHR showed a significant decrease in receptor density in lamina 2 (21.9%) of the thoracic spinal cord and an increase in specific binding in Pa5 (36.1%). We suggest that in the medulla, chronic exercise could hyper stimulate the KKS enhancing their efficiency through the increase of B2 receptor density, involving this receptor in central cardiovascular control during exercise or stress. In the lamina 2, B2 receptor might be involved in the exercise-induced hypotension.
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Ventrículos Cerebrales/metabolismo , Condicionamiento Físico Animal/fisiología , Receptor de Bradiquinina B2/metabolismo , Animales , Presión Sanguínea/fisiología , Ventrículos Cerebrales/irrigación sanguínea , Ventrículos Cerebrales/fisiología , Calicreínas/fisiología , Cininas/fisiología , Masculino , Bulbo Raquídeo/irrigación sanguínea , Bulbo Raquídeo/metabolismo , Bulbo Raquídeo/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Receptor de Bradiquinina B2/biosíntesis , Médula Espinal/irrigación sanguínea , Médula Espinal/metabolismo , Médula Espinal/fisiología , Estrés Fisiológico , Factores de Tiempo , Regulación hacia Arriba/fisiologíaRESUMEN
AIMS/HYPOTHESIS: We aimed to understand early alterations in kinin-mediated migration of circulating angio-supportive cells and dysfunction of kinin-sensitive cells in type-1 diabetic (T1D) patients before the onset of cardiovascular disease. METHODS: Total mononuclear cells (MNC) were isolated from peripheral blood of 28 T1D patients free from cardiovascular complications except mild background retinopathy (age: 34.8+/-1.6 years, HbA(1C): 7.9+/-0.2%) and 28 age- and sex-matched non-diabetic controls (H). We tested expression of kinin receptors by flow cytometry and migratory capacity of circulating monocytes and progenitor cells towards bradykinin (BK) in transwell migration assays. MNC migrating towards BK (BK(mig)) were assessed for capacity to support endothelial cell function in a matrigel assay, as well as generation of nitric oxide (NO) and superoxide (O(2) (-)*) by using the fluorescent probes diaminofluorescein and dihydroethidium. RESULTS: CD14(hi)CD16(neg), CD14(hi)CD16(pos) and CD14(lo)CD16(pos) monocytes and circulating CD34(pos) progenitor cells did not differ between T1D and H subjects in their kinin receptor expression and migration towards BK. T1D BK(mig) failed to generate NO upon BK stimulation and supported endothelial cell network formation less efficiently than H BK(mig). In contrast, O(2) (-)* production was similar between groups. High glucose disturbed BK-induced NO generation by MNC-derived cultured angiogenic cells. CONCLUSIONS/INTERPRETATION: Our data point out alterations in kinin-mediated functions of circulating MNC from T1D patients, occurring before manifest macrovascular damage or progressed microvascular disease. Functional defects of MNC recruited to the vessel wall might compromise endothelial maintenance, initially without actively promoting endothelial damage, but rather by lacking supportive contribution to endothelial regeneration and healing.
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Diabetes Mellitus Tipo 1/sangre , Cininas/fisiología , Adolescente , Glucemia/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Femenino , Humanos , Inmunofenotipificación , Masculino , Monocitos/inmunología , Óxido Nítrico/biosíntesis , Superóxidos/metabolismoRESUMEN
The generation of bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) in blood and kallidin (Lys-BK) in tissues by the action of the kallikrein-kinin system has received little attention in non-mammalian vertebrates. In mammals, kallidin can be generated by the coronary endothelium and myocytes in response to ischemia, mediating cardioprotective events. The plasma of birds lacks two key components of the kallikrein-kinin system: the low molecular weight kininogen and a prekallikrein activator analogous to mammalian factor XII, but treatment with bovine plasma kallikrein generates ornitho-kinin [Thr6,Leu8]-BK. The possible cardioprotective effect of ornitho-kinin infusion was investigated in an anesthetized, open-chest chicken model of acute coronary occlusion. A branch of the left main coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. The iv injection of a low dose of ornitho-kinin (4 microg/kg) reduced mean arterial pressure from 88 +/- 12 to 42 +/- 7 mmHg and increased heart rate from 335 +/- 38 to 402 +/- 45 bpm (N = 5). The size of the infarct was reduced by pretreatment with ornitho-kinin (500 microg/kg infused over a period of 5 min) from 35 +/- 3 to 10 +/- 2% of the area at risk. These results suggest that the physiological role of the kallikrein-kinin system is preserved in this animal model in spite of the absence of two key components, i.e., low molecular weight kininogen and factor XII.