RESUMEN
BACKGROUND: Many drugs have been explored for their role in improving skin flap survival. 1-deamino-8-D-arginine vasopressin (DDAVP or desmopressin) is a synthesized form of anti-diuretic hormone (ADH) and a selective agonist for vasopressin type-2 receptors (V2 receptors). Desmopressin has been shown to improve endothelial function, induce vasodilation, and reduce inflammation. We aimed to evaluate its efficacy in enhancing flap survival and assess the role of vasopressin receptors in this process. MATERIALS AND METHODS: We randomly assigned six male Wistar rats to each study group. Different doses of desmopressin were injected intraperitoneally to find the most effective amount (8 µg/rat). SR-49059, a selective V1a receptor antagonist, was given at 2µg/rat before providing the most effective dose of desmopressin (8µg/rat). Histopathological assessments, quantitative measurements of interleukin-1ß (IL-1ß), Tumor necrosis factor-alpha (TNF-α), and Nuclear Factor-κB (NF-κB), optical imaging, and measurement of the expression levels of V2 receptor in the rat skin tissue were performed. RESULTS: Desmopressin (8µg/rat) significantly reduced the mean percentage of necrotic area compared to the control group (19.35% vs 73.57%). Histopathological evaluations revealed a notable reduction in tissue inflammation, edema, and degeneration following administration of desmopressin (8). The expression of the V2 receptor was increased following desmopressin administration. It also led to a reduction in IL-1ß, TNF-α, and NF-κB levels. The protective effect of desmopressin on flap survival was reversed upon giving SR-49059. The optical imaging revealed enhanced blood flow in the desmopressin group compared to the control group. CONCLUSIONS: Desmopressin could be repurposed to improve flap survival. V1a and V2 receptors probably mediate this effect.
Asunto(s)
Desamino Arginina Vasopresina , Receptores de Vasopresinas , Ratas , Masculino , Animales , Desamino Arginina Vasopresina/farmacología , Receptores de Vasopresinas/fisiología , FN-kappa B , Factor de Necrosis Tumoral alfa , Ratas Wistar , Antagonistas de los Receptores de Hormonas Antidiuréticas , Vasopresinas/farmacología , InflamaciónRESUMEN
BACKGROUND: Interstitial cells of Cajal generate slow wave gastric electrical activity, initiating spontaneous muscle contractions. This becomes dysrhythmic during nausea when [Arg8]-vasopressin (AVP) is also released. In human stomach AVP increased spontaneous contraction activity and muscle tone, not neuronally-mediated contractions. Rodents cannot vomit, releasing the related hormone, oxytocin (OT) instead. We hypothesised that rat stomach would behave differently. EXPERIMENTAL APPROACH: Spontaneous and electrically-evoked (EFS) contractions were measured in rat forestomach and antrum circular muscle. Custom software defined spontaneous contractions by analysing eight motility parameters. RESULTS: The forestomach was quiescent. Irregular antrum contractions became regular adjacent to the pylorus (1.7 ± 0.4 mN; 1.2 ± 0.1 contractions/min, n = 12). These were unaffected by tetrodotoxin (10-6 M), atropine (10-6 M) and L-NAME (3 × 10-4 M). In both regions, AVP (pEC50â¼9.0) and OT (â¼0.5 log10-unit less potent) caused contraction (greater in antrum), competitively antagonized by, respectively, SR49059 (pKBâ¼9.5) and L371257 (pKBâ¼9.0), reduced by tetrodotoxin but unaffected by atropine. In the antrum, AVP and OT (â¼2 log10-units less potent/efficacious) regularized and increased spontaneous contraction amplitude, frequency, rates of contraction/decay. In both regions, EFS-evoked contractions, abolished by atropine/tetrodotoxin, were reduced by AVP and OT, with AVP more potent and efficacious, particularly in forestomach. CONCLUSION: Irregular spontaneous contractions of gastric antrum suggest variable ICC-muscle coupling. AVP and less potently, OT, enhanced frequency and force of contractions via V1A and OT receptors. Compared with human, differences in contraction regularity, potency and ability of AVP/OT to affect neuronal function suggests caution when using rat stomach to model ICC functions and nauseagenic stimuli.
Asunto(s)
Arginina Vasopresina , Oxitocina , Animales , Ratas , Arginina , Arginina Vasopresina/farmacología , Atropina , Oxitocina/farmacología , Receptores de Oxitocina , Receptores de Vasopresinas/fisiología , Estómago , Tetrodotoxina , VasopresinasRESUMEN
The adverse effects of vasopressin (AVP) in diverse forms of chronic kidney disease have been well described. They depend on the antidiuretic action of AVP mediated by V2 receptors (V2R). Tolvaptan, a selective V2R antagonist, is now largely used for the treatment of patients with autosomal dominant polycystic kidney disease. Another way to reduce the adverse effects of AVP is to reduce endogenous AVP secretion by a voluntary increase in fluid intake. These two approaches differ in several ways, including the level of thirst and AVP. With voluntary increased drinking, plasma osmolality will decline and so will AVP secretion. Thus, not only will V2R-mediated effects be reduced, but also those mediated by V1a and V1b receptors (V1aR and V1bR). In contrast, selective V2R antagonism will induce a loss of fluid that will stimulate AVP secretion and thus increase AVP's influence on V1a and V1b receptors. V1aR is expressed in the luminal side of the collecting duct (CD) and in inner medullary interstitial cells, and their activation induces the production of prostaglandins, mostly prostaglandin E2 (PGE2). Intrarenal PGE2 has been shown to reduce sodium and water reabsorption in the CD and increase blood flow in the renal medulla, both effects contributing to increase sodium and water excretion and reduce urine-concentrating activity. Conversely, non-steroidal anti-inflammatory drugs have been shown to induce significant water and sodium retention and potentiate the antidiuretic effects of AVP. Thus, during V2R antagonism, V1aR-mediated actions may be responsible for part of the diuresis observed with this drug. These V1aR-dependent effects do not take place with a voluntary increase in fluid intake. In summary, while both strategies may have beneficial effects, the information reviewed here leads us to assume that pharmacological V2R antagonism, with resulting stimulation of V1aR and increased PGE2 production, may provide greater benefit than voluntary high water intake. The influence of tolvaptan on the PGE2 excretion rate and the possibility to use somewhat lower tolvaptan doses than presently prescribed remain to be evaluated.
Asunto(s)
Dinoprostona , Riñón , Humanos , Tolvaptán/uso terapéutico , Receptores de Vasopresinas/fisiología , Médula Renal , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Sodio , Arginina VasopresinaRESUMEN
The arginine vasopressin (AVP), a neurohypophysial hormone, is synthesized within specific sites of the central nervous system and axonally transported to multiple areas, acting as a neurotransmitter/ neuromodulator. In this context, AVP acts primarily through vasopressin receptors A and B and is involved in regulating complex social and cognition behaviors and basic autonomic function. Many earlier studies have shown that AVP as a neuromodulator affects synaptic plasticity. This review updates our current understanding of the underlying molecular mechanisms by which AVP affects synaptic plasticity. Moreover, we discuss AVP modulatory effects on event-related potentials and blood oxygen level-dependent responses in specific brain structures, and AVP effects on the network level oscillatory activity. We aimed at providing an overview of the AVP effects on the brain from the synaptic to the network level.
Asunto(s)
Arginina Vasopresina , Receptores de Vasopresinas , Humanos , Arginina Vasopresina/farmacología , Arginina Vasopresina/metabolismo , Receptores de Vasopresinas/fisiología , Encéfalo/metabolismo , Plasticidad Neuronal , NeurotransmisoresRESUMEN
Restraint stress (RS) is an unavoidable stress model that triggers activation of the autonomic nervous system, endocrine activity, and behavioral changes in rodents. Furthermore, RS induces secretion of oxytocin into the bloodstream, indicating a possible physiological role in the stress response in this model. The presence of oxytocin receptors in vessels and heart favors this possible idea. However, the role of oxytocin secreted in RS and effects on the cardiovascular system are still unclear. The aim of this study was to analyze the influence of oxytocin on cardiovascular effects during RS sessions. Rats were subjected to pharmacological (blockade of either oxytocin, vasopressin, or muscarinic receptors) or surgical (hypophysectomy or sinoaortic denervation) approaches to study the functional role of oxytocin and its receptor during RS. Plasma levels of oxytocin and vasopressin were measured after RS. RS increased arterial pressure, heart rate, and plasma oxytocin content, but not vasopressin. Treatment with atosiban (a Gi biased agonist) inhibited restraint-evoked tachycardia without affecting blood pressure. However, this effect was no longer observed after sinoaortic denervation, homatropine (M2 muscarinic antagonist) treatment or hypophysectomy, indicating that parasympathetic activation mediated by oxytocin secreted to the periphery is responsible for blocking the increase in tachycardic responses observed in the atosiban-treated group. Corroborating this, L-368,899 (oxytocin antagonist) treatment showed an opposite effect to atosiban, increasing tachycardic responses to restraint. Thus, this provides evidence that oxytocin secreted to the periphery attenuates tachycardic responses evoked by restraint via increased parasympathetic activity, promoting cardioprotection by reducing the stress-evoked heart rate increase.
Asunto(s)
Oxitocina/metabolismo , Restricción Física/fisiología , Estrés Psicológico/fisiopatología , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Agonistas Muscarínicos/farmacología , Oxitocina/sangre , Parasimpatolíticos/farmacología , Ratas Wistar , Receptor Muscarínico M2/antagonistas & inhibidores , Receptores de Vasopresinas/fisiología , Estrés Psicológico/sangre , Taquicardia/fisiopatología , Tropanos/farmacología , Vasopresinas/sangre , Vasotocina/análogos & derivados , Vasotocina/farmacologíaRESUMEN
The authors recently reported the presence and distribution of oxytocin/vasopressin-like peptide in Portunus pelagicus as well as demonstrated its function to inhibit ovarian steroid release (Saetan et al., 2018). Here, the full-length receptor of this peptide, namely oxytocin/vasopressin-like peptide receptor (PpelOT/VP-like peptide receptor) is reported. The coding region of the PpelOT/VP-like peptide receptor contained 1497 bp which translationally corresponded to 499 amino acids. Sequence analysis revealed its seven transmembrane characteristics, with -two N-linked glycosylation residues located before the first transmembrane domain (TM I). The phylogenetic tree revealed that the PpelOT/VP-like peptide receptor was placed in the group of invertebrate OT/VP-like receptors, and was clearly distinguishable from the V1R, V2R and OTR of vertebrates. Also, this receptor gene transcript was detected in several organs of the blue swimming crab with highest abundance found in brain tissue. In situ hybridization exhibited its distribution in all neuronal clusters of the eyestalk, brain, ventral nerve cord (VNC), as well as in the ovary. Comparative gene expressions between this receptor and its corresponding peptide in immature and mature female crabs revealed no significant difference of the PpelOT/VP-like peptide receptor gene expression in the central nervous system (CNS) and ovary. In contrast, the PpelOT/VP-like peptide gene was shown to significantly express higher in the VNC of immature crabs and in the ovary of mature crabs. Changes in expression of this peptide gene, but not its receptor, might result in ovarian steroid release inhibition. However, the detailed mechanism of this peptide in reproduction regulation will be included in our further studies.
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Braquiuros/fisiología , Oxitocina/metabolismo , Receptores de Péptidos/metabolismo , Receptores de Vasopresinas/fisiología , Vasopresinas/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Femenino , Perfilación de la Expresión Génica , Ovario/metabolismo , Péptidos/química , Filogenia , ARN Mensajero/metabolismo , Receptores de Péptidos/genética , Receptores de Vasopresinas/metabolismoRESUMEN
Methicillin-resistant Staphylococcus aureus (MRSA) sepsis is a severe condition associated with vascular leakage and poor prognosis. The hemodynamic management of sepsis targets hypotension, but there is no specific treatment available for vascular leakage. Arginine vasopressin (AVP) has been used in sepsis to promote vasoconstriction by activating AVP receptor 1 (V1R). However, recent evidence suggests that increased fluid retention may be associated with the AVP receptor 2 (V2R) activation worsening the outcome of sepsis. Hence, we hypothesized that the inhibition of V2R activation ameliorates the severity of microvascular hyperpermeability during sepsis. The hypothesis was tested using a well-characterized and clinically relevant ovine model of MRSA pneumonia/sepsis and in vitro assays of human lung microvascular endothelial cells (HMVECs). in vivo experiments demonstrated that the treatment of septic sheep with tolvaptan (TLVP), an FDA-approved V2R antagonist, significantly attenuated the sepsis-induced fluid retention and markedly reduced the lung water content. These pathological changes were not affected by the treatment with V2R agonist, desmopressin (DDAVP). Additionally, the incubation of cultured HMVECs with DDAVP, and DDAVP along with MRSA significantly increased the paracellular permeability. Finally, both the DDAVP and MRSA-induced hyperpermeability was significantly attenuated by TLVP. Subsequent protein and gene expression assays determined that the V2R-induced increase in permeability is mediated by phospholipase C beta (PLCß) and the potent permeability factor angiopoietin-2. In conclusion, our results indicate that the activation of the AVP-V2R axis is critical in the pathophysiology of severe microvascular hyperpermeability during Gram-positive sepsis. The use of the antagonist TLVP should be considered as adjuvant treatment for septic patients. The results from this clinically relevant animal study are highly translational to clinical practice.
Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Neumonía Estafilocócica/fisiopatología , Receptores de Vasopresinas/fisiología , Sepsis/fisiopatología , Enfermedades de las Ovejas/fisiopatología , Angiopoyetina 2/genética , Angiopoyetina 2/metabolismo , Animales , Fármacos Antidiuréticos/uso terapéutico , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Permeabilidad Capilar/efectos de los fármacos , Células Cultivadas , Desamino Arginina Vasopresina/uso terapéutico , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Fosfolipasa C beta/genética , Neumonía Estafilocócica/tratamiento farmacológico , Neumonía Estafilocócica/veterinaria , Receptores de Vasopresinas/agonistas , Sepsis/tratamiento farmacológico , Sepsis/veterinaria , Ovinos , Enfermedades de las Ovejas/tratamiento farmacológico , Tolvaptán/uso terapéuticoRESUMEN
For an endocrinologist, nephrogenic diabetes insipidus (NDI) is an end-organ disease, that is the antidiuretic hormone, arginine-vasopressin (AVP) is normally produced but not recognized by the kidney with an inability to concentrate urine despite elevated plasma concentrations of AVP. Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. For a geneticist, hereditary NDI is a rare disease with a prevalence of five per million males secondary to loss of function of the vasopressin V2 receptor, an X-linked gene, or loss of function of the water channel AQP2. These are small genes, easily sequenced, with a number of both recurrent and private mutations described as disease causing. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter's syndrome and cystinosis. MAGED2 mutations are responsible for a transient form of Bartter's syndrome with severe polyhydramnios. The purpose of this review is to describe classical phenotype findings that will help physicians to identify early, before dehydration episodes with hypernatremia, patients with familial NDI. A number of patients are still diagnosed late with repeated dehydration episodes and large dilations of the urinary tract leading to a flow obstructive nephropathy with progressive deterioration of glomerular function. Families with ancestral X-linked AVPR2 mutations could be reconstructed and all female heterozygote patients identified with subsequent perinatal genetic testing to recognize affected males within 2 weeks of birth. Prevention of dehydration episodes is of critical importance in early life and beyond and decreasing solute intake will diminish total urine output.
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Diabetes Insípida Nefrogénica/genética , Diabetes Insípida Nefrogénica/fisiopatología , Deshidratación/prevención & control , Diabetes Insípida Nefrogénica/terapia , Femenino , Tamización de Portadores Genéticos , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Pruebas Genéticas , Humanos , Hipernatremia , Recién Nacido , Glomérulos Renales/fisiopatología , Masculino , Mutación , Neurofisinas/sangre , Neurofisinas/fisiología , Concentración Osmolar , Embarazo , Diagnóstico Prenatal , Precursores de Proteínas/sangre , Precursores de Proteínas/fisiología , Receptores de Vasopresinas/genética , Receptores de Vasopresinas/fisiología , Vasopresinas/sangre , Vasopresinas/fisiologíaRESUMEN
BACKGROUND: Fibrosis is a major cause of loss of renal function in autosomal dominant polycystic kidney disease (ADPKD). In this study, we examined whether vasopressin type-2 receptor (V2R) activity in cystic epithelial cells can stimulate interstitial myofibroblasts and fibrosis in ADPKD kidneys. METHODS: We treated Pkd1 gene knockout (Pkd1KO) mice with dDAVP, a V2R agonist, for 3 days and evaluated the effect on myofibroblast deposition of extracellular matrix (ECM). We also analyzed the effects of conditioned media from primary cultures of human ADPKD cystic epithelial cells on myofibroblast activation. Because secretion of the profibrotic connective tissue growth factor (CCN2) increased significantly in dDAVP-treated Pkd1KO mouse kidneys, we examined its role in V2R-dependent fibrosis in ADPKD as well as that of yes-associated protein (YAP). RESULTS: V2R stimulation using dDAVP increased the renal interstitial myofibroblast population and ECM deposition. Similarly, conditioned media from human ADPKD cystic epithelial cells increased myofibroblast activation in vitro, suggesting a paracrine mechanism. Renal collecting duct-specific gene deletion of CCN2 significantly reduced cyst growth and myofibroblasts in Pkd1KO mouse kidneys. We found that YAP regulates CCN2, and YAP inhibition or gene deletion reduces renal fibrosis in Pkd1KO mouse kidneys. Importantly, YAP inactivation blocks the dDAVP-induced increase in myofibroblasts in Pkd1KO kidneys. Further in vitro studies showed that V2R regulates YAP by an ERK1/2-dependent mechanism in human ADPKD cystic epithelial cells. CONCLUSIONS: Our results demonstrate a novel mechanism by which cystic epithelial cells stimulate myofibroblasts in the pericystic microenvironment, leading to fibrosis in ADPKD. The V2R-YAP-CCN2 cell signaling pathway may present a potential therapeutic target for fibrosis in ADPKD.
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Proteínas de Ciclo Celular/fisiología , Factor de Crecimiento del Tejido Conjuntivo/fisiología , Riñón/patología , Miofibroblastos/fisiología , Riñón Poliquístico Autosómico Dominante/patología , Receptores de Vasopresinas/fisiología , Factores de Transcripción/fisiología , Animales , Desamino Arginina Vasopresina/farmacología , Matriz Extracelular/metabolismo , Fibrosis , Humanos , Ratones , Canales Catiónicos TRPP/fisiologíaRESUMEN
It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus- or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness. SIGNIFICANCE STATEMENT: Motion sickness affects many people traveling or working. In the present study our results showed that activation of the inner ear arginine vasopressin-vaspopressin receptor 2 (V2R)-aquaporin 2 signaling pathway was potentially involved in the development of motion sickness and that blocking V2R with mozavaptan, a V2R antagonist, was much more effective in reducing motion sickness in both rat and dog; therefore, we demonstrated a new mechanism to underlie motion sickness and a new candidate drug to reduce motion sickness.
Asunto(s)
Acuaporina 2/fisiología , Arginina Vasopresina/fisiología , Oído Interno/fisiología , Mareo por Movimiento/etiología , Receptores de Vasopresinas/fisiología , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Arginina Vasopresina/sangre , Benzazepinas/uso terapéutico , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Perros , Femenino , Masculino , Mareo por Movimiento/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiologíaRESUMEN
The neuropeptide arginine-vasopressin (AVP) has long been implicated in the regulation of social behavior and communication in diverse taxa, often through its actions on the V1a receptor (V1aR) and in a sex-different and steroid-dependent way. One source of sex-different brain AVP is the steroid-sensitive and sexually-dimorphic AVP neurons in the bed nucleus of the stria terminalis (BNST), a cell population that regulates social behavior in a sex-dependent manner. Potential targets of these BNST-AVP cells include the lateral habenula (LHb) and dorsal raphe (DR), areas known to be important for social behavior, yet few studies have investigated AVP action within these regions. Consequently, to test if V1aR action in the LHb or DR controls social behavior in a sexually dimorphic manner, we administered a highly-specific V1aR antagonist (or saline vehicle) in the LHb or DR of C57BL/6 male and female mice and tested its effects on social investigation, social communication (urine marking, ultrasonic vocalizations), and territorial aggression. V1aR antagonism of the LHb or DR decreased male urine marking toward unfamiliar males, but not toward unfamiliar females. Additionally, V1aR blockade of the LHb decreased ultrasonic vocalizations generated in the presence of females. Social investigation, locomotion and aggressive behavior were not altered by V1aR antagonism in either area. Blocking V1aR in the LHb or DR of females had no effect, indicating V1aR action in the DR and LHb drives sex differences in social communication.
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Comunicación , Núcleo Dorsal del Rafe/metabolismo , Habénula/metabolismo , Receptores de Vasopresinas/metabolismo , Conducta Social , Agresión/psicología , Animales , Arginina Vasopresina/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Receptores de Vasopresinas/fisiología , Núcleos Septales/metabolismo , Caracteres Sexuales , Vasopresinas/metabolismoRESUMEN
The NOD-like receptor protein 6 (NLRP6), an intracytoplasmic pattern recognition receptor in the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, influences the inflammation reaction. The role of NLRP6 in cerebral ischemia-reperfusion (I/R) injury in rats is unclear. We explore the function of NLRP6 in cerebral I/R injury. The investigators used a middle cerebral artery occlusion/reperfusion model (MCAO) to imitate ischemic injury. We found the peak expression of NLRP6 is in 48-h post-cerebral I/R injury. The expression of NLRP6 siRNA, as well as the expression of protein and mRNA, was detected by Western blot and qRT-PCR. The degree of IL-1ß and IL-18 was assessed by ELISA. After downregulating NLRP6, the expression of IL-1ß, IL-18, cleaved Caspase-1, and myeloperoxidase (MPO) were reduced. In HE and Nissl staining, pathological injury of brain tissue after downregulating NLRP6 was improved. NLRP6 siRNA decreased the NLRP6-ASC binding states by CO-IP. NRP6 has a pro-inflammatory effect in cerebral I/R injury, which may provide a new target for the treatment of cerebral I/R injury.
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Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Proteínas del Tejido Nervioso/fisiología , Receptores de Angiotensina/fisiología , Receptores de Vasopresinas/fisiología , Daño por Reperfusión/tratamiento farmacológico , Animales , Encéfalo/patología , Edema Encefálico/etiología , Edema Encefálico/prevención & control , Caspasa 1/metabolismo , Regulación de la Expresión Génica , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Inflamación , Interleucina-18/biosíntesis , Interleucina-1beta/biosíntesis , Masculino , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Interferente Pequeño/farmacología , ARN Interferente Pequeño/uso terapéutico , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores de Angiotensina/genética , Receptores de Vasopresinas/genética , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Método Simple CiegoRESUMEN
We aimed to investigate the role of arginine vasopressin (AVP) acting via the AVPV1 receptor in the autonomic cardiovascular responses to cold stress (CS). The study was conducted on adult male Sprague-Dawley rats with telemetry transmitters implanted to monitor heart rate (HR) and systolic blood pressure (SBP) throughout the experiment course. Rats were divided into four groups and were given, respectively, saline (control group), AVPV1 antagonist (V1880) alone, and V1880 following the removal of sympathetic outflows using hexamethonium (HEX+V1880) or guanethidine (GUAâ¯+â¯V1880). Rats were subjected to the CS stimuli (rapid immersion of the rat's limbs into 4⯰C water). Hemodynamic responses were recorded at baseline (PreCS), during CS, and after CS. Data analysis was performed using descriptive methods and spectral and cross-spectral analysis of blood pressure variability (BPV) and heart rate variability (HRV). Key results showed that at PreCS, inhibition of AVPV1 increases SBP and HR as well as very-low-frequency BPV and low-frequency BPV, which is attenuated by hexamethonium (effect on SBP only) and guanethidine (effect on both SBP and HR). HEX+V1880 results in increased high-frequency BPV and attenuated very-low-frequency HRV, while GUAâ¯+â¯V1880 results in increased high-frequency HRV and attenuated very-low-frequency HRV. During CS, we observed that SBP and HR, as well as very-low-frequency BPV and low-frequency BPV, were similar in the control group and the group with AVPV1 inhibition, while AVPV1 inhibition results in attenuated high-frequency BPV. Furthermore, we observed that changes produced by AVPV1 inhibition alone were affected differently by HEX+V1880 and GUAâ¯+â¯V1880, particularly in low-frequency HRV and very-low-frequency HRV. The results support that AVPV1 mediates autonomic cardiovascular responses at both baseline and CS stimuli conditions are associated with central mechanism engagement.
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Antagonistas de los Receptores de Hormonas Antidiuréticas/administración & dosificación , Sistema Nervioso Autónomo/fisiología , Hemodinámica/fisiología , Receptores de Vasopresinas/fisiología , Vasopresinas/fisiología , Animales , Sistema Nervioso Autónomo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Frío , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Masculino , Ratas Sprague-DawleyRESUMEN
Despite the high prevalence of aggression across a wide range of disorders, there is a severe lack of pharmacological treatments. Recent rodent studies have shown both centrally and peripherally administered oxytocin is effective in reducing territorial aggression, an adaptive form of aggression not reflective of pathological hyper-aggression. The current study tested i.p. administered oxytocin and vasopressin in a model of non-territorial hyper-aggression and examined the involvement of oxytocin receptors (OXTR) and vasopressin V1a receptors (V1aR). Male Swiss mice (Nâ¯=â¯160) were either socially isolated or group housed for 6 weeks prior to the commencement of testing; wherein two unfamiliar weight and condition matched mice were placed into a neutral context for 10â¯min. Socially isolated mice exhibited heightened aggression that was powerfully and dose-dependently inhibited by oxytocin and vasopressin and that was accompanied by dose-dependent increases in close social contact (huddling) and grooming. These anti-aggressive effects of oxytocin were blocked by pre-treatment with a higher dose of selective V1aR antagonist SR49059 (20â¯mg/kg i.p.), but not a lower dose of SR49059 (5â¯mg/kg i.p.) or selective OXTR antagonist L-368,899 (10â¯mg/kg i.p.). This is consistent with a growing number of studies linking a range of effects of exogenous oxytocin to actions at the V1a receptor. Interestingly, the highest dose of the OXTR agonist TGOT (10â¯mg/kg) also reduced isolation-induced aggression. These results suggest that while activation of the V1a receptor appears critical for the anti-aggressive effects of oxytocin, activation of the oxytocin receptor cannot be excluded. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity.'
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Agresión/fisiología , Oxitocina/fisiología , Aislamiento Social , Vasopresinas/fisiología , Agresión/efectos de los fármacos , Animales , Arginina Vasopresina/administración & dosificación , Arginina Vasopresina/fisiología , Masculino , Ratones , Oxitocina/administración & dosificación , Receptores de Oxitocina/fisiología , Receptores de Vasopresinas/fisiología , Vasopresinas/administración & dosificaciónRESUMEN
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Recovery from pain after surgery is faster after cesarean delivery than after other abdominal procedures. The authors hypothesized that recovery in rats after surgery could be reversed by antagonism of spinal oxytocin or vasopressin receptors, that there may be a sex difference, and that spinal oxytocin innervation could change after surgery. METHODS: Male and female rats underwent partial spinal nerve ligation surgery. Effects of nonselective and selective oxytocin and vasopressin 1A receptor antagonists on mechanical hypersensitivity during partial recovery were assessed (n = 8 to 14/group). Oxytocin immunoreactivity in the dorsal horn of the spinal cord (n = 7 to 8/group) and messenger RNA (mRNA) expression for oxytocin-binding receptors in dorsal root ganglia and spinal cord (n = 8/group) were measured. RESULTS: Intrathecal injection of oxytocin and vasopressin receptor antagonists were similarly effective at reducing withdrawal threshold (in all experiments from 22 [19, 26] median [first quartile, third quartile]) g to 8.3 [6.4, 12] g after injection) in both sexes, while having no or minimal effects in animals without surgery. Oxytocin fiber immunoreactivity was 3- to 5-fold greater in lumbar than other regions of the spinal cord and was increased more than 2-fold in lumbar cord ipsilateral to surgery. Injury was also associated with a 6.5-fold increase in oxytocin receptor and a 2-fold increase in vasopressin 1A receptor messenger RNA expression in the L4 dorsal root ganglion ipsilateral to surgery. CONCLUSIONS: These findings suggest that the capacity for oxytocin signaling in the spinal cord increases after surgery and that spinal oxytocin signaling plays ongoing roles in both sexes in recovery from mechanical hypersensitivity after surgery with known nerve injury.
Asunto(s)
Receptores de Oxitocina/fisiología , Receptores de Vasopresinas/fisiología , Recuperación de la Función/fisiología , Transducción de Señal/fisiología , Nervios Espinales/lesiones , Nervios Espinales/cirugía , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Femenino , Hiperalgesia/etiología , Hiperalgesia/prevención & control , Inyecciones Espinales , Ligadura , Masculino , Oxitocina/antagonistas & inhibidores , Oxitocina/fisiología , Dolor Postoperatorio/etiología , Dolor Postoperatorio/prevención & control , Ratas , Ratas Sprague-Dawley , Receptores de Oxitocina/antagonistas & inhibidores , Recuperación de la Función/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Nervios Espinales/efectos de los fármacosRESUMEN
BACKGROUND: Diabetic nephropathy has become the most common cause of chronic kidney disease (CKD). Despite the progress accomplished in therapy, the prevalence of renal disorders remains high. Some modifiable factors driving the increase in incidence of CKD, in diabetes and other settings, might have been overlooked. Consistent evidence supports a role for vasopressin, hydration state, and urine concentration in kidney health. SUMMARY: Plasma vasopressin is elevated in diabetes, even if metabolic control is good. Several epidemiological studies have pointed to a positive association between markers of vasopressin secretion (24-h fluid intake, urine volume, plasma copeptin concentration) and renal function decline in both the community and populations at high risk of CKD, namely, diabetic patients. Research involving animal models also supports a critical causal role of the V2 receptor antidiuretic effects of vasopressin in the early signs of kidney disease associated with type 1 or type 2 diabetes. Key Messages: Data supporting the detrimental effects of chronic vasopressin action on the kidney is consistent in animal models and human observational studies. Since vasopressin secretion can be modulated by water intake, and its actions by selective receptor antagonists, the vasopressin-hydration system could be a potential therapeutic target for the prevention and treatment of diabetic nephropathy. Intervention studies are needed to examine the relevance of lifestyle or pharmacological interventions.
Asunto(s)
Nefropatías Diabéticas/fisiopatología , Receptores de Vasopresinas/fisiología , Vasopresinas/fisiología , Animales , Diabetes Mellitus Tipo 2/complicaciones , Modelos Animales de Enfermedad , Ingestión de Líquidos , Glicopéptidos/sangre , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Polycystic kidney disease (PKD) is a group of monogenetic conditions characterised by the progressive accumulation of multiple renal cysts and hypertension. One of the earliest features of PKD is a reduction in urinary concentrating capacity that impairs extracellular fluid conservation. Urinary concentrating impairment predisposes PKD patients to periods of hypohydration when fluid loss is not adequately compensated by fluid intake. The hypohydrated state provides a blood hyperosmotic stimulus for vasopressin release to minimise further water loss. However, over-activation of renal V2 receptors contributes to cyst expansion. Although suppressing vasopressin release with high water intake has been shown to impair disease progression in rodent models, whether this approach is efficacious in patients remains uncertain. The neural osmoregulatory pathway that controls vasopressin secretion also exerts a stimulatory action on vasomotor sympathetic activity and blood pressure during dehydration. Recurrent dehydration leads to a worsening of hypertension in rodents and cross-sectional data suggests that reduced urinary concentrating ability may contribute to hypertension development in the clinical PKD population. Experimental studies are required to evaluate this hypothesis and to determine the underlying mechanism.
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Hipertensión/fisiopatología , Osmorregulación , Enfermedades Renales Poliquísticas/fisiopatología , Animales , Progresión de la Enfermedad , Ingestión de Líquidos , Humanos , Hipertensión/complicaciones , Enfermedades Renales Poliquísticas/complicaciones , Receptores de Vasopresinas/fisiología , Orina/química , Vasopresinas/fisiologíaRESUMEN
Pharmacological chaperones recently opened new possibilities in G protein-coupled receptor drug discovery. Even more interestingly, some unique ligands combine pharmacological chaperoning and biased agonism properties, boosting their therapeutic interest in many human diseases resulting from G protein-coupled receptor mutation and misfolding. These compounds displaying dual characteristics would constitute a perfect treatment for congenital Nephrogenic Diabetes Insipidus, a typical conformational disease. This X-linked genetic pathology is mostly associated with inactivating mutations of the renal arginine-vasopressin V2 receptor leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of many V2 receptor mutants. In addition, different classes of specific ligands such as antagonists, agonists as well as biased agonists of the V2 receptor have proven their usefulness in rescuing mutant receptor function. This is particularly relevant for small-molecule biased agonists which only trigger Gs protein activation and cyclic adenosine monophosphate production, the V2-induced signaling pathway responsible for water reabsorption. In parallel, high-throughput screening assays based on receptor trafficking rescue approaches have been developed to discover novel V2 pharmacological chaperone molecules from different chemical libraries. These new hit compounds, which still need to be pharmacologically characterized and functionally tested in vivo, represent promising candidates for the treatment of congenital Nephrogenic Diabetes Insipidus.
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Diabetes Insípida Nefrogénica/tratamiento farmacológico , Chaperonas Moleculares/farmacología , Deficiencias en la Proteostasis/tratamiento farmacológico , Receptores de Vasopresinas/fisiología , Descubrimiento de Drogas , Humanos , Ligandos , Chaperonas Moleculares/uso terapéutico , Mutación , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/fisiología , Receptores de Vasopresinas/agonistas , Receptores de Vasopresinas/químicaRESUMEN
Almost all organisms on Earth have an internal biological clock, known as the circadian clock. This clock system drives robust oscillations in metabolism, physiology, and behavior, such as hormone secretions, blood pressure, and sleep/wake cycles, with a period of approximately 24h. In mammals, circadian rhythms are generated by a timing system comprised of a master pacemaker located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, which orchestrates the clocks in the peripheral tissues. Jet lag, caused by an abrupt change of environmental light-dark cycles, induces a temporal misalignment of the output signal from SCN. We revealed that arginine vasopressin/V1 receptor signaling in the SCN plays a critical role in the resilience of the circadian clock to jet lag. I here discuss a model of SCN neuronal system under a jet lag condition.
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Arginina Vasopresina/fisiología , Relojes Circadianos , Ritmo Circadiano , Síndrome Jet Lag/fisiopatología , Receptores de Vasopresinas/fisiología , Núcleo Supraquiasmático/fisiología , Animales , Humanos , Locomoción , Modelos Neurológicos , Neuronas/fisiología , Fotoperiodo , Transducción de Señal , Núcleo Supraquiasmático/fisiopatologíaRESUMEN
RATIONALE: Cannabis is a widely used illicit substance. ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, is known to cause catalepsy in rodents. Recent studies have shown that vasopressin V1a and V1b receptors are widely distributed in the central nervous system and are capable of influencing a wide variety of brain functions such as social behavior, emotionality, and learning and memory. OBJECTIVES: The present study was designed to examine the possible involvement of V1a and V1b receptors in THC-induced catalepsy-like immobilization. METHODS: The induction of catalepsy following treatment with THC (10 mg/kg, i.p.) or haloperidol (1 mg/kg, i.p.) was evaluated in wild-type (WT), V1a receptor knockout (V1aRKO), and V1b receptor knockout (V1bRKO) mice. The effect of treatment with the selective 5-hydroxytryptamine1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.) on THC-induced catalepsy was also evaluated in V1aRKO mice. Moreover, the effects of the V1a receptor antagonist VMAX-357 and the V1b receptor antagonist ORG-52186 on THC-induced catalepsy were evaluated in ddY mice. RESULTS: THC and haloperidol markedly caused catalepsy in V1bRKO mice as well as in WT mice. However, V1aRKO mice exhibited a reduction in catalepsy induced by THC but not by haloperidol. WAY100635 dramatically enhanced THC-induced catalepsy in V1aRKO mice. Although VMAX-357 (10 mg/kg, p.o.) but not ORG-52186 significantly attenuated THC-induced catalepsy, it had no significant effect on the enhancement of THC-induced catalepsy by WAY100635 in ddY mice. CONCLUSIONS: These findings suggest that V1a receptor regulates THC-induced catalepsy-like immobilization.