RESUMEN
At the end of 2019, there was an outbreak of a new Coronavirus 2019 (COVID-19 disease). Studies suggest that SARS-CoV-2 can cause infection in the central nervous system (CNS) and trigger neurological symptoms that include headache, nausea and vomiting, mental confusion and loss of smell or taste. These findings reveal that Coronaviruses have neurological tropism and neuroinvasive capacity. The spread of SARS-CoV-2 in the brain tissue possibly occurs through the systemic circulation as reported in patients affected by SARS-CoV. Evidence highlights similarity between the SARS-CoV genome and SARS-CoV-2 and that both interact with the angiotensin-converting enzyme type 2 (ACE2) located in the brain tissue of infected patients. Hence, the presence of ACE2 is likely in the CNS to mediate the entry of the SARS-CoV-2 virus into neural tissue. Our hypothesis suggests that SARS-CoV-2 can cause encephalitis through the production of inflammatory mediators and activation of immune system cells resulting from the interaction of the ACE2 receptor with the viral Spike protein that causes an increase in angiotensin II. This mechanism has the ability to activate immune system cells by exacerbating stimuli at the angiotensin 2 receptor (AT2R). Thus, it leads to a status of brain injury preceded by vascular damage and destruction of the blood-brain barrier, making it responsible for the installation of acute inflammation.
Asunto(s)
Barrera Hematoencefálica/fisiopatología , COVID-19/complicaciones , Encefalitis Viral/etiología , Receptor de Angiotensina Tipo 2/fisiología , Enzima Convertidora de Angiotensina 2/fisiología , Barrera Hematoencefálica/virología , COVID-19/fisiopatología , COVID-19/virología , Encefalitis Viral/fisiopatología , Encefalitis Viral/virología , Interacciones Microbiota-Huesped/fisiología , Humanos , Modelos Neurológicos , Pandemias , SARS-CoV-2/patogenicidadRESUMEN
Neuropathic and inflammatory pain results from cellular and molecular changes in dorsal root ganglion (DRG) neurons. The type-2 receptor for Angiotensin-II (AT2R) has been involved in this type of pain. However, the underlying mechanisms are poorly understood, including the role of the type-1 receptor for Angiotensin-II (AT1R). Here, we used a combination of immunohistochemistry and immunocytochemistry, RT-PCR and in vitro and in vivo pharmacological manipulation to examine how cutaneous inflammation affected the expression of AT1R and AT2R in subpopulations of rat DRG neurons and studied their impact on inflammation-induced neuritogenesis. We demonstrated that AT2R-neurons express C- or A-neuron markers, primarily IB4, trkA, and substance-P. AT1R expression was highest in small neurons and co-localized significantly with AT2R. In vitro, an inflammatory soup caused significant elevation of AT2R mRNA, whereas AT1R mRNA levels remained unchanged. In vivo, we found a unique pattern of change in the expression of AT1R and AT2R after cutaneous inflammation. AT2R increased in small neurons at 1 day and in medium size neurons at 4 days. Interestingly, cutaneous inflammation increased AT1R levels only in large neurons at 4 days. We found that in vitro and in vivo AT1R and AT2R acted co-operatively to regulate DRG neurite outgrowth. In vivo, AT2R inhibition impacted more on non-peptidergic C-neurons neuritogenesis, whereas AT1R blockade affected primarily peptidergic nerve terminals. Thus, cutaneous-induced inflammation regulated AT1R and AT2R expression and function in different DRG neuronal subpopulations at different times. These findings must be considered when targeting AT1R and AT2R to treat chronic inflammatory pain. Cover Image for this issue: doi: 10.1111/jnc.14737.
Asunto(s)
Dermatitis/fisiopatología , Receptor de Angiotensina Tipo 1/fisiología , Receptor de Angiotensina Tipo 2/fisiología , Células Receptoras Sensoriales/fisiología , Animales , Células Cultivadas , Dermatitis/etiología , Femenino , Adyuvante de Freund/administración & dosificación , Ganglios Espinales/citología , Neuritas/fisiología , Dolor/fisiopatología , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/análisis , Receptor de Angiotensina Tipo 2/análisis , Células Receptoras Sensoriales/química , Piel/inervaciónRESUMEN
The renin-angiotensin system modulates insulin action. Pharmacological stimulation of angiotensin type 2 receptor (AT2R) was shown to have beneficial metabolic effects in various animal models of insulin resistance and type 2 diabetes and also to increase insulin sensitivity in wild type mice. In this study we further explored the role of the AT2R on insulin action and glucose homeostasis by investigating the glycemic profile and in vivo insulin signaling status in insulin-target tissues from both male and female AT2R knockout (KO) mice. When compared to the respective wild-type (WT) group, glycemia and insulinemia was unaltered in AT2RKO mice regardless of sex. However, female AT2RKO mice displayed decreased insulin sensitivity compared to their WT littermates. This was accompanied by a compensatory increase in adiponectinemia and with a specific attenuation of the activity of main insulin signaling components (insulin receptor, Akt and ERK1/2) in adipose tissue with no apparent alterations in insulin signaling in either liver or skeletal muscle. These parameters remained unaltered in male AT2RKO mice as compared to male WT mice. Present data show that the AT2R has a physiological role in the conservation of insulin action in female but not in male mice. Our results suggest a sexual dimorphism in the control of insulin action and glucose homeostasis by the AT2R and reinforce the notion that pharmacological modulation of the balance between the AT1R and AT2R receptor could be important for treatment of metabolic syndrome and type 2 diabetes.
Asunto(s)
Adiponectina/sangre , Biomarcadores/sangre , Glucemia/metabolismo , Resistencia a la Insulina , Insulina/sangre , Receptor de Angiotensina Tipo 2/fisiología , Caracteres Sexuales , Tejido Adiposo/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factores Sexuales , Transducción de SeñalRESUMEN
Obesity is the major risk factor for several cardiovascular and metabolic disorders. Previous studies reported that deletion of Angiotensin II type 2 receptor (AT2R) protects against metabolic dysfunctions induced by high fat (HF) diet. However, the role of AT2R in obesity-induced cardiac hypertrophy remains unclear. Male AT2R knockout (AT2RKO) and wild type (AT2RWT) mice were fed with control or HF diet for 10 weeks. HF diet increased cardiac expression of AT2R in obese mice. Deletion of AT2R did not affect body weight gain, glucose intolerance and fat mass gain induced by HF feeding. However, loss of AT2R prevented HF diet-induced hypercholesterolemia and cardiac remodeling. Mechanistically, we found that pharmacological inhibition or knockdown of AT2R prevented leptin-induced cardiomyocyte hypertrophy in vitro. Collectively, our results suggest that AT2R is involved in obesity-induced cardiac hypertrophy.
Asunto(s)
Cardiomegalia/etiología , Dieta Alta en Grasa/efectos adversos , Intolerancia a la Glucosa/etiología , Hipercolesterolemia/etiología , Resistencia a la Insulina , Obesidad/complicaciones , Receptor de Angiotensina Tipo 2/fisiología , Animales , Cardiomegalia/metabolismo , Cardiomegalia/patología , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patología , Leptina/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patologíaRESUMEN
The renin-angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effect, whereas the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. To further explore the role of the AT2R on insulin action and glucose homeostasis, in this study we administered C57Bl/6 mice with the synthetic agonist of the AT2R C21 for 12 weeks (1 mg/kg per day; ip). Vehicle-treated animals were used as control. Metabolic parameters, glucose, and insulin tolerance, in vivo insulin signaling in main insulin-target tissues as well as adipose tissue levels of adiponectin, and TNF-α were assessed. C21-treated animals displayed decreased glycemia together with unaltered insulinemia, increased insulin sensitivity, and increased glucose tolerance compared to nontreated controls. This was accompanied by a significant decrease in adipocytes size in epididymal adipose tissue and significant increases in both adiponectin and UCP-1 expression in this tissue. C21-treated mice showed an increase in both basal Akt and ERK1/2 phosphorylation levels in the liver, and increased insulin-stimulated Akt activation in adipose tissue. This positive modulation of insulin action induced by C21 appeared not to involve the insulin receptor. In C21-treated mice, adipose tissue and skeletal muscle became unresponsive to insulin in terms of ERK1/2 phosphorylation levels. Present data show that chronic pharmacological activation of AT2R with C21 increases insulin sensitivity in mice and indicate that the AT2R has a physiological role in the conservation of insulin action.
Asunto(s)
Resistencia a la Insulina/fisiología , Receptor de Angiotensina Tipo 2/agonistas , Sulfonamidas/farmacología , Tiofenos/farmacología , Adipocitos/efectos de los fármacos , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Tamaño de la Célula/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Esquema de Medicación , Evaluación Preclínica de Medicamentos/métodos , Prueba de Tolerancia a la Glucosa , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratones Endogámicos C57BL , Receptor de Angiotensina Tipo 2/fisiología , Transducción de Señal , Sulfonamidas/administración & dosificación , Tiofenos/administración & dosificación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The prelimbic cortex (PL) is an important structure in the neural pathway integrating stress responses. Brain angiotensin is involved in cardiovascular control and modulation of stress responses. Blockade of angiotensin receptors has been reported to reduce stress responses. Acute restraint stress (ARS) is a stress model, which evokes sustained blood pressure increase, tachycardia, and reduction in tail temperature. We therefore hypothesized that PL locally generated angiotensin and angiotensin receptors modulate stress autonomic responses. To test this hypothesis, we microinjected an angiotensin-converting enzyme (ACE) inhibitor or angiotensin antagonists into the PL, prior to ARS. Male Wistar rats were used; guide cannulas were bilaterally implanted in the PL for microinjection of vehicle or drugs. A polyethylene catheter was introduced into the femoral artery to record cardiovascular parameters. Tail temperature was measured using a thermal camera. ARS was started 10 min after PL treatment with drugs. Pretreatment with ACE inhibitor lisinopril (0.5 nmol/100 nL) reduced the pressor response, but did not affect ARS-evoked tachycardia. At a dose of 1 nmol/100 nL, it reduced both ARS pressor and tachycardic responses. Pretreatment with candesartan, AT1 receptor antagonist reduced ARS-evoked pressor response, but not tachycardia. Pretreatment with PD123177, AT2 receptor antagonist, reduced tachycardia, but did not affect ARS pressor response. No treatment affected ARS fall in tail temperature. Results suggest involvement of PL angiotensin in the mediation of ARS cardiovascular responses, with participation of both AT1 and AT2 receptors. In conclusion, results indicate that PL AT1-receptors modulate the ARS-evoked pressor response, while AT2-receptors modulate the tachycardic component of the autonomic response.
Asunto(s)
Presión Sanguínea/fisiología , Corteza Cerebral/metabolismo , Frecuencia Cardíaca/fisiología , Receptor de Angiotensina Tipo 1/fisiología , Receptor de Angiotensina Tipo 2/fisiología , Estrés Psicológico/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Lóbulo Límbico/efectos de los fármacos , Lóbulo Límbico/metabolismo , Masculino , Ratas , Ratas Wistar , Restricción Física/fisiología , Restricción Física/psicología , Estrés Psicológico/psicologíaRESUMEN
Insulin-like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9) have been proposed to be important mediators in cardioprotection. A large body of evidence indicates that insulin like growth factor-1 has pleotropic actions in the heart (i.e., contractility, metabolism, hypertrophy, autophagy, senescence and cell death) and, conversely, its deficiency is associated with impaired cardiac function. Recently, we reported that insulin like growth factor-1 receptor is also located in plasma membrane invaginations with perinuclear localization, highlighting the role of nuclear Ca(2+) signaling in the heart. In parallel, angiotensin-(1-7) and angiotensin (1-9) acting through Mas receptor and angiotensin type 2 receptor have emerged as a novel anti-hypertensive molecules promoting vasodilatation and preventing heart hypertrophy. In this review we discuss the scientific evidence available regarding insulin-like growth factor-1, angiotensin-(1-7) and angiotensin-(1-9) in cardioprotection and its potential application as novel therapeutic targets for treating cardiac diseases.
Asunto(s)
Angiotensina I/fisiología , Fármacos Cardiovasculares/farmacología , Factor I del Crecimiento Similar a la Insulina/fisiología , Fragmentos de Péptidos/fisiología , Animales , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/fisiopatología , Fenómenos Fisiológicos Cardiovasculares , Sistema Cardiovascular/efectos de los fármacos , Humanos , Modelos Cardiovasculares , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/fisiología , Receptor de Angiotensina Tipo 2/fisiología , Receptor IGF Tipo 1/fisiología , Receptores Acoplados a Proteínas G/fisiología , Sistema Renina-Angiotensina/fisiología , Transducción de SeñalRESUMEN
The physiological roles of ANG-(3-4) (Val-Tyr), a potent ANG II-derived peptide, remain largely unknown. The present study 1)investigates whether ANG-(3-4) modulates ouabain-resistant Na(+)-ATPase resident in proximal tubule cells and 2) verifies whether its possible action on pumping activity, considered the fine tuner of Na(+) reabsorption in this nephron segment, depends on blood pressure. ANG-(3-4) inhibited Na(+)-ATPase activity in membranes of spontaneously hypertensive rats (SHR) at nanomolar concentrations, with no effect in Wistar-Kyoto (WKY) rats or on Na(+)-K(+)-ATPase. PD123319 (10(-7) M) and PKA(5-24) (10(-6) M), an AT2 receptor (AT2R) antagonist and a specific PKA inhibitor, respectively, abrogated this inhibition, indicating that AT2R and PKA are central in this pathway. Despite the lack of effect of ANG-(3-4) when assayed alone in WKY rats, the peptide (10(-8) M) completely blocked stimulation of Na(+)-ATPase induced by 10(-10) M ANG II in normotensive rats through a mechanism that also involves AT2R and PKA. Tubular membranes from WKY rats had higher levels of AT2R/AT1R heterodimers, which remain associated in 10(-10) M ANG II and dissociate to a very low dimerization state upon addition of 10(-8) M ANG-(3-4). This lower level of heterodimers was that found in SHR, and heterodimers did not dissociate when the same concentration of ANG-(3-4) was present. Oral administration of ANG-(3-4) (50 mg/kg body mass) increased urinary Na(+) concentration and urinary Na(+) excretion with a simultaneous decrease in systolic arterial pressure in SHR, but not in WKY rats. Thus the influence of ANG-(3-4) on Na(+) transport and its hypotensive action depend on receptor association and on blood pressure.
Asunto(s)
Adenosina Trifosfatasas/antagonistas & inhibidores , Proteínas de Transporte de Catión/antagonistas & inhibidores , Dipéptidos/farmacología , ATPasa Intercambiadora de Sodio-Potasio/antagonistas & inhibidores , Bloqueadores del Receptor Tipo 2 de Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Hipertensión/fisiopatología , Imidazoles/farmacología , Túbulos Renales Proximales/efectos de los fármacos , Ouabaína/farmacología , Piridinas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptor de Angiotensina Tipo 2/efectos de los fármacos , Receptor de Angiotensina Tipo 2/fisiología , Sodio/orina , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
In this study we investigated the effects of genetic deletion of the Angiotensin-(1-7) receptor Mas or the Angiotensin II receptor AT(2) on the expression of specific extracellular matrix (ECM) proteins in atria, right ventricles and atrioventricular (AV) valves of neonatal and adult mice. Quantification of collagen types I, III and VI and fibronectin was performed using immunofluorescence-labeling and confocal microscopy. Picrosirius red staining was used for the histological assessment of the overall collagen distribution pattern. ECM proteins, metalloproteinases (MMP), ERK1/2 and p38 levels were quantified by western blot analysis. Gelatin zymography was used to evaluate the activity of MMP-2 and MMP-9. We observed that the relative levels of collagen types I and III and fibronectin are significantly higher in both the right ventricle and AV valves of neonatal Mas(-/-) mouse hearts (e.g., collagen type I: 85.28±6.66 vs 43.50±4.41 arbitrary units in the right ventricles of Mas(+/+) mice). Conversely, the level of collagen type VI was lower in the right ventricle and AV valves of Mas(-/-) mice. Adult Mas(-/-) mouse hearts presented similar patterns as observed in neonates. No significant differences in ECM protein level were detected in atria. Likewise, no changes in ECM levels were observed in AT(2) knockout mouse hearts. Although deletion of Mas induced a significant reduction in the level of the active form of MMP-2 in neonate hearts and a reduction of both MMP-2 and MMP-9 in adult Mas(-/-) mice, no significant differences were observed in MMP enzymatic activities when compared to controls. The levels of the active, phosphorylated forms of ERK1/2 and p38 were higher in hearts of both neonatal and adult Mas(-/-) mice. These observations suggest that Mas is involved in the selective expression of specific ECM proteins within both the ventricular myocardium and AV valves. The changes in the ECM profile may alter the connective tissue framework and contribute to the decreased cardiac performance observed in Mas(-/-) mice.
Asunto(s)
Proteínas de la Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Corazón/fisiología , Proteínas Proto-Oncogénicas/fisiología , Receptor de Angiotensina Tipo 2/fisiología , Receptores Acoplados a Proteínas G/fisiología , Animales , Animales Recién Nacidos , Western Blotting , Ecocardiografía , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proto-Oncogenes MasRESUMEN
The functional role of AT(2) receptors is unclear and it activates unconventional signaling pathways, which in general do not involve a classical activation of a G-protein. In the present study, we aimed to investigate the transduction mechanism of AT(2) Ang II receptors in PND15 rat hindbrain membrane preparations, which represents a physiological developmental condition. To determine whether Ang II AT(2) receptors induced association to SHP-1 in rat hindbrain, co-immunoprecipitation assays were performed. Stimulation of Ang II AT(2) receptors induced both a transient tyr-phosphorylation and activation of SHP-1. The possible participation of c-Src in Ang II-mediated SHP-1 activation, we demonstrated by recruitment of c-Src in immunocomplexes obtained with anti AT(2) or anti-SHP-1 antibodies. The association of SHP-1 to c-Src was inhibited by PD123319 and the c-Src inhibitor PP2. Similarly, SHP-1 activity determined in AT(2)-immunocomplexes was inhibited by PD123319 and the c-Src inhibitor PP2. Following stimulation with Ang II, AT(2) receptors recruit c-Src, which was responsible for SHP-1 tyr-phosphorylation and activation. Since AT(2) receptors are involved in neuron migration, we tested the presence of FAK in immunocomplexes. Surprisingly, AT(2)-immunocomplexes contained mainly the 85kDa fragment of FAK. Besides, p125FAK associated to SHP-1. In summary, we demonstrated the presence of an active signal transduction mechanism in PND15 rat hindbrain, a developmental stage critical for cerebellar development. In this model, we showed a complex containing AT(2)/SHP-1/c-Src/p85FAK, suggesting a potential role of Ang II AT(2) receptors in cerebellar development and neuronal differentiation.
Asunto(s)
Angiotensina II/fisiología , Quinasa 1 de Adhesión Focal/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Receptor de Angiotensina Tipo 2/fisiología , Rombencéfalo/citología , Rombencéfalo/metabolismo , Animales , Animales Recién Nacidos , Proteína Tirosina Quinasa CSK , Movimiento Celular/fisiología , Cerebelo/citología , Cerebelo/enzimología , Cerebelo/metabolismo , Quinasa 1 de Adhesión Focal/química , Sustancias Macromoleculares/metabolismo , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Fosforilación/fisiología , Transporte de Proteínas/fisiología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 2/agonistas , Rombencéfalo/enzimología , Transducción de Señal/fisiología , Familia-src QuinasasRESUMEN
The role of angiotensin II (Ang II) in promoting cardiac hypertrophy is well known; however, its role in a spontaneous model of hypertrophy in mice lacking the protein caveolin-1 (Cav-1 KO) has not been explored. In this study, WT and Cav-1 KO mice were treated with angiotensin receptor blocker (ARB), telmisartan (Telm), and cardiac function was assessed by echocardiography. Treatment of Cav-1 KO mice with Telm significantly improved cardiac function compared with age-matched vehicle-treated Cav-1 KO mice, whereas Telm did not affect cardiac function in WT mice. Both left ventricular (LV) weight to body weight ratios and LV to tibial length ratios were also reverted by Telm in Cav-1 KO but not in WT mice. LV hypertrophy was associated with increased expression of natriuretic peptides A and B, ß-myosin heavy chain and TGF-ß, and Telm treatment normalized the expression of these genes. Telm reduced the expression of collagen genes (Col1A and Col3A) and associated perivascular fibrosis in intramyocardial vessels in Cav-1 KO mice. In conclusion, Telm treatment reduces indexes of cardiac hypertrophy in this unique genetic model of spontaneous LV hypertrophy.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Bencimidazoles/uso terapéutico , Benzoatos/uso terapéutico , Caveolina 1/deficiencia , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Angiotensina II/sangre , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Angiotensina Tipo 2/fisiología , TelmisartánRESUMEN
Although most of effects of Angiotensin II (Ang II) related to cardiac remodelling can be attributed to type 1 Ang II receptor (AT(1)R), the type 2 receptor (AT(2)R) has been shown to be involved in the development of some cardiac hypertrophy models. In the present study, we investigated whether the thyroid hormone (TH) action leading to cardiac hypertrophy is also mediated by increased Ang II levels or by change on AT(1)R and AT(2)R expression, which could contribute to this effect. In addition, we also evaluated the possible contribution of AT(2)R in the activation of Akt and in the development of TH-induced cardiac hypertrophy. To address these questions, Wistar rats were treated with thyroxine (T(4), 0.1 mg/kg BW/day, i.p.), with or without AT(2)R blocker (PD123319), for 14 days. Cardiac hypertrophy was identified based on heart/body weight ratio and confirmed by analysis of atrial natriuretic factor mRNA expression. Cardiomyocyte cultures were used to exclude the influence of TH-related hemodynamic effects. Our results demonstrate that the cardiac Ang II levels were significantly increased (80%, P < 0.001) as well as the AT(2)R expression (50%, P < 0.05) in TH-induced cardiac hypertrophy. The critical involvement of AT(2)R to the development of this cardiac hypertrophy in vivo was evidenced after administration of AT(2) blocker, which was able to prevent in 40% (P < 0.01) the cardiac mass gain and the Akt activation induced by TH. The role of AT(2)R to the TH-induced cardiomyocyte hypertrophy was also confirmed after using PD123319 in the in vitro studies. These findings improve understanding of the cardiac hypertrophy observed in hyperthyroidism and provide new insights into the generation of future therapeutic strategies.
Asunto(s)
Bloqueadores del Receptor Tipo 2 de Angiotensina II , Cardiopatías/inducido químicamente , Cardiopatías/prevención & control , Miocardio/patología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Tiroxina/efectos adversos , Angiotensina II/fisiología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Cardiopatías/fisiopatología , Hipertiroidismo/fisiopatología , Hipertrofia/inducido químicamente , Hipertrofia/fisiopatología , Hipertrofia/prevención & control , Imidazoles/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Proteínas Proto-Oncogénicas c-akt/fisiología , Piridinas/farmacología , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/fisiología , Receptor de Angiotensina Tipo 2/fisiología , Transducción de Señal/fisiologíaRESUMEN
IMPORTANCE OF THE FIELD: Severe sepsis is characterized by relative hypotension associated with a high cardiac output, peripheral vasodilation, and organ dysfunction. The renin-angiotensin-aldosterone system (RAAS) is primarily activated to increase blood pressure, but recently potential pro-inflammatory effects of angiotensin II have attracted interest because of the reported association between angiotensin II levels and organ failure and mortality in sepsis. RAAS antagonists could represent a new therapeutic option in this setting. AREAS COVERED IN THIS REVIEW: The role of RAAS activation in severe sepsis and septic shock, and the potential benefits (and risks) of using RAAS antagonists. WHAT THE READER WILL GAIN: Insight into RAAS function in severe sepsis and the potential for RAAS inhibitors to be used as an adjunctive therapy in patients with severe sepsis, with discussion of promising results from animal models of sepsis. TAKE HOME MESSAGE: Use of RAAS antagonists is an emerging therapeutic option in severe sepsis because these agents may reduce endothelial damage, organ failure, and mortality. However, timing of administration of RAAS antagonists is important because reduced RAAS function may contribute to refractive hypotension later on in septic shock and benefits of RAAS antagonists seem to be restricted to the early phases of sepsis.
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Sistema Renina-Angiotensina/efectos de los fármacos , Sepsis/tratamiento farmacológico , Angiotensina II/fisiología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Humanos , Microcirculación/efectos de los fármacos , Microcirculación/fisiología , Receptor de Angiotensina Tipo 2/metabolismo , Receptor de Angiotensina Tipo 2/fisiología , Sistema Renina-Angiotensina/fisiología , Sepsis/fisiopatologíaRESUMEN
We will address, in this review, the role of angiotensin II (AngII) on follicular development and ovulation. Over the last few years, our research group has focused on studying the contribution of renin-angiotensin system in antral follicle development and ovulation and a new concept of local regulation has been established using cattle as a model. We previously demonstrated that AT1 and AT2 receptors are expressed in both granulosa and theca cells. The abundance of AT2 mRNA in granulosa cells was higher in healthy compared with atretic follicles, whereas both receptors in theca cells and AT1 in granulosa cells did not change. Granulosa cells cultured with hormones that stimulate estradiol secretion increased AT2 mRNA and protein levels, whereas fibroblast growth factors (FGF-7 and 10) inhibited estradiol secretion and AT2 protein levels. We also found that the concentration of AngII increases in dominant follicle at expected time for follicular deviation. Transvaginal ultrasound has been used for intrafollicular injection to understand the regulation of follicular wave and ovulation. With this in vivo model, we have demonstrated that AngII-receptor blocker inhibits follicular growth and decreases estradiol concentration in follicular fluid and downregulates mRNA expression of genes involved in follicular development. Moreover, intrafollicular injection of AngII or AT2-specific agonist prevented the expected atresia of the second largest follicle, which continued to grow at a rate similar to the dominant follicle for 24 h. These findings have provided evidence that AngII plays an important role in follicle development. In regarding to ovulation, we demonstrated that AngII antagonists block ovulation in cattle when intrafollicularly injected at 0 and 6 h after applying GnRH agonist. Ovulation was also inhibited by AT2- but not by AT1-AngII receptor antagonist. Furthermore, AngII stimulates an enhancement in mRNA abundance of genes involved in ovulation. In addition, AngII stimulates genes involved in extracellular remodeling and follicular wall rupture. In conclusion, our data from in vitro and in vivo studies have demonstrated that AngII plays a pivotal role in the antral follicle development and early mechanism of ovulation via the AT2 receptor subtype in cattle.(AU)
Asunto(s)
Animales , Femenino , Bovinos , Sistema Renina-Angiotensina , Receptor de Angiotensina Tipo 2/fisiología , Angiotensina II/efectos adversos , Fase Folicular , Ovulación , Folículo Ovárico/fisiología , Estradiol/efectos adversos , Ultrasonografía/métodosRESUMEN
BACKGROUND: The Angiotensin II (Ang II) type 1 (AT(1)R) and type 2 (AT(2)R) receptors are increased in the heart following myocardial infarction and dilated cardiomyopathy, yet their contribution at a cellular level to compensation and/or failure remains controversial. METHODS: We ectopically expressed AT(1)R and AT(2)R in cultured adult rat cardiomyocytes and cardiac fibroblasts to investigate Ang II-mediated cardiomyocyte hypertrophy and cardiac cell viability. RESULTS: In adult rat cardiomyocytes, Ang II did not induce hypertrophy via the AT(1)R, and no effect of Ang II on cell viability was observed following AT(1)R or AT(2)R expression. In adult rat cardiac fibroblasts, Ang II stimulated cell death by apoptosis via the AT(1)R (but not the AT(2)R), which required the presence of extracellular calcium, and induced a rapid dissipation of mitochondrial membrane potential, which was significant from 8 h. CONCLUSIONS: We conclude that Ang II/AT(1)R triggers apoptosis in adult rat cardiac fibroblasts, which is dependent on Ca2+ influx.
Asunto(s)
Angiotensina II/farmacología , Miocitos Cardíacos/efectos de los fármacos , Receptor de Angiotensina Tipo 1/fisiología , Receptor de Angiotensina Tipo 2/fisiología , 1-Sarcosina-8-Isoleucina Angiotensina II/metabolismo , Adenoviridae/genética , Animales , Apoptosis/efectos de los fármacos , Calcio/fisiología , Muerte Celular/efectos de los fármacos , Células Cultivadas , Masculino , Miocitos Cardíacos/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción GenéticaRESUMEN
In the present study, we evaluated the involvement of the rennin-angiotensin system (RAS) in the control of the blood pressure (BP), baroreceptor-mediated bradycardia and the reactivity of caudal ventrolateral medulla (CVLM) neurons to Ang II and to AT(2) receptor antagonist in sedentary or trained renovascular hypertensive rats. Physical activity did not significantly change the baseline mean arterial pressure (MAP), heart rate (HR) or the sensitivity of the baroreflex bradycardia in normotensive Sham rats. However, in 2K1C hypertensive rats, physical activity induced a significant fall in baseline MAP and HR and produced an improvement of the baroreflex function (bradycardic component). The microinjections of Ang II into the CVLM produced similar decreases in MAP in all groups, Sham and 2K1C, sedentary and trained rats. The hypotensive effect of Ang II at the CVLM was blocked by previous microinjection of the AT(2) receptors antagonist, PD123319, in all groups of rats. Unexpectedly, microinjection of PD123319 at the CVLM produced a depressor effect in 2K1C sedentary that was attenuated in 2K1C trained rats. No significant changes in MAP were observed after PD123319 in Sham rats, sedentary or trained. These data showed that low-intensity physical activity is effective in lowering blood pressure and restoring the sensitivity of the baroreflex bradycardia, however these cardiovascular effects are not accompanied by changes in the responsiveness to Ang II at CVLM in normotensive or hypertensive, 2K1C rats. In addition, the blood pressure changes observed after AT(2) blockade in 2K1C rats suggest that hypertension may trigger an imbalance of AT(1)/AT(2) receptors at the CVLM that may be restored, at least in part, by low-intensity physical activity.
Asunto(s)
Hipertensión Renovascular/fisiopatología , Bulbo Raquídeo/fisiopatología , Receptor de Angiotensina Tipo 2/fisiología , Angiotensina II/administración & dosificación , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 2 de Angiotensina II , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Bradicardia/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Imidazoles/administración & dosificación , Microinyecciones , Neuronas/fisiología , Condicionamiento Físico Animal , Piridinas/administración & dosificación , Ratas , Ratas Endogámicas SHR , Sistema Renina-Angiotensina , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
In this study, we tested the hypothesis that angiotensin-(1-7) [Ang-(1-7)] acting in the neurons of paraventricular hypothalamic nucleus (PVN) contributes to the maintenance of sympathetic activity and blood pressure. For this purpose, the effects of microinjection of the A-779, the receptor Mas antagonist, into the PVN on mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were evaluated. In rats anesthetized with urethane (1.2 to 1.4 g/kg IP), bilateral microinjections of A-779 (0.1 nmol) into the PVN resulted in a selective and significant decrease in RSNA (-26+/-6% versus -2+/-3% vehicle; saline 0.9%). The magnitude of the decrease in RSNA produced by A-779 was comparable to that observed after microinjection of muscimol (1 nmol; -26+/-4%), a powerful neuronal inhibitor. A higher dose of A-779 (1 nmol) caused a reduction in RSNA (-21+/-4%) that was comparable in magnitude to the reduction observed with the lower dose. When compared with vehicle solution, no significant changes in MAP or HR were observed with both doses of A-779 tested. A decrease in RSNA was also observed after microinjections into the PVN of the angiotensin II type 2 (AT2) receptor antagonist PD123319 (1 nmol; -18+/-4%). Microinjections of the AT1 antagonist losartan but not CV 11974 reduced MAP without changing RSNA. These results suggest that Ang-(1-7) Mas receptors and AT2 receptors in the PVN neurons play a role in mediating the tonic maintenance of RSNA.
Asunto(s)
Angiotensina I/fisiología , Riñón/inervación , Núcleo Hipotalámico Paraventricular/metabolismo , Fragmentos de Péptidos/fisiología , Sistema Nervioso Simpático/fisiología , Angiotensina I/antagonistas & inhibidores , Angiotensina II/administración & dosificación , Angiotensina II/análogos & derivados , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 2 de Angiotensina II , Antagonistas de Receptores de Angiotensina , Animales , Relación Dosis-Respuesta a Droga , Imidazoles/administración & dosificación , Imidazoles/farmacología , Microinyecciones , Muscimol/administración & dosificación , Muscimol/farmacología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Piridinas/administración & dosificación , Piridinas/farmacología , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 2/fisiología , Receptores de Angiotensina/fisiología , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
RATIONALE AND OBJECTIVES: Several studies suggest that the brain renin-angiotensin system is involved in memory consolidation. However, the participation of angiotensin II (AII) in this process is controversial. This is probably due to the fact that many of the studies carried out to elucidate this matter employed multitrial learning paradigms together with pretraining intracerebroventricular infusions, and therefore were unable to distinguish between consolidation and retrieval related events and lacked anatomical specificity. To circumvent this problem, we analyzed the role played in memory consolidation by AII using the hippocampal-dependent, one-trial, step-down inhibitory avoidance task (IA) in combination with stereotaxically localized intrahippocampal infusion of drugs. METHODS AND RESULTS: Rats bilaterally implanted with infusion cannulae into the CA1 region of the dorsal hippocampus (CA1) were trained in IA and tested for memory retention 24 h later. We found that when infused into CA1 immediately or 30 min after training but not later, AII produced a dose-dependent amnesic effect without altering locomotor activity, exploratory behavior or anxiety state. The amnesic effect of AII was not mimicked by angiotensin IV (AIV) and was totally blocked by the AII-type 2 receptor (AT2) antagonist, PD123319, but not by the AII-type 1 receptor (AT1) antagonist, losartan. Importantly, when infused alone, neither PD123319 nor losartan produced any effect on memory retention. CONCLUSIONS: Our data indicate that, when given into CA1, AII blocks memory formation through a mechanism involving activation of AT2 receptors; however, endogenous AII does not seem to participate in the consolidation of IA long-term memory.
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Angiotensina II/administración & dosificación , Memoria/efectos de los fármacos , Receptor de Angiotensina Tipo 2/agonistas , Receptor de Angiotensina Tipo 2/fisiología , Amnesia/inducido químicamente , Amnesia/metabolismo , Angiotensina II/toxicidad , Bloqueadores del Receptor Tipo 2 de Angiotensina II , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Relación Dosis-Respuesta a Droga , Imidazoles/farmacología , Inyecciones Intraventriculares , Masculino , Memoria/fisiología , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Piridinas/farmacología , Ratas , Ratas WistarRESUMEN
The specific arginine(8)-vasopressin (AVP) V(1) receptors antagonist (AAVP) was injected (20, 40 and 80 nmol) into the lateral septal area (LSA) to determine the effects of selective septal V(1) receptor on water and 3% sodium intake in rats. Was also observed the effects of losartan and CGP42112A (select ligands of the AT(1) and AT(2) ANG II receptors, respectively) injected into LSA prior AVP on the same appetites. Twenty-four hours before the experiments, the rats were deprived of water. The volume of drug solution injected was 0.5 microl. Water and sodium intake were measured at 0.25, 0.5, 1.0 and 2.0 h. Injection of AVP reduced the water and sodium ingestion vs. control (0.15 M saline). Pre-treatment with AAVP (40, 80 and 160 nmol) did not alter the decrease in the water ingestion induced by AVP, whereas AAVP abolished the action of AVP-induced sodium intake. Losartan (40, 80 and 160 nmol) did not alter the effect of AVP on water and sodium intake, whereas CGP42112A (20, 40 and 60 nmol) at the first 30 min increased water ingestion. Losartan and CGP42112A together increased the actions of AVP, showing more pronounced effects than when the two antagonists were injected alone. The results showed that AVP inhibited the appetites and these effects were increased by the AAVP. The involvement of angiotensinergic receptors in the effects of AVP is also suggested.
Asunto(s)
Arginina Vasopresina/análogos & derivados , Arginina Vasopresina/farmacología , Ingestión de Líquidos/fisiología , Receptores de Angiotensina/fisiología , Receptores de Vasopresinas/fisiología , Cloruro de Sodio Dietético/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Bloqueadores del Receptor Tipo 2 de Angiotensina II , Antagonistas de Receptores de Angiotensina , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Arginina Vasopresina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Histocitoquímica , Losartán/farmacología , Masculino , Oligopéptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/fisiología , Receptor de Angiotensina Tipo 2/fisiología , Tabique del Cerebro/efectos de los fármacos , Tabique del Cerebro/fisiología , Sodio/metabolismo , Cloruro de Sodio Dietético/metabolismo , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
1. The mechanisms involved in the vasodilator actions of angiotensin II (Ang II) have not yet been completely elucidated. We investigated the potential mechanisms that seem to be involved in the Ang II vasodilator effect using rat isolated mesenteric vascular bed (MVB). 2. Under basal conditions, Ang II does not affect the perfusion pressure of MVB. However, in vessels precontracted with norepinephrine, Ang II induces vasodilation followed by vasoconstriction. Vasoconstrictor, but not the vasodilation of Ang II, is inhibited by AT(1) antagonist (losartan). The vasodilator effect of Ang II was not inhibited by AT(2), angiotensin IV and angiotensin 1-7 receptor antagonists alone (PD 123319, divalinal, A 779, respectively). 3. The vasodilator effect of Ang II is significantly reduced by endothelial removal (deoxycholic acid), but not by indomethacin. Inhibition of NO-synthase by N(G)-nitro-l-arginine methyl ester (l-NAME) and guanylyl cyclase by 1H-[1,2,3] oxadiazolo [4,4-a] quinoxalin-1-one (ODQ) reduces the vasodilator effect of Ang II. This effect is also reduced by tetraethylammonium (TEA) or l-NAME, and a combination of l-NAME plus TEA increases the inhibitory effect of the antagonists alone. However, indomethacin does not change the residual vasodilator effect observed in vessels pretreated with l-NAME plus TEA. 4. In vessels precontracted with norepinephrine and depolarized with KCl 25 mm or treated with Ca(2+)-dependent K(+) channel blockers (charybdotoxin plus apamin), the effect of Ang II was significantly reduced. However, this effect is not affected by ATP and voltage-dependent K(+) channel blockers (glybenclamide and 4-aminopyridine). 5. Inhibition of kininase II with captopril significantly potentiates the vasodilator effect of bradykinin (BK) and Ang II in the rat MVB. The inhibitory effect of the B(2) receptor antagonist HOE 140 on the vasodilator effect of Ang II is further enhanced by PD 123319 and/or A 779. 6. The present findings suggest that BK plays an important role in the endothelium-dependent vasodilator effect of Ang II. Probably, the link between Ang II and BK release is modulated by receptors that bind PD 123319 and A 779.