ABSTRACT
Insulin vasorelaxant effect in metabolic syndrome has been shown on precontracted vessels. However, the insulin effects on basal vascular tone and its interrelationship with nitric oxide (NO) and K-channels are unknown. To test the effect of insulin on the basal vascular tone in isolated aortic rings from the cafeteria diet-induced hypertensive rats and to determine the role of NO and K-channels on this insulin effect. Male Wistar rats were randomized into two groups: one group fed with a cafeteria diet (CafR) and another fed with a standard chow diet (control rats: CR). Then, in isolated aortic rings, the insulin effect on the basal tone and the role of K-channels were evaluated. Also, the endothelial function, NO levels, and resting membrane potential were measured. CafR increased blood pressure (138 ± 6.2 mmHg; n = 9 vs. CR: 109 ± 1.4 mmHg; n = 9; p < 0.001) and vascular basal tone. Insulin 400 mU/ml reduced basal tone in aortic rings (-284 ± 47 mg; n = 9). This effect was unaffected by endothelium removal or NG-nitro-l-arginine methyl ester (L-NAME) treatment. Likewise, CafR showed low NO levels and a hyperpolarized resting membrane potential. Insulin decreased the resting membrane potential and the KCa and Kv channels blockers abolished this effect. In CafR, endothelial dysfunction is accompanied by an increased basal tone. Insulin reduced it by Kv and KCa channels dependent mechanisms, using an endothelium-independent pathway. These results highlight a novel insulin effect on basal tone of aortic rings from animals with metabolic syndrome and endothelial dysfunction, pathophysiological conditions associated with human hypertension.
Subject(s)
Hypertension , Metabolic Syndrome , Animals , Diet , Endothelium, Vascular , Hypertension/metabolism , Insulin/metabolism , Male , Metabolic Syndrome/etiology , Metabolic Syndrome/metabolism , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Rats , Rats, Wistar , VasodilationABSTRACT
This study aimed to evaluate vascular function changes and autonomic balance during the first trimester of pregnancy and its relationship with the new-born weight. This prospective study performed in pregnant (PG) women and after delivery (not pregnant: NPG) evaluated the endothelial function (EF) and arterial stiffness (AS) by a non-invasive method. We evaluated the heart rate variability (HRV), parasympathetic nervous system (PNS), sympathetic nervous system (SNS) indexes by electrocardiogram (5 min) and the urinary nitrite excretion (NOx). PG increased EF and NOx and decreased AS and HRV. PG decreased the PNS index and augmented the SNS index. The new-born weight positively correlated with the PNS index (Pearson's r: 0.4291; p<.05), NOx, HRV and negatively correlated with AS. In summary, in pregnancy, although haemodynamically, the SNS activation plays a compensatory role, the low rates of PNS inhibition are essential to ensure normal foetal growth.Impact StatementWhat is already known on this subject? In pregnancy, there are adaptive physiological changes in the cardiovascular system that include increases of EF and decreases AS with an SNS activation. The study of HRV lets to predict the SNS and PNS balance and how they affect blood pressure and vascular function.What the results of this study add? Although it is known that SNS activation plays a compensatory role in healthy pregnancy, this study adds the critical role of PNS. Early in pregnancy, the low rates of PNS inhibition are essential to ensure normal foetal growth.What the implications are of these findings for clinical practice and/or further research? The present results show a potential predictive value of SNS and PNS activity early in pregnancy. It will provide valuable information not only on the pregnant woman's vascular function but also on the new-born weight.
Subject(s)
Autonomic Nervous System , Parasympathetic Nervous System , Autonomic Nervous System/physiology , Female , Heart Rate/physiology , Humans , Parasympathetic Nervous System/physiology , Pregnancy , Pregnancy Trimester, First , Prospective StudiesABSTRACT
INTRODUCCIÓN: Una Agenda Nacional de Investigación en Salud Pública (ANISP) participativa y con priorización temática constituye un elemento estratégico para generar recomendaciones y políticas públicas basadas en evidencia, que impacten positivamente en la salud de las poblaciones y permitan lograr los objetivos sanitarios. En la actualización de la ANISP participaron la Dirección de Investigación en Salud (DIS) del Ministerio de Salud de la Nación (MSAL), a través de la Red Ministerial de Investigación en Salud (REMINSA), y actores de los niveles gubernamentales provinciales y nacionales pertenecientes a los sectores público, privado, de la salud, académico y de investigación. Se adaptó la herramienta original propuesta por la Organización Panamericana de la Salud, utilizada en el proceso en 2019. La actualización abarcó diferentes etapas. La selección de los temas contó con la legitimidad, reconocimiento y participación de los actores vinculados a la salud, a la gestión gubernamental y privada y a la investigación científica; se trabajó de manera federal y transversal, por consenso con las redes provinciales y un Comité Central Asesor en el MSAL. A partir de los lineamientos preliminares obtenidos, se elaboró una encuesta en línea semiestructurada, que fue distribuida a todos los actores federales y recibió 431 respuestas. El proceso resultó en 55 lineamientos priorizados, divididos en 6 áreas temáticas y 33 subtemas, seleccionados por votación según importancia, impacto y factibilidad.
Subject(s)
Argentina , Research , Public HealthSubject(s)
Antiparasitic Agents/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/prevention & control , Carrageenan/administration & dosage , Health Personnel , Ivermectin/administration & dosage , Pre-Exposure Prophylaxis/methods , Adult , Antiparasitic Agents/therapeutic use , Antiviral Agents/therapeutic use , Argentina , Carrageenan/therapeutic use , Female , Humans , Ivermectin/therapeutic use , Male , SARS-CoV-2 , Treatment OutcomeABSTRACT
INTRODUCCIÓN: Una Agenda Nacional de Investigación en Salud Pública (ANISP) participativa y con priorización temática constituye un elemento estratégico para generar recomendaciones y políticas públicas basadas en evidencia, que impacten positivamente en la salud de las poblaciones y permitan lograr los objetivos sanitarios. En la actualización de la ANISP participaron la Dirección de Investigación en Salud (DIS) del Ministerio de Salud de la Nación (MSAL), a través de la Red Ministerial de Investigación en Salud (REMINSA), y actores de los niveles gubernamentales provinciales y nacionales pertenecientes a los sectores público, privado, de la salud, académico y de investigación. Se adaptó la herramienta original propuesta por la Organización Panamericana de la Salud, utilizada en el proceso en 2019. La actualización abarcó diferentes etapas. La selección de los temas contó con la legitimidad, reconocimiento y participación de los actores vinculados a la salud, a la gestión gubernamental y privada y a la investigación científica; se trabajó de manera federal y transversal, por consenso con las redes provinciales y un Comité Central Asesor en el MSAL. A partir de los lineamientos preliminares obtenidos, se elaboró una encuesta en línea semiestructurada, que fue distribuida a todos los actores federales y recibió 431 respuestas. El proceso resultó en 55 lineamientos priorizados, divididos en 6 áreas temáticas y 33 subtemas, seleccionados por votación según importancia, impacto y factibilidad
Subject(s)
Argentina , Public HealthABSTRACT
BACKGROUND: Oxidative stress plays an essential role in the vascular tone in hypertension; however, the mechanisms remain unclear. AIM: This study aimed to determine the antioxidant effect of tempol and vitamin C (Vit-C) on the basal tone and vascular remodeling of the aorta in nitric oxide (NO) deficiency-induced hypertensive rats. METHOD: Male Sprague-Dawley rats were induced to hypertension by Nω-nitro-L-arginine methyl ester (L-NAME). Animals were randomized as follows: vehicle (Control: CR), CR-tempol, CR-Vit-C, L-NAME, L-NAME-tempol, and L-NAME-Vit-C. After 6 weeks of treatment, the basal aortic tone was evaluated by sodium nitroprusside (SNP) and calcium-free medium. Endothelial function, NO, reduced-to-oxidized glutathione (GSH/GSSG) ratio, resting membrane potential (mP), and vascular remodeling were also measured. RESULTS: L-NAME rats showed an increased basal tone that was blunted by both SNP (-547 ± 69; n = 7 vs. CR: -7.5 ± 6.7 mg; n = 7; p < 0.001) and calcium-free medium. Tempol or Vit-C did not reverse hypertension, and the high basal tone was decreased only with tempol. In L-NAME rats, only tempol partially improved endothelial function, GSH-to-GSSG ratio, mP values, and vascular remodeling. CONCLUSIONS: Tempol decreased calcium-dependent basal aortic tone and improved vascular homeostasis in L-NAME rats. Vit-C did not lead to a similar effect, suggesting that alterations in the superoxide dismutase pathway may play a role in the basal aortic tone.
Subject(s)
Antioxidants/pharmacology , Aorta, Thoracic/drug effects , Ascorbic Acid/pharmacology , Cyclic N-Oxides/pharmacology , Dietary Supplements , Hypertension/drug therapy , Oxidative Stress/drug effects , Vascular Remodeling/drug effects , Vasoconstriction/drug effects , Animals , Aorta, Thoracic/metabolism , Aorta, Thoracic/physiopathology , Disease Models, Animal , Glutathione/metabolism , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/physiopathology , Male , Membrane Potentials/drug effects , NG-Nitroarginine Methyl Ester , Nitric Oxide/metabolism , Oxidation-Reduction , Rats, Sprague-Dawley , Spin LabelsABSTRACT
UNLABELLED: Low birthweight (LBW) increases the risk of developing cardiovascular diseases (CVD). Few studies have established its impact at early ages. AIMS: To study endothelial function (EF) and arterial stiffness (AS) and their relationship to early markers of CVD risk in children with LBW. METHODS: In children with LBW (4-6 years; n = 53), anthropometric, haemodynamic and laboratory parameters, including HOMA-IR, hs-CRP, adiponectin and leptin, were determined. EF and AS were evaluated by digital pulse plethysmography. Data were compared with a control group (n = 33). RESULTS: In both groups, anthropometric parameters remained within normal limits. Insulin and HOMA-IR had normal values, but they were significantly augmented in LBW children. LBW children showed higher leptin and hs-CRP levels than the control group. The LBW group had decreased EF (37.5 ± 5.6%) compared with the control group (75.0 ± 11.9%; p < 0.01), however without differences in AS. In LBW children, EF was negatively correlated with waist circumference, leptin, hs-CRP and with a cumulative score of risk factors. CONCLUSIONS: LBW children display altered EF that is related to early changes in CVD risk factors. The differences found in the metabolic parameters might indicate a pro-inflammatory state. This hypothesis is also supported by the laboratory findings and the correlation between EF and the number of CVD risk factors, suggesting that very early lifestyle interventions may be needed.
Subject(s)
C-Reactive Protein/metabolism , Cardiovascular Diseases , Endothelium, Vascular , Hemodynamics , Infant, Low Birth Weight/blood , Leptin/blood , Vascular Stiffness , Cardiovascular Diseases/blood , Cardiovascular Diseases/etiology , Cardiovascular Diseases/physiopathology , Child , Child, Preschool , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Female , Follow-Up Studies , Humans , Male , Risk FactorsABSTRACT
Objetivos: Determinar los programas y proyectos de investigación e intervención, incluyendo diagnósticos de salud, entre Abril de 2001 a Diciembre del 2007, en la Provincia de Tucumán, Argentina. Materiales y Métodos: Para los proyectos de investigación científica en salud se utilizó la base de datos del Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) y la Universidad Nacional de Tucumán (UNT). Para las investigaciones socio-sanitarias se realizaron entrevistas a actores claves involucrados en la gestión del conocimiento, funcionarios del gobierno del Ministerio de Salud y de la Secretaría de Ciencia y Técnica de Innovación Productiva de la Provincia, Ministerio de Desarrollo Social y a autoridades del Sistema Provincial de Salud. Resultados: Medicina representó el 4,9% del total de Proyectos financiados por la Universidad y el 1,9% del total de Programas aprobados por la Secretaría de Ciencia y Técnica de la UNT. Una situación similar se describe para nuestra provincia en relación a los subsidios otorgados por CONICET con el 2% del total de financiamiento. La Investigación Clínica y Epidemiológica fueron los temas más investigados de acuerdo a la clasificación presentada. De acuerdo con la encuesta, el 32% de los entrevistados opinó que “articula bastante” la investigación científica con los programas de la Atención Primaria de la Salud. Conclusiones: Hay escaso conocimiento sobre los proyectos de investigación en salud financiados por entidades públicas en las diferentes áreas geográficas estudiadas (Metropolitana, Agroindustrial y SILOS). Se observó que a nivel institucional universitario el área de Ciencias de la Salud y especialmente Medicina, es un área de vacancia.
Aim: To determine programs and projects of research and intervention, including diagnosis of health, during April 2001 to December 2007, in the Province of Tucuman, Argentina. Material and Methods: Data were obtained from public organisms of the Province of Tucuman. For research in health were used the data base of the National Scientific and Technical Research Council - Argentina (CONICET) and the National University of Tucuman (UNT). For research in Health and social care were realized interviews to key actors directly involved in knowledge management, Government officials of the Ministry of Health and the Secretary of Science and Technology of Productive Innovation of the Province of Tucuman, and Ministry of Social Development and the officials of the Health System of Tucuman. Results: Medicine accounted 4.9% of all projects funded by the University and 1.9% of total approved by the Ministry of Science and Technology of UNT. A similar situation is described for our province in relation to grants from CONICET with the 2% of total funding. Clinical and Epidemiological Research were the most investigated according to the classification presented. According to the survey, 32% of respondents felt that “articulates quite” the scientific research programs with Primary Health Care. Conclusions: There is little knowledge about health research projects funded by public entities in different geographical areas studied (Metropolitan, Agroindustrial and SILOS). It was noted that in a university institutional area, Health Sciences, and Medicine in particular, is an area of vacancy.
Subject(s)
Humans , Primary Health Care , Research Design , Social Change , Knowledge Management , Argentina , Research , Social Support , Technology , Universities , Knowledge , Creativity , DiagnosisABSTRACT
BACKGROUND/AIM: Renal preglomerular vessels play a central role in modulating renal function and injury, especially during conditions of renal hemodynamic stress such as hypertension. We evaluated whether improving the balance between nitric oxide (NO) and oxidative stress improves the morphological alterations of renal afferent arterioles that occur in NO deficiency-induced hypertension. METHODS: We measured indices of NO and oxidative stress and evaluated renal morphology and afferent arteriolar remodeling in rats treated with vehicle, L-NAME or L-NAME plus tempol (a superoxide dismutase mimetic) for 6 weeks. RESULTS: L-NAME-treated rats had hypertension, lower urinary and renal NO indices, higher renal cortical levels of TBARS, GSSG and GSSG/GSH. This was associated with significant eutrophic inward remodeling of the afferent arterioles; they had a marked decrease in arteriolar lumen area and a striking increase in arteriolar wall thickness and media to lumen ratio. Tempol did not significantly reduce blood pressure, but increased NO levels, decreased oxidative stress and partially blunted L-NAME-induced remodeling of afferent arterioles. CONCLUSION: L-NAME-induced remodeling of afferent arterioles is blunted by tempol. This beneficial effect on remodeling is associated with increases in NO indices, decreases in oxidative stress, without significant decreases in blood pressure. Thus, the balance between these components may contribute to the altered renal hemodynamics and function in this model.
Subject(s)
Arterioles/drug effects , Cyclic N-Oxides/pharmacology , Hypertension/drug therapy , Nitric Oxide/deficiency , Vascular Remodeling , Animals , Antioxidants/pharmacology , Blood Pressure/drug effects , Hemodynamics/drug effects , Hypertension/physiopathology , Male , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Spin LabelsABSTRACT
BACKGROUND: Obesity is related to an increase in the rates of cardiovascular disease. OBJECTIVE: To establish the impact of obesity on vascular function (endothelial function and arterial stiffness) in children and adolescents and its relationship to cardiovascular risk factors. METHODS: In obese (OB) children and adolescents, endothelial function and arterial stiffness were evaluated by a pulse plethysmography method (reactive hyperemia and index of digital volume waveforms, respectively). Data were compared with the non-obese (non-OB) group (body mass index >10th to <97th percentile). Anthropometric parameters, body fat percentage, fasting glucose, lipid profile, insulinemia, HOMA-IR and hemodynamic parameters were determined in both groups. RESULTS: Body mass index, weight, waist circumference, body fat, insulinemia and HOMA-IR were significantly higher in the OB group. The OB group showed impaired endothelial function (15.8 ± 0.2%, n = 37) compared to the non-OB group (41.4 ± 5%, n = 20; p < 0.001) and increased arterial stiffness. Endothelial function was only negatively correlated with waist circumference and HOMA-IR in the OB group, whereas a positive correlation was found between insulinemia and HOMA-IR. CONCLUSIONS: This study shows that impaired vascular function is already present in OB children and adolescents. The fact that obesity is associated with some markers of cardiovascular risk suggests the importance of early lifestyle interventions in this population to prevent cardiovascular disease.
Subject(s)
Endothelium, Vascular/physiopathology , Obesity/physiopathology , Vascular Stiffness , Adolescent , Body Mass Index , Child , Endothelium, Vascular/pathology , Female , Humans , Hyperemia/pathology , Hyperemia/physiopathology , Male , Obesity/pathology , Plethysmography , Waist CircumferenceABSTRACT
Nonischemic 5/6 nephrectomized rat (NefR) is a model of chronic kidney disease. However, little is known about vascular dysfunction and its relation with hypertension in NefR. Aims. To evaluate possible alterations of endothelial function, NO-bioavailability, and basal tone in aorta from NefR and the role of oxidative stress. Sprague Dawley rats were divided into sham rats (SR), NefR, and NefR treated with tempol (NefR-T). Mean arterial pressure (MAP) and renal function were determined. In isolated aortic rings the following was measured: 1-endothelial function, 2-basal tone, 3-NO levels, 4-membrane potential (MP), and 5-oxidative stress. NefR increased MAP (SR: 119 ± 4 mmHg; n = 7; NefR: 169 ± 6; n = 8; P < 0.001). Tempol did not modify MAP (NefR-T: 168 ± 10; n = 6; P < 0.001). NefR showed endothelial dysfunction, increased basal tone and decreased NO levels (SR: 32 ± 2 nA; n = 7, NefR: 10 ± 2; n = 8; P < 0.001). In both in vitro and in vivo tempol improves basal tone, NO levels, and MP. Oxidative stress in NefR was reverted in NefR-T. We described, for the first time, that aorta from NefR presented increased basal tone related to endothelial dysfunction and decreased NO-bioavailability. The fact that tempol improves NO-contents and basal tone, without decrease MAP, indicates that oxidative stress could be implicated early and independently to hypertension, in the vascular alterations.
ABSTRACT
Objective. To evaluate the impact of oxidative stress on vascular reactivity to vasoconstrictors and on nitric oxide (NO) bioavailability in saphenous vein (SV) graft with endothelial dysfunction from hypertensive patients (HT). Methods. Endothelial function, vascular reactivity, oxidative state, nitrites and NO release were studied in isolated SV rings from HT and normotensive patients (NT). Only rings with endothelial dysfunction were used. Results. HT rings presented a hyperreactivity to vasoconstrictors that was reverted by diphenylene iodonium (DPI). In NT, no effect of DPI was obtained, but Nω-nitro-(L)-arginine methyl ester (L-NAME) increased the contractile response. NO was present in SV rings without endothelial function. Nitrites were higher in NT than in HT (1066.1 ± 86.3 pmol/mg; n = 11 versus 487.8 ± 51.6; n = 23; P < 0.01) and inhibited by nNOS inhibitor. L-arginine reversed this effect. Antioxidant agents increased nitrites and NO contents only in HT. The anti-nNOS-stained area by immunohistochemistry was higher in NT than HT. HT showed an elevation of oxidative state. Conclusions. Extraendothelial NO counter-regulates contractility in SV. However, this action could be altered in hypertensive situations by an increased oxidative stress or a decreased ability of nNOS to produce NO. Further studies should be performed to evaluate the implication of these results in graft patency rates.
ABSTRACT
UNLABELLED: Previously, our group showed a prothrombotic state in asymptomatic patients with chronic Chagas disease. The current paper studies the inflammatory status and endothelial function in these patients. METHODS: In 40 patients and 40 healthy volunteers, we evaluated prothrombotic state, blood parasitemia (molecular biology: polymerized chain reaction [PCR]-amplification), tissue factor pathway inhibitor antibodies (aTFPI), interleukin 6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1). Endothelial function was determined by reactive hyperemia (pulse plethysmography). RESULTS: In patients, prothrombin fragment 1 + 2, d-dimer, PAI-1, and fibrinogen were higher. Amplification of 121/122 primers (Trypanosoma cruzi) was positive in 45% of the patients. Patients presented higher values of aTFPI- immunoglobulin G (IgG; P < .05), aTFPI-IgM (P < .001), IL-6 (P = .004), and VCAM-1 (P = .00001). In both groups, endothelial function was preserved. CONCLUSIONS: We found that asymptomatic patients with chronic Chagas disease presented a prothrombotic/inflammatory status. The fact that endothelial function is still preserved suggests that prothrombosis and inflammation are primarily implicated in the beginning of cardiovascular damage.
Subject(s)
Chagas Disease/blood , Fibrin Fibrinogen Degradation Products/metabolism , Hyperemia/blood , Peptide Fragments/blood , Plasminogen Activator Inhibitor 1/blood , Adult , Autoantibodies/blood , Chagas Disease/complications , Chagas Disease/parasitology , Chronic Disease , Endothelium, Vascular/metabolism , Endothelium, Vascular/parasitology , Female , Humans , Hyperemia/parasitology , Inflammation/blood , Inflammation/parasitology , Interleukin-6/blood , Lipoproteins/blood , Male , Parasitemia , Prothrombin , Thrombosis/blood , Thrombosis/etiology , Thrombosis/parasitology , Vascular Cell Adhesion Molecule-1/bloodABSTRACT
Introducción: En el estadio indeterminado de la enfermedad de Chagas crónica, se comprobó un estado protrombótico asociado con factores de riesgo trombofílicos. La etiopatogenia de la enfermedad de Chagas es multifactorial sin que ninguno de los mecanismos involucrados explique por sí mismo el inicio y progresión de las lesiones. Objetivo: Evaluar probables mecanismos involucrados en la etiopatogenia del estado protrombótico en el estadio indeterminado de la enfermedad de Chagas crónica. Material y Métodos: Desde marzo de 2004 hasta diciembre de 2006 se evaluaron 40 pacientes chagásicos crónicos, 14 varones y 26 mujeres, (33.5 ± 4.9 años); en clase funcional I, de la clasificación clínica de la miocardiopatía chagásica crónica, comparándolos con un muestreo accidental de 40 voluntarios sanos, 19 varones y 21 mujeres (28.8 ± 6.3 años). Se evaluó la presencia del parásito por técnica de amplificación de las cadenas de polimerasa (PCR) y se determinó anticuerpo inhibidor de la vía extrínseca de la coagulación (aTFPI) por un método de ELISA optimizado, con valor de corte para aTFPI IgG >18 Uml-1 y para aTFPI IgM >15 Uml-1. Valores altos de aTFPI (IgG e IgM) se consideraron los >50 Uml-1. Se tomaron también muestras de sangre para la determinación por ELISA de dos marcadores de inflamación; Interleuquina 6 (IL-6) y de la molécula de adhesión a célula vascular (VCAM-1). La función endotelial se evaluó por pletismografía de onda de pulso digital para determinar hiperemia reactiva, la que discrimina sujetos con y sin disfunción endotelial. Resultados: En los pacientes chagásicos estudiados se detectó presencia del parásito por la técnica de amplificación de PCR utilizada en el 45 por ciento (n=18) de los casos. Los pacientes chagásicos presentaron valores de aTFPI mayores que los controles, con una p<0.05 para aTFPI IgG y p<0.001 para aTFPI IgM; superando en muy pocos casos los valores de corte establecidos para el método...
Subject(s)
Humans , Male , Adult , Female , Young Adult , Middle Aged , Chagas Disease/etiology , Chagas Disease/pathology , Thrombosis/etiology , Chagas Cardiomyopathy , Chronic Disease , Disease ProgressionABSTRACT
This study characterised the effect of a hypercholesterolemic diet on the interactions of hormone receptors in the rabbit aorta, both in homologous desensitisation to angiotensin II and cross talk between alpha(1)-adrenoceptors and angiotensin AT(1) receptors. Rabbits were fed either a normal chow or a diet containing 1% cholesterol for 6-7-weeks. Isometric contractions were measured in endothelium-intact or endothelium-removed aortic rings from control and hypercholesterolemic rabbits. Concentration response curves to angiotensin II or noradrenaline incubated with or without prazosin or losartan were performed. In another group, the resting potential was recorded at baseline and following angiotensin II or noradrenaline stimulation. Rabbits fed a hypercholesterolemic diet showed higher plasma levels of total cholesterol and LDL-cholesterol and impaired relaxation to acetylcholine. Homologous desensitisation to angiotensin II was found in endothelium-intact but not in endothelium-removed arteries. Cross talk between alpha(1)-adrenoceptors and angiotensin AT(1) receptors was modified with respect to physiological conditions. In control rabbits, angiotensin II desensitised the noradrenaline response but noradrenaline did not modify the angiotensin II-response. However, in hypercholesterolemic rabbits, angiotensin II sensitised the noradrenaline-response and noradrenaline desensitised the angiotensin II-response. Furthermore, the resting potential remains hyperpolarised after noradrenaline stimulation in hypercholesterolemic rabbits. Modifications in homologous desensitisation to angiotensin II and cross talk between alpha(1)-adrenoceptors and angiotensin AT(1) receptors suggest that hypercholesterolemia induces early tissue dysfunction by altering endothelial and smooth muscle cell regulatory properties. This may be one of the mechanisms by which hypercholesterolemia could be involved in the onset and progression of chronic vascular diseases such as hypertension and arteriosclerosis.
Subject(s)
Angiotensin II/metabolism , Aorta/metabolism , Hypercholesterolemia/metabolism , Hypercholesterolemia/pathology , Receptor Cross-Talk , Receptor, Angiotensin, Type 1/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Acetylcholine/pharmacology , Animals , Aorta/drug effects , Aorta/physiopathology , Blood Pressure/drug effects , Dietary Fats/adverse effects , Homeostasis/drug effects , Hypercholesterolemia/physiopathology , In Vitro Techniques , Male , Membrane Potentials/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Muscle, Smooth/physiopathology , Norepinephrine/pharmacology , Rabbits , Receptor Cross-Talk/drug effects , Rest , Vasoconstriction/drug effectsABSTRACT
NADPH oxidase is critically involved in increased blood pressure, vascular hypertrophy, inflammation and endothelial dysfunction in experimental and clinical hypertension. We hypothesized that NADPH oxidase might also play a role in the development of spontaneous aortic tone in spontaneously hypertensive rats (SHR). Wistar Kyoto rats (WKY) were used as normotensive controls. Tone was recorded under isometric conditions. NADPH oxidase activity was measured by both lucigenin luminescence and dihydroethidium fluorescence. p47phox protein was localized by immunohistochemistry. SHR (but not WKY rat) aortae showed spontaneous tone in the absence of exogenous vasoconstrictors as evidenced by a stronger relaxant effect of Ca2+-free sodium nitroprusside solution. This tone was enhanced in endothelium-denuded arteries and was inhibited by superoxide dismutase, apocynin, diphenylene iodonium and quercetin. Aortic NADPH oxidase activity, measured by both lucigenin luminescence and dihydroethidium fluorescence, was increased in SHR compared with WKY rats. Immunohistochemical analysis revealed a strong increase in p47phox expression in the medial layer in SHR. Taken together, the present results indicate that enhanced NADPH oxidase activity and, hence, NADPH driven O2- production, is involved in the spontaneous aortic tone in SHR. This was associated with an increased expression of p47phox in the medial layer of the aorta.
Subject(s)
Antihypertensive Agents/pharmacology , Aorta/metabolism , Hypertension/enzymology , NADPH Oxidases/metabolism , Animals , Aorta/enzymology , Aorta/pathology , Calcium/metabolism , Disease Models, Animal , Hypertension/pathology , Immunohistochemistry , Male , Nitroprusside/pharmacology , Oxygen/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKYABSTRACT
UNLABELLED: This study investigated the modulation of angiotensin II-induced endothelial prostanoid release in rabbit aortic rings. Two cumulative dose response curves with 90-min washing interval were performed. Incubation with L-N(G)-nitroarginine methyl ester (L-NAME) 10(-4) M increased angiotensin II maximal contractile response (E(max)). This effect was reversed by indomethacin 10(-5) M, diphenyliodinum 10(-5) M, Tempol 10(-5) M or ascorbic acid 10(-4) M in both cumulative dose response curves and by SQ 29548 10(-6) M in the second cumulative dose response curve. When segments were treated with tetraethylamonium 10(-3) M but not with glibenclamide 10(-5) M during the washing period, L-NAME recovered its ability to enhance the E(max) in arteries incubated with SQ 29548. CONCLUSIONS: nitric oxide modulates angiotensin II-induced endothelial release of cyclooxygenase-dependent eicosanoids, one of which acts through thromboxane A(2)/prostaglandin H(2) receptors and would decrease K(Ca) channel activity. An increase in free radical production may account for the enhancement of such prostanoid release. Furthermore, it was found that in the present conditions, the release of the hyperpolarizing factor would improve in order to maintain the vascular tone.
Subject(s)
Angiotensin II/pharmacology , Endothelium, Vascular/drug effects , Nitric Oxide/physiology , Vasoconstriction , Vasomotor System/drug effects , Animals , Antioxidants/pharmacology , Aorta, Thoracic , Ascorbic Acid/pharmacology , Bridged Bicyclo Compounds, Heterocyclic , Cyclooxygenase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Endothelium, Vascular/metabolism , Fatty Acids, Unsaturated , Hydrazines/pharmacology , In Vitro Techniques , Indomethacin/pharmacology , Male , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Potassium Channel Blockers/pharmacology , Prostaglandins/metabolism , Rabbits , Receptors, Thromboxane/antagonists & inhibitors , Tetraethylammonium/pharmacology , Vasomotor System/physiologyABSTRACT
Una estimación de la función endotelial de arterias mamarias (art mam) y venas safenas (vena saf) usadas parabypass coronario sería medir la liberación de oxido nítrico (NO). En nuestro laboratorio observamos, en arterias de conejos, que el estiramiento (stretching) incrementa el NO. Objetivos: Determinar la presencia de endotelio en art mam y vena saf en pacientes (p) de bypass coronario y dosar el contenido de NO. Evaluar el rol del estiramiento. Métodos: Se usaron restos (1-4 anillos) de art mam y vena saf de 44 p del CMC con o sin factores de riesgo (FR) asociados. Se efectuaron dos protocolos in vitro: NT) anillos no tensados (precarga de 0g) y T) anillos tensados (precarga de 2g:art mam o 3g:vena saf). La presencia de endotelio se determinó por relajación (con endotelio) o no (sin endotelio) a acetilcolina 10-6M o bradiquinina 10-7M sobre precontractura con noradrenalina en baño de órgano aislado. El NO se dosó por método de Griess a los 15 min y en una curva de tiempo (90 min) con y sin tratamiento con L-Name 10-3M o Ang II (10-9 a -6M). Resultados: 7 p presentaron endotelio sin asociación con los FR. En T el NO basal fue mayor en vasos con endotelio en art mam (1829±259 vs 3699±65 pmol/mg n=19; p<0,05) y vena saf (694±103 vs 1290±216 pmol/mg, n=18; p<0,01). T estimuló laliberación de NO, este efecto es mayor en art mam con endotelio que en vena saf (p<0,001) y se mantiene aúnen anillos sin endotelio a los 90 min. En NT no hubo diferencias entre art mam y vena saf. Ang II mostródiferencias entre T y NT. L-Name solo inhibió el NO en vena saf con endotelio. Conclusiones: Los vasospresentaron disfunción endotelial generalizada sin asociación con ningún FR. Sin embargo, hubo liberación deNO incluso en anillos sin endotelio. Demostramos mayores niveles de NO en art mam. Sin embargo art mam yvena saf aumentan su liberación si se someten a T y este aumento se mantiene en la disfunción endotelial. Suorigen involucraría activación de la enzima NO Sintetasa neuronal(nNOS). La T activaría la nNOS, situaciónhomologable in vivo a la T que sufriere el vaso injertado en el circuito arterial coronario. Este mecanismocompensador de NO ayudaría a explicar la buena perfomance, aun en vena saf, de los puentes coronarios, más allá del FR asociado.
Subject(s)
Male , Animals , Female , Nitric Oxide/metabolism , Coronary Artery Bypass/methods , Mammary Arteries , Endothelium, Vascular/physiology , Endothelium, Vascular/physiopathology , Endothelium/physiology , Endothelium/physiopathology , Saphenous VeinABSTRACT
Una estimación de la función endotelial de arterias mamarias (art mam) y venas safenas (vena saf) usadas parabypass coronario sería medir la liberación de oxido nítrico (NO). En nuestro laboratorio observamos, en arterias de conejos, que el estiramiento (stretching) incrementa el NO. Objetivos: Determinar la presencia de endotelio en art mam y vena saf en pacientes (p) de bypass coronario y dosar el contenido de NO. Evaluar el rol del estiramiento. Métodos: Se usaron restos (1-4 anillos) de art mam y vena saf de 44 p del CMC con o sin factores de riesgo (FR) asociados. Se efectuaron dos protocolos in vitro: NT) anillos no tensados (precarga de 0g) y T) anillos tensados (precarga de 2g:art mam o 3g:vena saf). La presencia de endotelio se determinó por relajación (con endotelio) o no (sin endotelio) a acetilcolina 10-6M o bradiquinina 10-7M sobre precontractura con noradrenalina en baño de órgano aislado. El NO se dosó por método de Griess a los 15 min y en una curva de tiempo (90 min) con y sin tratamiento con L-Name 10-3M o Ang II (10-9 a -6M). Resultados: 7 p presentaron endotelio sin asociación con los FR. En T el NO basal fue mayor en vasos con endotelio en art mam (1829±259 vs 3699±65 pmol/mg n=19; p<0,05) y vena saf (694±103 vs 1290±216 pmol/mg, n=18; p<0,01). T estimuló laliberación de NO, este efecto es mayor en art mam con endotelio que en vena saf (p<0,001) y se mantiene aúnen anillos sin endotelio a los 90 min. En NT no hubo diferencias entre art mam y vena saf. Ang II mostródiferencias entre T y NT. L-Name solo inhibió el NO en vena saf con endotelio. Conclusiones: Los vasospresentaron disfunción endotelial generalizada sin asociación con ningún FR. Sin embargo, hubo liberación deNO incluso en anillos sin endotelio. Demostramos mayores niveles de NO en art mam. Sin embargo art mam yvena saf aumentan su liberación si se someten a T y este aumento se mantiene en la disfunción endotelial. Suorigen involucraría activación de la enzima NO Sintetasa neuronal(nNOS). La T activaría la nNOS, situaciónhomologable in vivo a la T que sufriere el vaso injertado en el circuito arterial coronario. Este mecanismocompensador de NO ayudaría a explicar la buena perfomance, aun en vena saf, de los puentes coronarios, más allá del FR asociado. (AU)
Subject(s)
Male , Animals , Female , Nitric Oxide/metabolism , Coronary Artery Bypass/methods , Mammary Arteries , Saphenous Vein , Endothelium, Vascular/physiology , Endothelium, Vascular/physiopathology , Endothelium/physiology , Endothelium/physiopathologyABSTRACT
BACKGROUND/AIM: We evaluated in diabetic-streptozotocin rats (STZR) the structural changes of glomeruli, preglomerular vessels, glomerular tuft and renal parenchyma in order to determine the degree of renal injury and the presence of remodeling in afferent arterioles developed by diabetes without overimposed hypertension. METHODS: Renal mass index and histological score (glomerular number, density, tubular lesions and degree of arteriosclerosis) were estimated. In afferent arterioles the ratio of wall thickness/lumen was obtained by stereological methods. RESULTS: STZR developed diabetes without hypertension; renal mass index increased and matched changes in glomeruli (decrease of capillary number and enlargement of mesangium and basement capillary membrane). Both glomerular number and density as well as afferent arteriole number were diminished. Degenerative changes in both proximal (glycogenic and hyaline degeneration) and distal tubules (hyaline casts) were also observed. At variance with preglomerular vessels, the efferent arterioles only presented initial arteriosclerosis. Finally, the stereological study of afferent arterioles showed a significantly lower arteriolar lumen area and arteriolar wall thickness in STZR, resulting in a remodeling without modification of wall/lumen ratio. CONCLUSION: Diabetes, uncomplicated by hypertension, is associated with (1) a reduction in glomerular number; (2) degeneration in parenchyma and renal tubules, and (3) a specific pattern of remodeling in preglomerular vessels different from that induced by hypertension. Although this work demonstrated that these changes are not triggered by hypertension, further investigations are required in order to determine which mediators are involved in diabetic-vascular renal dysfunction.
