RESUMEN
Evidence suggests that endothelin receptor antagonists may have therapeutic potential for the chronic treatment of heart failure. In the current study, the effects of an orally active mixed endothelin-A/endothelin-B (ETA /ETB ) receptor antagonist (enrasentan) were assessed in a model of cardiac hypertrophy and dysfunction (spontaneously hypertensive stroke prone rats) maintained on a high-salt/high-fat diet. Echocardiography was used to quantify cardiac performance and left ventricular dimensions. Enrasentan (1,200 and 2,400 parts per million in the high-salt/high-fat diet) had no significant effects on body weight and systolic blood pressure. However, increases in heart rate were not observed in the enrasentan-treated groups at 12 weeks (p < 0.05). Enrasentan-treated groups exhibited significantly improved survival (90-95% vs. 30% [control rats] at 18 weeks; p < 0.001). Enrasentan treatments also increased stroke volume (at 8, 12, and 16 weeks) and cardiac index (at 8 and 16 weeks) 33-50% and 45-63%, respectively. Enrasentan treatments reduced the relative wall thickness (14-27% at 8 and 12 weeks), ratio of left ventricular mass to body weight (20% at 12 weeks), and ratio of terminal heart weight to body weight (16-23%, p < 0.05). Finally, circulating aldosterone concentration (54-57%) and proANF fragment (33%) were reduced in enrasentan-treated groups (54-57% and 33%, respectively). Mixed ETA /ETB receptor antagonism improves cardiac performance and attenuates ventricular remodeling and premature mortality in an aggressive hypertension model.
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Ácidos Carboxílicos/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Indanos/uso terapéutico , Remodelación Ventricular/efectos de los fármacos , Aldosterona/sangre , Animales , Factor Natriurético Atrial/sangre , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Antagonistas de los Receptores de Endotelina , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hipertensión/sangre , Hipertensión/mortalidad , Hipertrofia Ventricular Izquierda/sangre , Hipertrofia Ventricular Izquierda/mortalidad , Masculino , Miocardio/metabolismo , Precursores de Proteínas/sangre , Ratas , Ratas Endogámicas SHR , Tasa de Supervivencia , Remodelación Ventricular/fisiologíaRESUMEN
BACKGROUND: Numerous pathological mediators of cardiac hypertrophy (eg, neurohormones, cytokines, and stretch) have been shown to activate p38 MAPK. The purpose of the present study was to examine p38 MAPK activation and the effects of its long-term inhibition in a model of hypertensive cardiac hypertrophy/dysfunction and end-organ damage. METHODS AND RESULTS: In spontaneously hypertensive stroke-prone (SP) rats receiving a high-salt/high-fat diet (SFD), myocardial p38 MAPK was activated persistently during the development of cardiac hypertrophy and inactivated during decompensation. Long-term oral treatment of SFD-SP rats with a selective p38 MAPK inhibitor (SB239063) significantly enhanced survival over an 18-week period compared with the untreated group (100% versus 50%). Periodic echocardiographic analysis revealed a significant reduction in LV hypertrophy and dysfunction in the SB239063-treatment groups. Little or no difference in blood pressure was noted in the treatment or vehicle groups. Basal and stimulated (lipopolysaccharide) plasma tumor necrosis factor-alpha concentrations were reduced in the SB239063-treatment groups. In vitro vasoreactivity studies demonstrated a significant preservation of endothelium-dependent relaxation in animals treated with the p38 MAPK inhibitor without effects on contraction or NO-mediated vasorelaxation. Proteinuria and the incidence of stroke (53% versus 7%) were also reduced significantly in the SB239063-treated groups. CONCLUSIONS: These results demonstrate a crucial role for p38 MAPK in hypertensive cardiac hypertrophy and end-organ damage. Interrupting its function with a specific p38 MAPK inhibitor halts clinical deterioration.
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Cardiomegalia/fisiopatología , Hipertensión/fisiopatología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Animales , Cardiomegalia/enzimología , Cardiomegalia/mortalidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ecocardiografía , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Activación Enzimática , Corazón/efectos de los fármacos , Corazón/fisiopatología , Hemodinámica/efectos de los fármacos , Imidazoles/farmacología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Lipopolisacáridos/farmacología , Masculino , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Miocardio/metabolismo , Miocardio/patología , Fosforilación , Proteinuria/prevención & control , Proteinuria/orina , Pirimidinas/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/prevención & control , Tasa de Supervivencia , Factores de Tiempo , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Vasodilatación/efectos de los fármacos , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Ultrasound imaging utilizes the interaction of sound waves with living tissue to produce an image of the tissue or, in Doppler-based modes, determine the velocity of a moving tissue, primarily blood. These dynamic, real time images can be analyzed to obtain quantitative structural and functional information from the target organ. This versatile, noninvasive diagnostic tool is widely used and accepted in human and veterinary medicine. Until recently its application as a research tool was limited primarily to larger, nonrodent species. Due to advances in ultrasound imaging technology, commercially available ultrasound systems now have the spatial and temporal resolution to obtain accurate images of rat and mouse hearts, kidneys, and other target tissues including tumor masses. As a result, ultrasound imaging is being used more frequently as a research tool to image rats and mice, and particularly to evaluate cardiac structure and function. The developing technology of ultrasound biomicroscopy has even greater spatial resolution and has been used to evaluate developing mouse embryos and guide site-specific injections into mouse embryos. Additional ultrasound imaging technologies, including contrast-enhanced imaging and intravascular ultrasound transducers adapted for transesophageal use, have been utilized in rats and mice. This paper provides an overview of basic ultrasound principles, equipment, and research applications. The use of noninvasive ultrasound imaging in research represents both a significant refinement as a potential replacement for more invasive techniques and a significant advancement in research techniques to study rats and mice.
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Animales de Laboratorio , Ultrasonografía/métodos , Animales , Humanos , Ratones , Ratas , Proyectos de Investigación , Ultrasonografía/instrumentaciónRESUMEN
OBJECTIVE: Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP). METHODS: SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) (n = 25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats (n = 25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups. RESULTS: Eprosartan decreased the severely elevated arterial pressure (-12%; P < 0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (-13%; P < 0.05) and marked mortality (50% by week 6 and 95% by week 9; P < 0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion (P < 0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (-15.9%), chamber volume (-32.7%), stroke volume (-48.7%) and ejection fraction (-22.3%), and a remarkable decrease in cardiac output (-59.3%) compared to controls (all P < 0.05). These same parameters in eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P < 0.05). Cardiac-gated MRI data confirmed the ability of eprosartan to prevent cardiac pathology/remodeling (P < 0.05). Histopathological analysis of hearts and kidneys indicated that eprosartan treatment significantly reduced end-organ damage (P < 0.01) and provided corroborative evidence that eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by eprosartan (P < 0.05). CONCLUSION: These data demonstrate that eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.
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Acrilatos/uso terapéutico , Antihipertensivos/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Imidazoles/uso terapéutico , Tiofenos , Animales , Factor Natriurético Atrial/sangre , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Riñón/patología , Imagen por Resonancia Magnética , Masculino , Miocardio/patología , Natriuresis/fisiología , Tamaño de los Órganos/efectos de los fármacos , Fragmentos de Péptidos/sangre , Precursores de Proteínas/sangre , Proteinuria/prevención & control , Ratas , Ratas Endogámicas SHR , Accidente Cerebrovascular/prevención & control , Tasa de Supervivencia , Remodelación Ventricular/efectos de los fármacosRESUMEN
INTRODUCTION: Chronic measurement of respiratory function in the conscious monkey has been limited by the ability to monitor pleural pressure. Previous attempts to measure pleural pressure chronically in conscious animals have involved surgical implantation of pressure-sensitive catheters directly into the pleural cavity. The success of these techniques has been limited by lung damage and/or tissue growth and encapsulation of the pressure-sensitive catheter with damping or loss of the signal. These problems have been eliminated by developing a novel surgical procedure for placement of a pressure-sensitive catheter beneath the pleural surface. METHODS: A pressure-sensitive catheter (attached to a radiotelemetry transmitter) was surgically implanted beneath the serosal layer of the esophagus within the thoracic cavity. This was accomplished by performing a midline laparotomy, making a small incision in the serosal layer of the esophagus caudal to the diaphragm, and advancing the catheter cranially along the esophagus and beneath the serosal layer into the thoracic cavity. The catheter was secured to the esophageal wall and the telemetry transmitter was sutured to the inner abdominal wall. Respiratory airflow measurements were obtained using a restraint chair equipped with a clear plastic helmet (plethysmograph chamber) that seals around the neck and encloses the head. RESULTS: The decreases in pleural pressure during inspiration ranged from -5 to -15 mmHg and remained constant for at least 36 weeks following surgery. Intravenous administration of the respiratory depressant morphine, exposure to the respiratory stimulant 8% CO2, and intravenous administration of the bronchoconstrictive agent methacholine verified that this technique was able to detect and quantify ventilatory changes and an increase in airway resistance. DISCUSSION: This novel method for chronic measurement of pleural pressure will facilitate evaluation of the effects of drugs, environmental agents, or disease on respiratory function by allowing repeated measurements of both ventilatory (breathing) patterns and the mechanical properties of the lung in a conscious nonhuman primate.
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Pulmón/fisiología , Macaca fascicularis/fisiología , Ventilación Pulmonar/fisiología , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Broncoconstrictores/farmacología , Estado de Conciencia/fisiología , Relación Dosis-Respuesta a Droga , Pulmón/efectos de los fármacos , Masculino , Cloruro de Metacolina/farmacología , Morfina/farmacología , Pletismografía/veterinaria , Ventilación Pulmonar/efectos de los fármacos , Pruebas de Función Respiratoria/instrumentación , Pruebas de Función Respiratoria/veterinaria , Telemetría/veterinaria , Volumen de Ventilación Pulmonar/efectos de los fármacos , Volumen de Ventilación Pulmonar/fisiologíaRESUMEN
The observation that the novel G-protein-coupled receptor (GPCR) GPR14 and its cognate ligand, urotensin-II (U-II), are expressed within the mammalian vasculature raises the possibility that they may influence cardiohemodynamic homeostasis. To this end, this study examined the vasoactive properties of U-II in rodents, dogs and primates. In vitro, human U-II was a sustained vasoconstrictor with a potency (pD2s < or = 9) approximately an order of magnitude greater than that seen with endothelin-1 (ET-1), making it one of the most, if not the most, potent mammalian vasoconstrictor identified to date. However, in vitro responses exhibited significant anatomical and/or species-dependency, that is, human U-II was a selective 'aorto-coronary' vasoconstrictor in rats and dogs, inactive in mice and contracted all primate arteries studied. In vivo, this peptide evoked a complex, dose-dependent hemodynamic response in the anesthetized primate, culminating in severe myocardial depression and fatal circulatory collapse. As such, U-II may represent a novel neurohumoral regulator of mammalian cardiovascular physiology and pathology in particular disorders characterized by aberrant vascular smooth muscle and/or myocardial function.
Asunto(s)
Urotensinas/farmacología , Vasoconstricción/efectos de los fármacos , Animales , Perros , Relación Dosis-Respuesta a Droga , Hemodinámica/efectos de los fármacos , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Especificidad de la EspecieRESUMEN
BACKGROUND: Chemokines are potent proinflammatory and immune modulators. Increased expression of chemokines, eg, monocyte chemoattractant protein-1 (MCP-1), has recently been described in clinical and experimental heart failure. The present report is aimed at exploring the expression, localization, and binding site regulation of MCP-1, a member of the C-C chemokine family, in a rat model of volume-overload congestive heart failure (CHF). METHODS AND RESULTS: An aortocaval fistula was surgically created between the abdominal aorta and inferior vena cava. Rats with CHF were further subdivided into compensated and decompensated subgroups. Northern blot analysis and real-time quantitative polymerase chain reaction demonstrated upregulation of MCP-1 mRNA expression correlating with the severity of CHF (288+/-22, 502+/-62, and 826+/-138 copies/ng total RNA for sham, compensated, and decompensated animals, respectively; n=5, P:<0.05). MCP-1 protein was localized by immunohistochemistry in cardiomyocytes, vascular endothelium and smooth muscle cells, infiltrating leukocytes, and interstitial fibroblasts, and its intensity increased with severity of CHF. In addition, rats with CHF displayed a significant decrease of (125)I-labeled MCP-1 binding sites to myocardium-derived membranes (384.3+/-57.0, 181.3+/-8.8, and 123.3+/-14.1 fmol/mg protein for sham, compensated, and decompensated animals, respectively). CONCLUSIONS: Volume-overload CHF in rats is associated with alterations in the expression, immunohistochemical localization, and receptor binding of the MCP-1 chemokine in the myocardium. These changes were more pronounced in rats with decompensated CHF. The data suggest that activation of the MCP-1 system may contribute to the progressive cardiac decompensation and development of CHF in rats with aortocaval fistula.
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Quimiocina CCL2/metabolismo , Insuficiencia Cardíaca/metabolismo , Animales , Unión Competitiva , Northern Blotting , Insuficiencia Cardíaca/diagnóstico por imagen , Inmunohistoquímica , Técnicas In Vitro , Masculino , Miocardio/metabolismo , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Wistar , Ultrasonografía , Regulación hacia ArribaRESUMEN
OBJECTIVE: The purpose of this study was to evaluate the ossification state of the meniscus in the guinea-pig stifle joint using micro-computerized tomography. DESIGN: Hind limbs from six (N=12) and 24 (N=11) month-old male Hartley guinea-pigs were removed and the joints were imaged using high resolution micro-computerized tomography. The ossified volume of the medial and lateral menisci from both groups of animals was quantified. RESULTS: Ossification of both the medial and lateral menisci of the both the 6- and 24-month-old animals was observed. In both age groups, the ossified region of the medial meniscus was significantly larger than the lateral meniscus. In addition, there is a significant increase in ossified volume of the medial meniscus between 6 and 24 months of age. CONCLUSIONS: There is a significant amount of ossification of the menisci in the male Hartley guinea-pig, with the medial compartment showing more bone than the lateral. In addition, as the animals age, there is an increase in ossification within the medial compartment. Bone remodeling and cartilage degeneration is evident in the medial compartment within these animals as they age. It is possible that the increased ossification of the medial meniscus could alter the joint biomechanics and, in part, stimulate this medial compartment joint destruction.
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Enfermedades de los Cartílagos/complicaciones , Meniscos Tibiales , Osificación Heterotópica/complicaciones , Osteoartritis/etiología , Envejecimiento/patología , Animales , Enfermedades de los Cartílagos/diagnóstico por imagen , Enfermedades de los Cartílagos/patología , Cobayas , Miembro Posterior , Masculino , Meniscos Tibiales/diagnóstico por imagen , Osificación Heterotópica/diagnóstico por imagen , Osificación Heterotópica/patología , Tomografía Computarizada por Rayos XRESUMEN
Urotensin-II (U-II) is a vasoactive 'somatostatin-like' cyclic peptide which was originally isolated from fish spinal cords, and which has recently been cloned from man. Here we describe the identification of an orphan human G-protein-coupled receptor homologous to rat GPR14 and expressed predominantly in cardiovascular tissue, which functions as a U-II receptor. Goby and human U-II bind to recombinant human GPR14 with high affinity, and the binding is functionally coupled to calcium mobilization. Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates. The potency of vasoconstriction of U-II is an order of magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far. In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a response associated with profound cardiac contractile dysfunction. Furthermore, as U-II immunoreactivity is also found within central nervous system and endocrine tissues, it may have additional activities.
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Proteínas de Unión al GTP/agonistas , Proteínas de Unión al GTP/metabolismo , Receptores de Superficie Celular/agonistas , Receptores Acoplados a Proteínas G , Urotensinas/farmacología , Vasoconstrictores/farmacología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Calcio/metabolismo , Línea Celular , Clonación Molecular , ADN Complementario , Proteínas de Unión al GTP/genética , Humanos , Macaca fascicularis , Masculino , Datos de Secuencia Molecular , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Homología de Secuencia de Aminoácido , Distribución Tisular , Urotensinas/metabolismo , Vasoconstrictores/metabolismoRESUMEN
The neuroprotective effects of isradipine, a 2,4-dihydropyridine calcium channel blocker, has been well studied in the rat model of focal ischemia (induced by middle cerebral artery occlusion, MCAO). The present study was designed to evaluate whether isradipine pretreatment caused early (0-3 h after stroke) ischemic changes in diffusion- weighted magnetic resonance imaging (DWI) and if such changes were predictive of previously documented protection in brain infarction. An initial dose-response study using neurological deficit scores and estimates of protection from brain infarction (by histology) showed that isradipine reduced cortical infarctions compared to vehicle-treated animals at most doses (between 1.25 and 5 mg/kg/day s.c. for 6 days) with the best results obtained at 5 mg/kg/day, where a 78.5% reduction was observed. This dose was utilized to perform the DWI study. Early quantitative estimates of infarct size, as measured by DWI at 1, 2 and 3 h after MCAO, were similar to those obtained with late histology at 24 h. These data indicate that in pretreatment protocols, DWI can be used to quantitatively predict areas at risk of permanent damage. This work also demonstrates that neurological deficits, developing from the damaged forebrain following focal stroke, may provide an index of isradipine's neuroprotective activity.
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Isquemia Encefálica/prevención & control , Bloqueadores de los Canales de Calcio/uso terapéutico , Isradipino/uso terapéutico , Imagen por Resonancia Magnética/métodos , Enfermedades del Sistema Nervioso/clasificación , Animales , Isquemia Encefálica/patología , Bloqueadores de los Canales de Calcio/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inyecciones Subcutáneas , Isradipino/administración & dosificación , Masculino , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Endogámicas SHRRESUMEN
BACKGROUND: Alleviating vascular restenosis after percutaneous transluminal angioplasty remains a formidable challenge. Although multiple factors have been implicated in the pathophysiology of this vascular remodeling disorder, only limited therapeutic success has been achieved. Endothelin (ET)-1 has recently been implicated in the pathogenesis of neointimal growth. We report the in vivo efficacy of SB 217242, a nonpeptide dual ET(A)/ET(B) receptor antagonist with high oral bioavailability, in the rat carotid artery balloon angioplasty model. METHODS AND RESULTS: The lumen volumes of carotid arteries were estimated serially with magnetic resonance imaging (MRI) at baseline and at day 7 and day 14 after balloon catheter-induced denudation of the carotid arterial wall in the rat. Histomorphometric analysis was performed at day 14 after surgery to quantitate intimal hyperplasia. Statistical analysis was performed with ANOVA followed by post hoc Newman-Keuls multiple comparison test. In comparison to vehicle-treated animals, a 20% protection (P<0.05) from reduction was shown in the estimated lumen volume with long-term administration of SB 217242 (15 mg/kg BID p.o.). Histologic analyses indicated a 42% decrease (P<0.05) in neointimal growth. The MRI lumen volumes had a significant correlation with the corresponding histologic indices. CONCLUSIONS: Serial MRI provides the opportunity to assess the progression of vascular lumen volume in vivo after balloon angioplasty. MRI measurements can, in conjunction with in vitro histologic measurements, contribute to the understanding of the actions of pharmacologic agents in experimental models of neointima formation. With the use of serial MRI and histologic measurements, it is demonstrated that protection from both lumen volume reduction and neointima formation is obtained in this model by use of a potent, nonpeptide dual ET(A)/ET(B) receptor antagonist, SB 217242. Furthermore, this study provides additional support to the implication of ET-1 in the pathophysiology of neointima formation.
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Ácidos Carboxílicos/uso terapéutico , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/crecimiento & desarrollo , Antagonistas de los Receptores de Endotelina , Indanos/uso terapéutico , Imagen por Resonancia Magnética/métodos , Túnica Íntima/efectos de los fármacos , Túnica Íntima/crecimiento & desarrollo , Angioplastia de Balón , Animales , Arterias Carótidas/patología , Estenosis Carotídea/prevención & control , Estenosis Carotídea/terapia , Masculino , Ratas , Ratas Sprague-Dawley , Recurrencia , Túnica Íntima/patologíaRESUMEN
There is a tremendous unmet therapeutic need for the treatment of osteoporosis and osteoarthritis. The ovariectomized rat and the guinea pig are widely used animal models for the evaluation of new therapeutics for osteoporosis and osteoarthritis, respectively. We have utilized X-ray micro-CT techniques to quantitatively evaluate the differences in trabecular bone in the rat proximal tibia following ovariectomy and treatment with estrogen (17-B-estradiol). Results demonstrate a loss of trabecular bone and architecture following ovariectomy (p < 0.001), and a marked inhibition of trabecular bone loss in the estrogen treated group (p < 0.001). A similar change in architecture can be visualized in images obtained by high resolution MR microscopy. In addition, a good correlation was observed between the values of trabecular bone fraction (BV/TV) in the rat tibiae as obtained from 3-dimensional micro-CT data and 2-dimensional static histomorphometry (r = 0.89, 0.73, 0.79 for sham, OVX, and treated groups, respectively). Micro-CT images were also obtained from a set of lumbar vertebrae from sham operated and ovariectomized rats. Significant bone loss can be measured as early as 8 weeks following ovariectomy (p < 0.005). Micro-CT and MR images were also obtained to study age related changes in the stifle joint of the guinea pig. Significant boney changes can be seen in the tibia and femur from the animals at various ages. Changes in cartilage and joint space can also be visualized in the images. The utility of micro-CT imaging in evaluating the mouse skeletal system is illustrated by obtaining morphological and architectural details from high resolution images of the mouse hind limb and proximal tibia, respectively. The results demonstrate the advantages that multi-dimensional imaging techniques can offer in evaluating bone and joint related changes in animal models of osteoporosis and osteoarthritis.
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Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Osteoartritis/patología , Osteoporosis/patología , Tomografía Computarizada por Rayos X/métodos , Animales , Artrografía/métodos , Modelos Animales de Enfermedad , Terapia de Reemplazo de Estrógeno , Cobayas , Miembro Posterior/diagnóstico por imagen , Humanos , Ratones , Ratones Endogámicos BALB C , Osteoporosis/terapia , Ratas , Ratas Sprague-Dawley , Columna Vertebral/diagnóstico por imagen , Tibia/diagnóstico por imagenRESUMEN
Four cynomolgus macaques housed at our facility became acutely ill with dysenteric symptoms. Enteric isolates established an etiologic diagnosis of Shigella flexneri. Enrofloxacin antimicrobial therapy cleared the infection with no perceptible bacterial shedding or clinical signs of disease. High-dose methyl-prednisolone therapy was administered to the four monkeys for 5 weeks. The animals were monitored for signs of shigellosis and bacterial shedding weekly throughout the study, for a total of 7 weeks. Although methylprednisolone therapy induced marked cellular immunosuppression in all four animals, as measured by in vitro assays, no animal had evidence of clinical shigellosis or bacterial shedding. These results suggest that cynomolgus macaques naturally infected with S. flexneri and appropriately treated with enrofloxacin are unlikely to have reactivation of shigellosis and shedding of bacteria in the feces during periods of stress or profound immunosuppression.
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Antiinfecciosos/uso terapéutico , Disentería Bacilar/veterinaria , Fluoroquinolonas , Inmunosupresores/farmacología , Macaca fascicularis , Metilprednisolona/farmacología , Enfermedades de los Monos/tratamiento farmacológico , Quinolonas/uso terapéutico , Shigella flexneri/fisiología , Animales , Células Cultivadas , ADN/metabolismo , Relación Dosis-Respuesta a Droga , Disentería Bacilar/tratamiento farmacológico , Disentería Bacilar/inmunología , Enrofloxacina , Heces/microbiología , Femenino , Sistema Inmunológico/fisiología , Activación de Linfocitos , Masculino , Enfermedades de los Monos/inmunología , Enfermedades de los Monos/microbiología , Fitohemaglutininas/farmacología , Shigella flexneri/aislamiento & purificación , TritioRESUMEN
The cardiovascular response to feeding consists of two phases. The anticipation/ingestion phase is a brief, generalized cardiovascular response mediated by sympathetic neural activity. The digestive/absorptive phase is a longer, locally mediated vascular response to luminal nutrients. This post-prandial hyperaemia is localized primarily to the intestinal segment and tissue layer (mucosa) exposed to chyme. The stimuli for this hyperaemia are the digested products of food, and bile. Micellar fatty acids induce the greatest hyperaemia, followed by glucose. Individual amino acids have little effect, but by-products of protein digestion may increase blood flow. Bile enhances the glucose-induced hyperaemia and renders fatty acids and amino acids vasoactive. The mechanisms involved in the initiation and maintenance of the hyperaemia are complex and involve numerous factors that may vary with the type of nutrient. The factors involved include intestinal activity such as absorption, motility and secretion, tissue oxidative metabolism, adenosine, tissue oxygen tension, the enteric nervous system, gastrointestinal peptides such as vasoactive intestinal polypeptide, and paracrine substances such as histamine and prostanoids. The post prandial intestinal hyperaemia is probably the net result of the complex interaction of all these factors on the intestinal vascular smooth muscle.
Asunto(s)
Alimentación Animal , Perros/fisiología , Intestinos/irrigación sanguínea , Animales , Fenómenos Fisiológicos Cardiovasculares , Digestión , Hiperemia/fisiopatología , Hiperemia/veterinaria , Absorción Intestinal , Mucosa Intestinal/irrigación sanguínea , Flujo Sanguíneo RegionalRESUMEN
1. The effects of the inhibitor of nitric oxide (NO) synthesis, NG-nitro-L-arginine methyl ester (L-NAME), on systemic arterial blood pressure and jejunal motility, blood flow, and oxygen uptake have been investigated in anaesthetized dogs. 2. L-NAME (cumulative doses of 0.1-20 mg kg-1, i.v.) dose-dependently increased blood pressure and jejunal motility and decreased heart rate. The maximal response of these three variables occurred at doses, 3, 10 and 10 mg kg-1, respectively. L-NAME (cumulative doses of 0.5-5 mg kg-1) also dose-dependently induced jejunal vasoconstriction. The jejunal vascular resistance returned to control values as the cumulative doses reached 10 and 20 mg kg-1, which corresponded to the maximal increase in jejunal motility. 3. A single intravenous injection of L-NAME (10 mg kg-1) produced a prompt increase in blood pressure, which lasted for at least 50 min. 4. L-NAME (10 mg kg-1) produced a progressive rise in jejunal motility reaching its maximum (47 +/- 6 mmHg) 15 min after the administration, and lasting for 40-50 min. Both the basal lumen pressure and the amplitude of rhythmic contractions increased during this period. 5. L-NAME (10 mg kg-1) produced a triphasic change in jejunal vascular resistance and blood flow measured by timed collection of venous outflow. The blood flow decreased initially (-43% at 5 min), increased (+35%) and returned to control value between 15 and 35 min, then decreased (-35%) 40-50 min post-infusion. Jejunal vascular resistance reflected the blood flow response (+88% at both 5 and 50 min). The time during which the reversal of the vasoconstriction occurred (15-35 min) corresponded to the time of marked increase in motility, and was accompanied by a significant increase in jejunal oxygen uptake (+ 18%).6. The L-NAME-induced increase in motility was prevented by L-arginine (1 g kg-1, i.v.) but not by D-arginine pretreatment. The interim (15-35 min) changes in jejunal blood flow, vascular resistance and oxygen uptake were also prevented by L-arginine pretreatment.7. L-Arginine pretreatment attenuated L-NAME-induced hypertension for 5 min.8. The L-NAME-induced increases in jejunal vascular resistance and motility were inhibited by either local intra-arterial infusion of L-arginine (32 mM local arterial blood concentration) or topical application of 2 MicroM nitroglycerin. Infusion of D-arginine (32 mM local arterial blood concentration) had no such effect.9. The L-NAME-induced increase in blood pressure was not the mechanism by which jejunal motility was increased, because similar increases in blood pressure by mefenamate (10 mg kg-1, i.v.) had no such effect.10. Thus, inhibition of nitric oxide synthesis by L-NAME increased jejunal motility and vascular resistance and the marked increase in motility can abolish or reverse the vasoconstriction. Endogenous nitric oxide may play a role in regulating motility and blood flow in the resting canine jejunum.
Asunto(s)
Arginina/análogos & derivados , Presión Sanguínea/efectos de los fármacos , Yeyuno/efectos de los fármacos , Óxido Nítrico/antagonistas & inhibidores , Consumo de Oxígeno/efectos de los fármacos , Animales , Arginina/administración & dosificación , Arginina/farmacología , Perros , Relación Dosis-Respuesta a Droga , Electrofisiología , Femenino , Motilidad Gastrointestinal/efectos de los fármacos , Yeyuno/irrigación sanguínea , Yeyuno/fisiología , Masculino , NG-Nitroarginina Metil Éster , Nitroglicerina/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , Estereoisomerismo , Resistencia Vascular/efectos de los fármacosRESUMEN
A 13-year-old Belgian stallion developed a squamous cell carcinoma at the site of a neck laceration that had been treated topically with various irritating chemicals for 18 months. Orthovoltage treatments at 3 times over 5 years controlled the tumor. Eight years after the initial hospitalization, the area was healed and the stallion appeared healthy.
Asunto(s)
Carcinoma de Células Escamosas/veterinaria , Enfermedades de los Caballos/etiología , Neoplasias Cutáneas/veterinaria , Piel/lesiones , Anestesia General/veterinaria , Animales , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/radioterapia , Enfermedades de los Caballos/radioterapia , Caballos , Masculino , Cuello , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/radioterapia , Heridas y Lesiones/complicaciones , Heridas y Lesiones/veterinariaRESUMEN
An obstructive enterolith was diagnosed in an 11-month-old 68-kg miniature horse with a 24-hour history of mild, intermittent colic. Abdominal radiography revealed gas distention of the cecum and the right and left ascending colon, and a radiodense elliptical structure in the area of the left kidney. During exploratory laparotomy, the right dorsal colon was noticed to contain ecchymotic hemorrhage and generalized discoloration in the portion proximal to the location of the enterolith. While exteriorizing the ascending colon, it ruptured caudal to the diaphragmatic flexure in the right dorsal colon. Radiography of the enterolith did not reveal a metallic center, but division of the stone allowed identification of a canvas cloth, and chemical analysis determined the stone's composition to be ammonium magnesium phosphate. Although equine enteroliths were reported over 100 years ago and the factors involved in their formation were investigated, the reasons for their development have yet to be determined. The mean reported age of horses requiring abdominal surgery because of an obstructive enterolith is 10 years, with the youngest being 4 years. The time required for an enterolith to enlarge is unknown, although a true enterolith has not been reported in horses younger than 4 years of age.
Asunto(s)
Cálculos/veterinaria , Enfermedades del Colon/veterinaria , Enfermedades de los Caballos/etiología , Obstrucción Intestinal/veterinaria , Animales , Cálculos/química , Cálculos/complicaciones , Enfermedades del Colon/complicaciones , Enfermedades del Colon/diagnóstico por imagen , Enfermedades del Colon/etiología , Enfermedades de los Caballos/diagnóstico por imagen , Caballos , Obstrucción Intestinal/diagnóstico por imagen , Obstrucción Intestinal/etiología , Masculino , RadiografíaRESUMEN
A 5-year-old Arabian stallion with moderate effusion in the right carpal canal and intermittent lameness in this limb was diagnosed to have an osteochondroma projecting from the distal portion of the radius into the carpal canal. oral phenylbutazone treatment over the next 3 years allowed the stallion to continue its show career. Right forelimb lameness returned at that time, and ultrasonography revealed the osteochondroma impinging on the dorsal surface of the deep digital flexor tendon. The owner elected to have the osteochondroma surgically removed. The horse was anesthetized, and the carpal sheath was distended with balanced polyionic solution. A 4-mm arthroscope was inserted into the carpal sheath, and the osteochondroma projecting into the sheath was identified. The osteochondroma was removed by use of a Ferris-Smith bone rongeur, which was inserted into the carpal sheath through a stab incision over the osteochondroma. The effusion in the carpal sheath and the lameness resolved by 2 months, and the horse was returned to training 4 months after surgery.
Asunto(s)
Neoplasias Óseas/veterinaria , Síndrome del Túnel Carpiano/veterinaria , Enfermedades de los Caballos/cirugía , Cojera Animal/etiología , Osteocondroma/veterinaria , Animales , Artroscopía/veterinaria , Neoplasias Óseas/complicaciones , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/cirugía , Síndrome del Túnel Carpiano/etiología , Carpo Animal/cirugía , Quimioterapia Adyuvante , Enfermedades de los Caballos/etiología , Caballos , Masculino , Osteocondroma/complicaciones , Osteocondroma/tratamiento farmacológico , Osteocondroma/cirugía , Fenilbutazona/uso terapéuticoRESUMEN
The specific aim of this research was to test the hypothesis that intoxication with alcohol results in poor tolerance to hemorrhage. This was evaluated on the basis of blood pressure, cardiac output respiratory rate, blood flow to organs, and survival for 4 hr after hemorrhage. Four groups of six swine per group were used (control, intoxicated, hemorrhage, and intoxicated-hemorrhage). The results revealed that blood alcohol concentrations near 0.1% greatly reduced tolerance to hemorrhage. Intoxicated animals subjected to hemorrhage were unable to maintain an adequate cardiac output, blood pressure, or respiratory rate to sustain life. Pigs tolerated higher blood alcohol concentrations, up to 0.35%, when not exposed to hemorrhage. Also, unintoxicated pigs were able to compensate for severe hemorrhage. Only one of the six pigs in the intoxicated-hemorrhage group survived for 4 hr after hemorrhage. In conclusion the body's ability to compensate and recover from hemorrhage was greatly reduced during intoxication. It is logical to assume that the ability to overcome numerous other stressors may also be reduced during intoxication.