RESUMEN
Epidemiological and clinical studies have demonstrated that excessive salt intake causes severe hypertension and exacerbates organ derangement, such as in chronic kidney disease (CKD). In this study, we focused on evaluating the histological and gene expression effects in the kidneys of stroke-prone spontaneously hypertensive rats (SHRSP) with a high salt intake and the thromboxane A2 / prostaglandin H2 receptor (TPR) blocker ONO-8809. Six-week-old SHRSPs were divided into three groups and were fed normal chow containing 0.4% NaCl, 2.0%NaCl or 2.0%NaCl + ONO-8809 (0.6 mg/kg p.o. daily). Histological analyses with immunohistochemistry and a gene expression assay with a DNA kidney microarray were performed after 8 weeks. The following changes were observed in SHRSPs with the high salt intake. Glomerular sclerotic changes were remarkably observed in the juxtamedullary cortex areas. The ED1, monocyte chemoattractant protein-1 (MCP-1), nitrotyrosine and hypoxia inducible factor 1α (HIF-1α) staining areas were increased in the glomeruli and interstitial portion of the kidneys. The genes Tbxa2r (that encodes TPR), Prcp and Car7 were significantly underexpressed in the kidneys. The plasma 8-isoprostane level was significantly elevated and was attenuated with the ONO-8809 treatment. Thromboxane A2 (TXA2 ) and oxidative stress exaggerated renal dysfunction in the salt-loaded SHRSPs, and ONO-8809 as a TPR blocker suppressed these changes. Therefore, ONO-8809 is a candidate drug to prevent CKD in hypertensive patients when CKD is associated with a high salt intake.
Asunto(s)
Compuestos Bicíclicos con Puentes/farmacología , Ácidos Grasos Monoinsaturados/farmacología , Hipertensión/tratamiento farmacológico , Enfermedades Renales/tratamiento farmacológico , Receptores de Tromboxano A2 y Prostaglandina H2/antagonistas & inhibidores , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Hipertensión/patología , Hipertensión/fisiopatología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Masculino , Ratas , Ratas Endogámicas SHR , Cloruro de Sodio/administración & dosificación , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatologíaRESUMEN
Successful prevention and treatment of hypertension depend on the appropriate combination of antihypertensive drug therapy and nondrug lifestyle modification. While most hypertension guidelines recommend moderate- to high-intensity exercise, we decided to explore a mild yet effective type of exercise to add to hypertension management, especially in populations with complications or frailty. After comparing the short-term cardiovascular effects of low-speed walking versus high-speed walking for 3 kilometers (km) (3 km/h versus 6 km/h) in young, healthy volunteers, we delivered low-speed walking (low-intensity walking, 2.5 metabolic equivalents of task, METs) as exercise therapy in 42 prehypertensive and 43 hypertensive subjects. We found that one session of 3 km low-intensity walking exerted a transient pressure-lowering effect as well as a mild negative chronotropic effect on heart rate in both the prehypertensive and hypertensive subjects; these short-term benefits on blood pressure and heart rate were accompanied by a brief increase in urine ß-endorphin output. Then we prescribed regular low-intensity walking with a target exercise dose (exercise volume) of 500-1000 METs·min/week (50-60 min/day and 5-7 times/week) in hypertensive subjects in addition to their daily activities. Regular low-intensity walking also showed mild but significant blood pressure-lowering and heart rate-reducing effects in 7 hypertensive subjects within two months. It is hypothesized that regular low-intensity exercise of the necessary dose could be taken as a pragmatic and supplementary medication for hypertension management.
Asunto(s)
Hipertensión/terapia , Prehipertensión/terapia , Caminata , Adulto , Anciano , Presión Sanguínea/fisiología , Terapia por Ejercicio/métodos , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Prehipertensión/fisiopatología , betaendorfina/orinaRESUMEN
BACKGROUND: Far-infrared (FIR) is well known with various therapeutic benefits. Recently, we have developed a novel FIR bathing system called the Enseki sandbath. In this regard, we focused on physical nature of ceramic to radiate FIR rays when heated adequately. METHODS: A bathtub was filled with ceramic beads and was equipped with computerized system which enabled to supply hot water over the ceramic beads and to drain out when beads were sufficiently heated. This system was used like sandbathing. Healthy volunteers were laid in bathtubs, covered in heated ceramic beads and were bathed for 15 minutes. Microbiological analysis was done in samples obtained from the skin surface, ceramic beads, or drained water. Furthermore, various physiological parameters were monitored, including blood pressure, heart rates, oral temperature, body weight, and blood viscosity. Blood samples were simultaneously collected and subjected to biochemical analysis, including blood glucose, HbA1c, uric acid, lactate, fatty acid, and others. RESULTS: All data showed no physiological overload for tested individuals, and any biochemical analysis did not present abnormal score. Bacteriological culture grew no pathogens. Results of questionnaires demonstrated that 90% of the participants answered the comfort and wished to further repeat the bathing. LIMITATIONS: This is a nonrandomized prospective case study. CONCLUSION: We concluded that the Enseki method is a safe and well-tolerated FIR bathing procedure for regeneration and relaxation.
Asunto(s)
Baños/instrumentación , Baños/métodos , Rayos Infrarrojos , Seguridad , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Although the mesenteric artery plays a key role in regulating peripheral blood pressure, the molecular mechanisms that underlie the development of essential hypertension are not yet fully understood. MATERIALS AND METHODS: We explored candidate genes for hypertension using three related strains of spontaneously hypertensive rats (SHRs) that mimic human essential hypertension. In this study we used DNA microarrays, a powerful tool for studying genetic diseases, to compare gene expression in the mesenteric artery of three SHR substrains: SHR, stroke-prone SHR (SHRSP), and malignant SHRSP (M-SHRSP). RESULTS: Compared to normotensive 6-week old Wistar Kyoto rats (WKY), higher blood pressure correlated with overexpression of 31 genes and with down regulation of 24 genes. Adam23, which negatively regulates potassium current, and the potassium channel genes, Kcnc2 and Kcnq5, were associated with the onset of hypertension. In addition, Spock2 and Agtrap were identified as strengtheners of hypertension by analyzing up and down regulated genes at 9-weeks of age. CONCLUSIONS: Adam23, Kcnc2 and Kcnq5 appear to be factors for the onset of hypertension, while Spock2 and Agtrap are as factors that strengthen hypertension. These findings contribute to our understanding of the pathophysiology of hypertension and to the development of treatment for this condition.
Asunto(s)
Hipertensión , Animales , Presión Sanguínea/genética , Hipertensión Esencial/metabolismo , Hipertensión/genética , Hipertensión/metabolismo , Arterias Mesentéricas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Endogámicas SHRRESUMEN
Although both diabetes and hypertension are risk factors for cardiovascular disease, the role of hyperglycaemia per se in endothelial dysfunction is controversial. This study was designed to examine whether hyperglycaemia, or streptozotocin-induced diabetes, could aggravate endothelial dysfunction in stroke-prone spontaneously hypertensive rats (SHRSP). Hyperglycaemia was induced by streptozotocin in 2-month-old SHRSP and age-matched normotensive Wistar-Kyoto (WKY) rats. The aorta was isolated 8 weeks after induction of hyperglycaemia to record its function and to examine its morphology with transmission electron microscopy. Endothelial/inducible nitric oxide synthase (eNOS/iNOS) and inducible/constitutive haem oxygenase (HO-1/HO-2) levels were determined with Western blotting. Aortic endothelial function and production of reactive oxygen species and nitric oxide were assayed after incubation in vitro in hyperglycaemic, hyperosmolar solution. Streptozotocin-induced diabetes of 8 weeks duration did not result in endothelial dysfunction in normotensive WKY rats. In contrast, hyperglycaemic WKY rats showed significantly enhanced endothelium-dependent vasodilatation, which was abrogated by simultaneous blocking of NOS and HO. The enhanced vasodilatation was associated with elevation of vascular eNOS and HO-1. Significant endothelial dysfunction and massive macrophage-monocyte infiltration were found in SHRSP aorta (the ratio of the number of macrophages to endothelial cells in the intima, expressed as a percentage, was 20.9 ± 2.8% in SHRSP versus 1.9 ± 0.5% in WKY rats, P < 0.01), which was attenuated significantly in hyperglycaemic SHRSP (11.3 ± 1.6%, P < 0.01 versus SHRSP). Acute hyperglycaemia (10 min) aggravated endothelial dysfunction in SHRSP, with a marked increase in intracellular reactive oxygen species and NO production. Sustained in vitro incubation in hyperglycaemic/hyperosmolar conditions (addition of an extra 50 mmol L(-1) of glucose or mannitol to the usual buffer, to produce a final osmolarity of 350 mosmol L(-1)) for 5 h enhanced endothelium-dependent vasodilatation, with elevated vessel NO production and upregulation of eNOS/HO-1 proteins. Sustained hyperglycaemia does not aggravate endothelial dysfunction and macrophage infiltration in SHRSP. Hyperglycaemia/hyperosmolarity-induced upregulation of eNOS and HO-1 may play a role in this paradoxical adaptation of endothelial function.
Asunto(s)
Aorta Torácica/fisiopatología , Diabetes Mellitus Experimental/fisiopatología , Hiperglucemia/fisiopatología , Hipertensión/fisiopatología , Vasodilatación , Acetilcolina/farmacología , Animales , Antihipertensivos/farmacología , Aorta Torácica/metabolismo , Aorta Torácica/ultraestructura , Diabetes Mellitus Experimental/metabolismo , Hemo Oxigenasa (Desciclizante)/metabolismo , Hiperglucemia/inducido químicamente , Hiperglucemia/metabolismo , Hipertensión/metabolismo , Técnicas In Vitro , Macrófagos/fisiología , Macrófagos/ultraestructura , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Nitroprusiato/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismo , Estreptozocina , Túnica Íntima/patología , Túnica Íntima/ultraestructura , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
PURPOSE: Systemic carbamazepine, a voltage-gated sodium channel blocker, has been reported to dose-dependently reduce inflammatory hyperalgesia. However, the antinociceptive effects of carbamazepine on the spinal cord in inflammatory conditions are unclear. The aim of the present study was to evaluate the antinociceptive effects of carbamazepine on the spinal cord in a chronic inflammatory condition. METHODS: In Sprague-Dawley rats, a chronic inflammatory condition was induced by complete Freund's adjuvant (CFA) inoculation into the tail. Tail flick (TF) latencies were measured following intraperitoneal carbamazepine, or intrathecal carbamazepine or tetrodotoxin injection in intact rats and in the chronic inflammatory rats. From the values of TF latency at 60 min after drug injection, the effective dose required to produce 50% response (ED(50)) of each drug was derived. RESULTS: Carbamazepine attenuated thermal responses with both systemic and intrathecal administration. The effect was more evident in rats with chronic inflammation than in intact rats; the ED(50s) of intraperitoneal carbamazepine in intact and inflamed rats were 12.39 and 1.54 mg/kg, and those of intrathecal carbamazepine were 0.311 and 0.048 nmol, respectively. Intrathecal tetrodotoxin also clearly inhibited the response, with ED(50s) of 1.006 pmol in intact rats and 0.310 pmol in inflamed rats. The relative potencies of intrathecal carbamazepine versus tetrodotoxin for inhibition were approximately 1:150-1:300 in intact and inflamed rats. CONCLUSION: These results indicate that the inhibition of voltage-gated sodium channels, at least tetrodotoxin-sensitive channels, may contribute to the antinociceptive effect of carbamazepine on CFA-induced inflammatory pain, since lower doses of intrathecal carbamazepine and tetrodotoxin attenuated thermal responses to a greater extent in inflamed rats than in intact rats.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Artritis Experimental/complicaciones , Carbamazepina/farmacología , Hipoestesia/tratamiento farmacológico , Inflamación/complicaciones , Columna Vertebral/efectos de los fármacos , Analgésicos no Narcóticos/administración & dosificación , Anestésicos Locales/administración & dosificación , Anestésicos Locales/farmacología , Animales , Artritis Experimental/tratamiento farmacológico , Carbamazepina/administración & dosificación , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Adyuvante de Freund , Hipoestesia/etiología , Hipoestesia/patología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inyecciones Intraperitoneales , Inyecciones Espinales , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Bloqueadores de los Canales de Sodio/farmacología , Cola (estructura animal)/patología , Tetrodotoxina/administración & dosificación , Tetrodotoxina/farmacologíaRESUMEN
Stroke-prone spontaneously hypertensive rats (SHRSP) used as a model of essential hypertension cause a high incidence of brain stroke on the course of hypertension. Incidences and sizes of brain lesions are known to relate to the astrocyte activities. Therefore, relation between brain damage and the expression profile of the astrocytes was investigated with morphometric and immunohistochemical analyses using astrocyte marker antibodies of S100B and glial fibrillary acidic protein (GFAP) with or without arundic acid administration, a suppressor on the activation of astrocytes. Arundic acid extended the average life span of SHRSP. An increase in brain tissue weight was inhibited concomitant with a lower rate of gliosis/hemosiderin deposit/scarring in brain lesions. S100B- or GFAP-positive dot and filamentous structures were decreased in arundic acid-treated SHRSP, and this effect was most pronounced in the cerebral cortex, white matter, and pons, and less so in the hippocampus, diencephalon, midbrain, and cerebellum. Blood pressure decreased after administration of arundic acid in the high-dose group (100 mg/kg/day arundic acid), but not in the low-dose group (30 mg/kg/day). These data indicate that arundic acid can prevent hypertension-induced stroke, and may inhibit the enlargement of the stroke lesion by preventing the inflammatory changes caused by overproduction of the S100B protein in the astrocytes.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Caprilatos/farmacología , Fármacos del Sistema Nervioso Central/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Proteínas S100/metabolismo , Animales , Anticuerpos/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/fisiología , Presión Sanguínea/efectos de los fármacos , Encéfalo/patología , Caprilatos/administración & dosificación , Fármacos del Sistema Nervioso Central/administración & dosificación , Relación Dosis-Respuesta a Droga , Proteína Ácida Fibrilar de la Glía/inmunología , Gliosis/tratamiento farmacológico , Gliosis/metabolismo , Gliosis/patología , Hemosiderina/metabolismo , Inmunohistoquímica , Longevidad/efectos de los fármacos , Masculino , Factores de Crecimiento Nervioso/antagonistas & inhibidores , Factores de Crecimiento Nervioso/inmunología , Tamaño de los Órganos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Subunidad beta de la Proteína de Unión al Calcio S100 , Proteínas S100/antagonistas & inhibidores , Proteínas S100/inmunologíaRESUMEN
Essential hypertension is a disease of unknown pathogenesis, although renal function has been implicated as an important factor in its cause. Stroke-prone spontaneously hypertensive (SHRSP) rats provide an animal model of essential hypertension. To understand the cause of hypertension, identifying proteins that are differentially expressed between hypertensive and normotensive rats may provide a key. Here, proteins in the renal cortex from SHRSP rats, malignant stroke-prone spontaneously hypertensive (M-SHRSP) rats, and Wistar Kyoto (WKY) rats as a normotensive control were subjected to two-dimensional difference gel electrophoresis (2D-DIGE). After in-gel digestion by trypsin, proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). Several proteins showed differential expression patterns between hypertensive and normotensive rats. Among them, we focused on catechol-O-methyltransferase (COMT) because this enzyme inactivates catecholamines, possibly affecting blood pressure. To confirm the differential expression of COMT in each animal, we conducted Western blot analysis, which revealed that the expression of COMT is lower in M-SHRSP rats than in control and SHRSP rats, indicating that blood pressure and expression of COMT are related. In fact, the blood pressure of M-SHRSP rats was significantly higher than that of SHRSP rats at age of 10 weeks. Immunohistochemical and immunofluorescence studies showed that COMT in renal cortex is localized in tubular epithelial cells. The expression of COMT is lower in the renal cortex tubular epithelium of M-SHRSP rats than in normotensive rats. These results suggest that the decreased expression of COMT may be an important factor leading to the development of hypertension.
Asunto(s)
Catecol O-Metiltransferasa/metabolismo , Corteza Renal/enzimología , Corteza Renal/patología , Animales , Presión Sanguínea , Western Blotting , Electroforesis en Gel Bidimensional , Fluorescencia , Inmunohistoquímica , Corteza Renal/fisiopatología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Fracciones Subcelulares/enzimologíaRESUMEN
PURPOSE: For the suppression of descending inhibitory pathways in animals, single-dose lidocaine blockade is reversible and causes less damage than chronic spinal cord injury, decerebration, and cold blockade of the spinal cord. However, single-dose blockade has a variable onset and is relatively short-lived. To surmount these disadvantages, we devised a continuous thoracic intrathecal lidocaine infusion and evaluated its effects in rats. METHODS: Rats were administered continuous intrathecal infusions of 0, 0.25%, 0.5%, and 1% lidocaine at 10 &gml.h(-1) following a 10-&gml bolus. The effects of the continuous thoracic blockade on tail-flick (TF) latency (estimated by the percent maximum possible effect [%MPE]) and on the release of neurotransmitters in the cerebrospinal fluid (CSF) were evaluated. RESULTS: Continuous thoracic blockade with 0.5% and 1% lidocaine infusion reversibly shortened TF latency (%MPE, -22.0 +/- 11.0 % and -21.2 +/- 4.6 %, respectively, versus baseline; P < 0.05) during drug infusion. Compared with normal saline, thoracic intrathecal infusion of lidocaine significantly lowered norepinephrine and serotonin concentrations in the CSF at 1 h of infusion (P = 0.02 for both). CONCLUSION: Continuous thoracic blockade by local anesthetic resulted in reversible suppression of descending inhibitory pathways for varying durations. Such blockade may provide further information regarding nociceptive transmission and the mechanisms of antinociception in animals.
Asunto(s)
Anestésicos Locales/farmacología , Lidocaína/farmacología , Vías Nerviosas/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Anestésicos Locales/administración & dosificación , Animales , Calor , Inyecciones Espinales , Lidocaína/administración & dosificación , Masculino , Neurotransmisores/líquido cefalorraquídeo , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacosRESUMEN
OBJECTIVE: Hypertension is one of the most prevalent diseases in humans who live a modern lifestyle. Alongside more effective care, clarification of the genetic background of hypertension is urgently required. Gene expression in mesenteric resistance arteries of spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP) and two types of renal hypertensive Wistar Kyoto rats (WKY), two kidneys and one clip renal hypertensive rat (2K1C) and one kidney and one clip renal hypertensive rat (1K1C), was compared using DNA microarrays. METHODS: We used a simultaneous equation and comparative selection method to identify genes associated with hypertension using the Reactome analysis tool and GenBank database. RESULTS: The expression of 298 genes was altered between SHR and WKY (44 upregulated and 254 downregulated), while the expression of 290 genes was altered between SHRSP and WKY (83 upregulated and 207 downregulated). For SHRSP versus SHR, the expression of 60 genes was altered (36 upregulated and 24 downregulated). Several genes expressed in SHR and SHRSP were also expressed in the renovascular hypertensive 2K1C and 1K1C rats, indicative of the existence of hyper-renin and/or hypervolemic pathophysiological changes in SHR and SHRSP. CONCLUSION: The overexpression of Kcnq1, Crlf1, Alb and Xirp1 and the inhibition of Galr2, Kcnh1, Ache, Chrm2 and Slc5a7 expression may indicate that a relationship exists between these genes and the cause and/or worsening of hypertension in SHR and SHRSP.
Asunto(s)
Hipertensión , Arterias Mesentéricas , Transcriptoma/genética , Animales , Perfilación de la Expresión Génica , Hipertensión/genética , Hipertensión/metabolismo , Arterias Mesentéricas/química , Arterias Mesentéricas/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
Inflammatory processes may play a pivotal role in the pathogenesis of cerebrovascular injury in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). Recent reports revealed that acetylsalicylic acid (aspirin) has anti-oxidative properties and elicits nitric oxide release by a direct activation of the endothelial NO synthase. The present study was designed to determine whether low-dose aspirin might prevent cerebrovascular injury in salt-loaded SHRSP by protecting oxidative damage. Nine-week-old SHRSP were fed a 0.4% NaCl or a 4% NaCl diet with or without treatment by naproxen (20 mg/kg/day), salicylic acid (5 mg/kg/day), or aspirin (5 mg/kg/day) for 5 weeks. Blood pressure, blood brain barrier impairment, mortality, and the parameters of cerebrovascular inflammation and damage were compared among them. High salt intake in SHRSP significantly increased blood brain barrier impairment and early mortality, which were suppressed by treatment with aspirin independent of changes in blood pressure. Salt loading significantly increased superoxide production in basilar arteries of SHRSP, which were significantly suppressed by treatment with aspirin. Salt loading also significantly decreased NOS activity in the basilar arteries of SHRSP, which were significantly improved by treatment with aspirin. At 5 weeks after salt loading, macrophage accumulation and matrix metalloproteinase-9 activity at the stroke-negative area in cerebral cortex of SHRSP were significantly reduced by treatment with aspirin. These results suggest that low-dose aspirin may exert protective effects against cerebrovascular inflammation and damage by salt loading through down-regulation of superoxide production and induction of nitric oxide synthesis.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Estrés Oxidativo/efectos de los fármacos , Cloruro de Sodio Dietético/administración & dosificación , Accidente Cerebrovascular/prevención & control , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/uso terapéutico , Arteria Basilar/efectos de los fármacos , Arteria Basilar/enzimología , Arteria Basilar/metabolismo , Presión Sanguínea/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Masculino , Óxido Nítrico Sintasa/metabolismo , Ratas , Ratas Endogámicas , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/fisiopatología , Superóxidos/metabolismoRESUMEN
1. Although increased oxidative stress has been shown repeatedly to be implicated in diabetes, the cardiovascular anti-oxidant state and heart response to ischaemia in long-term Type 1 diabetes remain largely unknown. The present study was designed to observe heart tolerance to ischaemia-reperfusion and endogenous anti-oxidants in the cardiovascular system in long-term hyperglycaemic rats. 2. Hearts from Sprague-Dawley rats surviving up to 6 months with streptozocin-induced severe hyperglycaemia (blood glucose > 20 mmol/L) were isolated and subjected to global ischaemia and reperfusion. Cardiac function, electrocardiogram and anti-oxidants in the myocardium and aorta were examined. In addition, the morphology of the myocardial mitochondria and the in vitro function of aortic vessels were assessed. 3. Hearts from diabetic rats demonstrated lower baseline heart function but had higher postischaemic coronary flow and left ventricular developed pressure compared with their respective controls (P < 0.05). In addition, hearts from diabetic animals had fewer arrhythmias (P < 0.01) and lower left ventricular end-diastolic pressure during reperfusion (P < 0.05). Higher catalase and heme oxygenase-1 content was found in the aorta and myocardium from diabetic rats (P < 0.01). In aortas from diabetic animals, acetylcholine-induced vasodilatation was enhanced and was approximately 15% after inhibition of nitric oxide synthase, compared with 0% in controls. The 15% relaxation was abrogated by heme oxygenase blockade. Mitochondria from the myocardium of diabetic rats showed significant increases in both size and number (P < 0.05). 4. Hearts of long-term Type 1 diabetic rats demonstrated improved recovery of postischaemic cardiac function and reduced reperfusion arrhythmia. Hyperglycaemia may enhance cardiovascular anti-oxidant capacity and mitochondrial neogenesis, which renders the heart resistant to ischaemia and oxidative injury.
Asunto(s)
Antioxidantes/fisiología , Catalasa/biosíntesis , Diabetes Mellitus Tipo 1/enzimología , Hemo-Oxigenasa 1/biosíntesis , Isquemia Miocárdica/enzimología , Recuperación de la Función/fisiología , Animales , Antioxidantes/metabolismo , Arritmias Cardíacas/enzimología , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/prevención & control , Catalasa/fisiología , Diabetes Mellitus Tipo 1/fisiopatología , Diabetes Mellitus Tipo 1/terapia , Activación Enzimática/fisiología , Hemo-Oxigenasa 1/fisiología , Técnicas In Vitro , Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/prevención & control , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Inflammatory processes may play a pivotal role in the pathogenesis of cerebrovascular injury in salt-loaded, stroke-prone, spontaneously hypertensive rats (SHRSP). Thromboxane A2 (TP) receptor stimulation by 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) is involved in the process of vascular inflammation. OBJECTIVE: In the present study, we examined the involvement of TP receptor in the development of cerebrovascular damage in salt-loaded SHRSP. METHODS: Nine-week-old SHRSP were fed a 0.4% NaCl or a 4% NaCl diet with or without ONO-8809 treatment (a TP receptor antagonist) for 5 weeks. Blood pressure, mortality, and the parameters of cerebrovascular inflammation and damage were compared between the groups. Moreover, we examined the effect of 8-iso-PGF2alpha infusion on cerebrovascular injury of SHRSP. RESULTS: High salt intake in SHRSP significantly increased blood-brain barrier impairment and early mortality, which were suppressed by ONO-8809 treatment independent of changes in blood pressure. Salt loading also significantly increased superoxide production in basilar arteries of SHRSP, which was suppressed by ONO-8809 treatment. Macrophage accumulation and matrix metalloproteinase-9 (MMP-9) activity in the stroke-negative area in the contralateral cerebral cortex to the stroke lesion of salt-loaded SHRSP and 8-iso-PGF2alpha-treated SHRSP were significantly reduced by ONO-8809 treatment. The ONO-8809 treatment prevented thinning of the vessel layer in cerebral arterioles of salt-loaded SHRSP and 8-iso-PGF2alpha-treated SHRSP. CONCLUSIONS: These results suggest that TP receptor stimulation by 8-iso-PGF2alpha may involve salt loading-induced stroke through activation of cerebrovascular inflammation and damage.
Asunto(s)
Dinoprost/análogos & derivados , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismo , Cloruro de Sodio Dietético/efectos adversos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/metabolismo , Vasoconstrictores/farmacología , Análisis de Varianza , Animales , Arteria Basilar/efectos de los fármacos , Arteria Basilar/metabolismo , Biomarcadores/sangre , Presión Sanguínea/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Compuestos Bicíclicos con Puentes/farmacología , Arterias Cerebrales/efectos de los fármacos , Arterias Cerebrales/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Quimiocina CCL2/sangre , Dinoprost/farmacología , Modelos Animales de Enfermedad , Ácidos Grasos Monoinsaturados/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Ratas , Ratas Endogámicas SHR , Receptores de Tromboxano A2 y Prostaglandina H2/antagonistas & inhibidores , Receptores de Tromboxano A2 y Prostaglandina H2/efectos de los fármacos , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/fisiopatología , Superóxidos/metabolismo , Factores de Tiempo , Túnica Media/efectos de los fármacos , Túnica Media/metabolismo , Túnica Media/fisiopatologíaRESUMEN
In order to examine the effects of Kami-kihi-to (KKT or Jia-Wei-Gui-Pi-Tang) on osteopenia, we measured bone mineral density using computed X-ray absorptometry and monitored metabolism and bone tissue in an ovariectomized (OVX) rat model. Bone mineral density was significantly lower in the OVX group than in normal group 3 months after ovariectomy. However, the bone mineral density of the OVX group administered KKT was clearly higher than that of the untreated OVX group. Locomotor activity was regular in the normal group and in the OVX groups before administration of KKT. After 6-month administration of KKT, in OVX groups, the pattern of locomotor activity became diphasic with clear active and resting phases, as was also observed in the normal group. The locomotor activity did not decrease in the OVX groups after administration of KKT. At 6 months, the continuity of the trabecular bone was higher in the OVX group administered KKT than in the untreated OVX group. These results indicate that KKT improved the menopausal symptoms and increased the locomotor activity of the OVX group, thereby increasing bone mineral density.
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Enfermedades Óseas Metabólicas/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Osteoporosis/tratamiento farmacológico , Animales , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas Metabólicas/patología , Femenino , Actividad Motora/efectos de los fármacos , Osteoporosis/patología , Ovariectomía , Ratas , Ratas WistarRESUMEN
Cardiovascular disease is one of the most important causes of morbidity and mortality in diabetes mellitus, but there has been controversy over functional impairment of diabetic hearts and their tolerance to ischemia. We studied ischemic heart function in type 2 diabetic rats with different degrees of hyperglycemia and its relationship with cardiac norepinephrine release. Otsuka Long-Evans Tokushima Fatty rats (OLETF) and age-matched Long-Evans Tokushima Otsuka normal rats (LETO) were used. One group of OLETF rats was given 30% sucrose in drinking water (OLETF-S). Hearts were isolated and perfused in a working heart preparation and subjected to 30 min ischemia followed by 40 min reperfusion at age of 12 months. Hemodynamics and coronary norepinephrine overflow were examined. Fasting plasma glucose in OLETF increased markedly at 12 months and sucrose administration exacerbated hyperglycemia in diabetic rats (LETO 6.6 +/- 0.5, OLETF 8.3 +/- 0.7, OLETF-S 15.0 +/- 1.7 mmol/L, P < 0.01). Basic cardiac output in OLETF was decreased as compared with LETO and OLETF-S (LETO 29.4 +/- 2.5, OLETF 24.0 +/- 2.4, OLETF-S 27.0 +/- 0.9 ml/min/g, P < 0.05) and remained very low after ischemia, while in OLETF-S it was well preserved (OLETF 4.2 +/- 2.1, OLETF-S 13.7 +/- 2.6 ml/min/g, P < 0.01). Correspondently, cardiac norepinephrine released during ischemia and reperfusion was lower in OLETF-S (OLETF 2.3 +/- 1.0, OLETF-S 0.7 +/- 0.1 pmol/ml, P < 0.01). Thus, OLETF hearts were more vulnerable to ischemia but sucrose feeding rendered their hearts resistant to ischemia. Less norepinephrine release may play a role in preventing postischemic functional deterioration in sucrose-fed diabetic hearts.
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Diabetes Mellitus Tipo 2/fisiopatología , Isquemia Miocárdica/fisiopatología , Sacarosa/farmacología , Envejecimiento/fisiología , Animales , Arritmias Cardíacas/fisiopatología , Glucemia/metabolismo , Circulación Coronaria/fisiología , Diabetes Mellitus Tipo 2/patología , Masculino , Isquemia Miocárdica/patología , Reperfusión Miocárdica , Miocardio/metabolismo , Miocardio/patología , Norepinefrina/metabolismo , Norepinefrina/orina , Ratas , Ratas Endogámicas OLETF , Sistema Nervioso Simpático/fisiologíaRESUMEN
To examine the effectiveness of the herbal medicine prescription, Shu-Jing-Huo-Xue-Tang (SJHXT), for pain relief, we performed a study using rats with adjuvant arthritis (AA). After injecting the adjuvant, AA rats were maintained for 6 months as a chronic pain model. Starting at 6 months, SJHXT was administered for 12 weeks. We measured the tail skin temperature and locomotor activity of rats using thermography and a metabolism measuring system, respectively, before and after 12 weeks of SJHXT administration. Normal rats were used as controls. Before SJHXT administration, the tail surface temperature and locomotor activity were significantly lower in the AA rats than in the control rats. The tail skin temperature and locomotor activity of SJHXT-treated AA rats were significantly higher than those of the control rats. These findings suggest that the pain relief effects of SJHXT may be primarily due to increased blood circulation.
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Artritis Experimental/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Dolor/tratamiento farmacológico , Animales , Temperatura Corporal , Femenino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Cola (estructura animal) , Termografía , AguaRESUMEN
OBJECTIVE: To clarify the role of chymase in hypertension, we evaluated the effect of a chymase inhibitor, TY-51469, on vascular dysfunction and survival in stroke-prone spontaneously hypertensive rats (SHR-SP). METHODS: SHR-SP were treated with TY-51469 (1âmg/kg per day) or placebo from 4 to 12 weeks old or until death. Wistar-Kyoto rats were used as a normal group. RESULTS: SBP was significantly higher in both the placebo and TY-51469 groups than in the normal group, but there was no significant difference between the two treatment groups. Plasma renin, angiotensin-converting enzyme activity and angiotensin II levels were not different between the placebo and TY-51469 groups. In contrast, vascular chymase-like activity was significantly higher in the placebo than in the normal group, but it was reduced by TY-51469. Acetylcholine-induced vascular relaxation was significantly higher in the TY-51469 group than in the placebo group. There was significant augmentation of the number of monocytes/macrophages and matrix metalloproteinase-9 activity in aortic tissue from the placebo group compared with the normal group, and these changes were attenuated by TY-51469. There were also significant increases in mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-α in the placebo group that were attenuated by TY-51469. Cumulative survival was significantly prolonged in the TY-51469 group compared with the placebo group. CONCLUSION: Chymase might play an important role in vascular dysfunction via augmentation both of matrix metalloproteinase-9 activity and monocyte/macrophage accumulation in SHR-SP, and its inhibition may be useful for preventing vascular remodeling and prolonging survival.
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Quimasas/antagonistas & inhibidores , Endotelio Vascular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Sulfonamidas/uso terapéutico , Tiofenos/uso terapéutico , Animales , Peso Corporal , Quimasas/genética , Quimasas/fisiología , Endotelio Vascular/fisiopatología , Hipertensión/mortalidad , Hipertensión/fisiopatología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Miocardio/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Endogámicas SHR , Renina/sangre , Sulfonamidas/farmacología , Sístole/efectos de los fármacos , Sístole/fisiología , Tiofenos/farmacologíaRESUMEN
We investigated large vessel function in lean Goto-Kakizaki diabetic rats (GK) and Otsuka Long-Evans Tokushima Fatty diabetic rats (OLETF) with possible roles of hyperglycemia/hyperosmolarity and insulin. Both young and old GK showed marked hyperglycemia with normal insulin level and well-preserved endothelium-dependent and endothelium-independent vasodilation in aorta and carotid artery. There were significant elevations in endothelial/inducible nitric oxide synthase (eNOS/iNOS) and inducible/constitutive heme oxygenase (HO-1/HO-2) in GK. The endothelium-dependent vasodilation in GK was inhibited partly by NOS blockade and completely by simultaneous blocking of HO and NOS. In contrast, OLETF showed hyperinsulinemia and mild hyperglycemia but significant endothelium dysfunction beginning at early ages with concomitantly reduced eNOS. Insulin injection corrected hyperglycemia in GK but induced endothelium dysfunction and intima hyperplasia. Hyperglycemia/hyperosmolarity in vitro enhanced vessel eNOS/HO. We suggest that hyperinsulinemia plays a role in endothelium dysfunction in obese diabetic OLETF, while hyperglycemia/hyperosmolarity-induced eNOS/HO upregulation participates in the adaptation of endothelium function in lean diabetic GK.