Neuroprotective Effect of Plasminogen Activator Inhibitor-1 Antagonist in the Rat Model of Mild Traumatic Brain Injury.

Plasminogen activator inhibitor-1 (PAI-1) antagonists are known for their neuroprotective effects. In this study, it was aimed to investigate the possible protective effects of PAI-1 antagonists in a rat mild traumatic brain injury (TBI) model. Sprague-Dawley male rats were grouped as sham (n = 7), TBI (n = 9), and TBI + PAI-1 antagonist (5 and 10 mg/kg TM5441 and TM5484; n = 6-7). Under anesthesia, TBI was induced by dropping a metal 300-g weight from a height of 1 m on the skull. Before and 24-h after trauma neurological examination, tail suspension, Y-maze, and novel object recognition tests were performed. Twenty-four hours after TBI, the rats were decapitated and activities of myeloperoxidase, nitric oxide release, luminol-, and lucigenin-enhanced chemiluminescence were measured. Also, interleukin-1ß, interleukin-6, tumor necrosis factor, interleukin-10, tumor growth factor-ß, caspase-3, cleaved caspase-3, and PAI levels were measured with the ELISA method in the brain tissue. Brain injury was graded histopathologically following hematoxylin-eosin staining. Western blot and immunohistochemical investigation for low-density lipoprotein receptor, matrix metalloproteinase-3, and nuclear factor-κB were also performed. Data were analyzed using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA) and expressed as means ± SEM. Values of p < 0.05 were considered to be statistically significant. Higher levels of myeloperoxidase activity in the TBI group (p < 0.05) were found to be suppressed in 5 and 10 mg/kg TM5441 treatment groups (p < 0.05-p < 0.01). The tail suspension test score was increased in the TBI group (p < 0.001) and decreased in all treatment groups (p < 0.05-0.001). The histologic damage score was increased statistically significantly in the cortex, dentate gyrus, and CA3 regions in the TBI group (p < 0.01-0.001), decreased in the treatment groups in the cortex and dentate gyrus (p < 0.05-0.001). PAI antagonists, especially TM5441, have antioxidant and anti-inflammatory properties against mild TBI in the acute period. Behavioral test results were also improved after PAI antagonist treatment after mild TBI.

Daily Physical Activity in Children and Adolescents with Low Lumbar and Sacral Level Myelomeningocele.

PURPOSE: Children with low lumbar and sacral level myelomeningocele are expected to be community ambulators. However, they do not always meet the expected ambulation level by the time they reach adulthood. The purpose of this study is to investigate daily activity energy expenditure and physical activity levels of these patients in daily routine. MATERIALS AND METHODS: 20 patients and 20 healthy peers were included in this case-control study. Omnidirectional accelerometer monitor was used for assessing activity energy expenditure, and daily durations spent in sedentary, light activity, and moderate to vigorous physical activity levels (NCT04186338). RESULTS: Mean activity energy expenditure and moderate to vigorous physical activity duration were significantly lower in the patient group, while age was positively correlated with sedentary time and negatively correlated with light activity time. CONCLUSIONS: In patients with myelomeningocele, increasing daily activity energy expenditure and moderate to vigorous physical activity and, especially as age progresses, decreasing the sedentary behavior may assist in providing the expected ambulation level. These patients should be encouraged to partake in regular exercise programs.

Effects of Three Different Frequencies of Aerobic Physical Activity on Heart and Kidney Tissues in Type 2 Diabetes-Induced Rats.

OBJECTIVE: Exercise has many beneficial effects in the treatment and prevention of Type 2 Diabetes Mellitus (T2DM). The aim of this study was to evaluate the effect of physical activities with different frequencies performed within a total total duration of one week on the heart and kidney tissues and vascular endothelial growth factor (VEGF) expressions in experimental T2DM model. METHOD: Rats (n: 30) were divided into sedentary control (SC), sedentary T2DM (SD), T2DM and continuous exercise (DEc, 30 min/day, 5 days/week), T2DM and short bouts exercise (DEsb, 3x10 min/day, 5 days/week), T2DM and weekend warrior exercise (DEww, 35+40 min/day, 2 days/week) groups. Rats were administered streptozotocin (65 mg/kg) and nicotinamide (110 mg/kg) through intraperitoneal route. After 6-weeks of swimming exercise (total duration 150 min/week), biochemical analyzes were performed to measure oral glucose tolerance test, insulin sensitivity and cytokines. Histopathological and immunohistochemical analyses [VEGF, capillary density, Transforming growth factor beta (TGF-ß)] were performed in heart and kidney tissues. RESULTS: Compared with sedentary T2DM rats, significant improvements were observed in all exercise groups in terms of blood glucose level, insulin sensitivity, capillary density in heart tissue, VEGF expressions in tissues, TGF-ß expressions in kidney tissue and all histopathological analysis (p<0.05). CONCLUSION: This study shows that physical activity at various frequencies may significantly ameliorate harmful effects of T2DM on heart and kidney tissue without significant differences between exercise frequencies, provided that the total duration of aerobic exercise remains the same (150 min/week).

Analysis of Postural Stability and Daily Energy Expenditure to Manage Tumor Patients' Functional Expectation.

BACKGROUND: Advances in surgical techniques, implant technology, radiotherapy, and chemotherapy have increased the recovery chances of patients with bone sarcomas. Accordingly, patients' expectations on life quality have also increased, highlighting the importance of objective evaluation of the functional results of reconstruction. METHODS: Thirteen patients with distal femoral endoprosthesis, who had been followed for an average of 2.9 years were evaluated. Postural stability, daily energy expenditure, muscle power, and range of motion were the four parameters analyzed in this study. The Musculoskeletal Tumor Society (MSTS) score and Toronto Extremity Salvage Score (TESS) were used to assess postoperative function and examine correlations with other parameters. RESULTS: Patients had sedentary activities in 84% of their daily lives. They exhibited a slower speed in the walk across test and a higher sway velocity in the sit-to-stand test (p = 0.005). MSTS scores were significantly correlated with the daily energy expenditure and walking speed. CONCLUSIONS: Objective functional results acquired from various clinics will provide significant data to compare reconstruction techniques, rehabilitation protocols, and surgical techniques. In this way, it will be possible to satisfy the expectations of patients that increase in relation to enhanced recovery.

Effects of different aerobic exercise frequencies on streptozotocin-nicotinamide-induced type 2 diabetic rats: Continuous versus short bouts and weekend warrior exercises.

BACKGROUND: Exercise training is known to have multiple beneficial effects on type 2 diabetes mellitus (T2DM). The aim of this study was to explore the effects of aerobic exercise frequency on diabetic parameters, the histopathological structure of skeletal muscle, diabetic myopathy, and mitochondrial enzyme activity in an experimental model of T2DM. METHODS: Sprague-Dawley rats (n = 35) were rendered diabetic by injection of nicotinamide (110 mg/kg) and streptozotocin (65 mg/kg). Rats with blood glucose concentrations between 7 and 17 mmol/L were used. Diabetic rats were randomly allocated to one of the following groups: (i) control sedentary; (ii) diabetic sedentary; (iii) diabetic with continuous exercise (30 min/day, 5 days/week); (iv) diabetic with short bouts of exercise (3 × 10 min/day, 5 days/week); and (v) diabetic rats as "weekend warriors" (35 + 40 min/day, 2 days/week). After 6 weeks swimming exercise (total duration 150 min/week), biochemical tests were performed to measure insulin, glucose, cytokines, serum and muscle myeloperoxidase (MPO), and malondialdehyde (MDA) levels. Histologic analysis (histomorphometric and mitochondrial enzyme analysis) was also performed. RESULTS: Compared with diabetic sedentary rats, significant improvements were observed in all exercise groups in terms of glucose levels, weight loss, tissue MPO and MDA levels, muscular connective tissue, muscle atrophy, mitochondrial enzyme, and all histomorphometric analyses. CONCLUSIONS: The results of the study emphasize the effects of training on inflammation, increased oxidative stress, myopathy, and mitochondrial damage in a rat model of T2DM, and demonstrate that there is no major difference between exercise modalities provided that the total duration of exercise remains the same.

Treatment with milk thistle extract (Silybum marianum), ursodeoxycholic acid, or their combination attenuates cholestatic liver injury in rats: Role of the hepatic stem cells.

BACKGROUND/AIMS: Cholestasis, which results in hepatic cell death, fibrosis, cirrhosis, and eventually liver failure, is associated with oxidative stress. The aim of this study was to evaluate the effects of milk thistle (MT, Silybum marianum) and ursodeoxycholic acid (UDCA) or their combination on the activation of hepatic stem cells and on the severity of cholestasis liver injury in rats. MATERIALS AND METHODS: Under anesthesia, bile ducts of female Sprague Dawley rats were ligated (BDL) or had sham operation. BDL rats were administered saline, UDCA (15 mg/kg/d), MT (600 mg/kg/d), or UDCA+MT by gavage for 10 days. On the 11th day, rats were sacrificed and blood and liver samples were obtained. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic malondialdehyde (MDA) levels, and myeloperoxidase (MPO) activity were measured. Hepatic injury, a-smooth muscle actin expression, and stem cell markers c-kit, c-Myc, Oct3/4, and SSEA-1 were histologically determined. RESULTS: Histological scores, serum ALT, and hepatic MDA levels were higher in BDL group than in the sham rats, while all treatments significantly reduced these levels. The reduction in ALT was significantly greater in UCDA+MT-treated group than in other treatment groups. c-Kit, c-Myc, Oct3/4, and SSEA-1 were increased in saline-treated BDL group with respect to sham-operated control group, and these markers were significantly reduced in all treatment groups. CONCLUSION: In addition to a modulatory effect on the stem cell-induced regenerative response of the liver, UDCA, MT, and their combination demonstrated similar anti-inflammatory and antiproliferative effects on cholestasis-induced hepatic injury.

Effects of MC4R, FTO, and NMB gene variants to obesity, physical activity, and eating behavior phenotypes.

Obesity is a major contributory factor of morbidity and mortality. It has been suggested that biological systems may be involved in the tendency to be and to remain physically inactive also behaviors such as food and beverage preferences and nutrient intake may at least partially genetically determined. Consequently, besides environment, genetic factors may also contribute to the level of physical activity and eating behaviors thus effect obesity. Therefore the aim of this study is to investigate the effect of various gene mutations on obesity, physical activity levels and eating behavior phenotypes. One hundred patients and 100 controls were enrolled to the study. Physical activity levels were measured with an actical acceloremeter device. Eating behaviors were evaluated using Three-Factor Eating questionnaire (TFEQ). Associations between eating behavior scores and physical characteristics were also evaluated. The information about other obesity risk factors were also collected. Mutations were investigated with PCR, direct sequencing and Real-Time PCR. rs1051168, rs8050146 -2778C > T mutations were found statistically significant in patients, rs1121980 was found statistically significant in controls. 21 mutations were found in MC4R and near MC4R of which 18 of them are novel and 8 of them cause amino acid change. In addition, it was found that, some obesity related factors and questions of TFEQ are associated with various investigated gene mutations. Any relation between gene mutations and physical activity levels were not detected. It is thought that, due to the genotype data and eating behaviors, it may be possible to recommend patients for proper eating patterns to prevent obesity. © 2016 IUBMB Life, 68(10):806-816, 2016.

PULMONARY AND BIOCHEMICAL CHARACTERISTICS OF SMOKER AND NON-SMOKER MODERN DANCERS / CARACTERISTICAS PULMONARES E BIOQUÍMICAS DE DANÇARINOS MODERNOS FUMANTES E NÃO-FUMANTES / CARACTERÍSTICAS PULMOMARES Y BIOQUÍMICAS DE BAILARINAS MODERNAS FUMADORAS Y NO FUMADORAS

ABSTRACT Introduction: Although the harmful effects of smoking on the cardiovascular and respiratory systems have been established for a long time, the effect on physiological and physical parameters in modern female dancers is not well documented. Objective: To determine differences in selected pulmonary functions, biochemical parameters, and body composition in female smoker and non-smoker modern dancers who are university or graduate students. Methods: A total of twenty-two female modern dancers (mean age of 24.6 ± 4.3 years), who were non-smokers (n = 11) and smokers (n = 11), voluntarily participated in the study. The smokers had been smoking 1 to 20 cigarettes per day for an average period of seven years. The pulmonary function test Mir Spirobank Spirometer, (Italy) was applied; selected biochemical parameters were tested, and various anthropometric measurements (height, weight and seven skinfold thickness) were performed. The results of body composition were evaluated using Jackson-Pollock equations. Intergroup comparisons were performed using the Mann-Whitney U test. Result: No significant differences were found between smoker and non-smoker dancers in terms of body composition (body fat, % body fat, lean body fat) and selected biochemical parameters (p > 0.05). However, non-smokers had prediction values of forced expiratory volume during the first second (FEV1) and peak expiratory flow (PEF) significantly better (p < 0.05). The effect of smoking on the performance of female modern dancers should be examined in a longitudinal study, with a higher number of participants. Conclusion: It was observed that smoking reduces lung pulmonary capacity at a certain rate, although the biochemical parameters and body composition of the female smoker and non-smoker dancers were similar.

RESUMO Introdução: Embora os efeitos nocivos do fumo nos sistemas cardiovascular e respiratório tenham sido estabelecidos há muito, o efeito sobre os parâmetros fisiológicos e físicos em bailarinas de dança moderna não foi bem documentado ainda. Objetivo: Determinar as diferenças em funções pulmonares selecionadas, parâmetros bioquímicos e composição corporal em bailarinas de dança moderna fumadoras e não-fumadoras, universitárias e pós-universitárias. Métodos: Vinte e duas bailarinas de dança moderna (média de idade de 24,6 ± 4,3 anos), não fumantes (n = 11) e fumantes (n = 11), participaram voluntariamente no estudo. As fumantesconsumiram de 1 a 20 cigarros por dia durante uma média de sete anos. Foi aplicado o teste funcional pulmonar Mir Spirobank Spirometer, (Itália), alguns parâmetros biomédicos selecionados foram testados e foram realizadas várias medições antropométricas (altura, peso e sete espessuras de pregas cutâneas). Os resultados da composição corporal foram avaliados usando equações Jackson-Pollock. As comparações intergrupo foram realizadas usando o teste "U" de Mann-Whitney. Resultado: Não foram encontradas diferenças significativas entre as bailarinas fumantes e não fumantes quanto à composição corporal (gordura corporal, % massa gorda, massa corporal magra) e nos parâmetros bioquímicos selecionados (p > 0,05). No entanto, as não fumantes tinham valores de predição do volume expiratório forçado no primeiro segundo (VEF1) e pico de fluxo expiratório (PFE) significativamente melhores (p < 0,05). O efeito do tabagismo no desempenho de bailarinas de dança moderna deveria ser examinado num estudo longitudinal, com um maior número de participantes. Conclusão: Foi observado que o fumo reduz a capacidade pulmonar a uma certa taxa, embora os padrões bioquímicos e a composição corporal das bailarinas fumantes e não fumantes fossem semelhantes.

RESUMEN Introducción: Aunque los efectos nocivos del tabaco en los sistemas cardiovascular y respiratorio hayan sido establecidos hace mucho, el efecto sobre los parámetros fisiológicos y físicos en bailarinas de danza moderna no fue aún bien documentado. Objetivo: Determinar las diferencias en funciones pulmonares seleccionadas, parámetros bioquímicos y composición corporal en bailarinas de danza moderna fumadoras y no fumadoras, universitarias y post universitarias. Método: Veintidós bailarinas de danza moderna (edad promedio de 24,6 ± 4,3 años), no fumadoras (n=11) y fumadoras (n=11), participaron voluntariamente en el estudio. Las fumadoras habían fumado desde 1 hasta 20 cigarrillos por día durante un promedio de siete años. Fue aplicado el test funcional pulmonar espirómetro Mir Spirobank, (Italia), y fueron hechos algunos tests de parámetros biomédicos seleccionados y hechas varias mediciones antropométricas (altura, peso y siete espesores de los pliegues cutáneos). Los resultados de la composición corporal fueron evaluados usando ecuaciones Jackson-Pollock. Las comparaciones intergrupales fueron realizadas usando el test Mann-Whitney U. Resultado: No fueron encontradas diferencias significativas entre bailarinas fumadoras y no fumadoras en la composición corporal (grasa corporal, % de masa grasa, masa corporal magra) y en los parámetros bioquímicos seleccionados (p > 0,05). Sin embargo, las no fumadoras tuvieron valores de predicción del volumen espiratorio forzado en el primer segundo (VEF1) y del flujo espiratorio máximo (FEM) significativamente mejores (p < 0,05). El efecto del tabaco en el desempeño de bailarinas de danza moderna debería ser examinado en un estudio longitudinal, con un aumento del número de participantes. Conclusión: Se observó que el tabaco reduce la capacidad pulmonar a una cierta tasa, aunque los estándares bioquímicos y la composición corporal de las bailarinas fumadoras y no fumadoras fueron similares.

Isokinetic strength profiles of thigh muscles of modern dancers in relation to their experience level.

UNLABELLED: The aim of this study was to determine maximal voluntary peak torque (PT), PT% body weight (PT%BW), total work (TW), and hamstring/quadriceps ratio (HQR) for bilateral and unilateral thigh muscle strength during isokinetic muscle contractions in modern dancers in relation to their experience level. METHODS: Twenty-two female dancers were divided into two groups: intermediate dancers (ID, n=11) and advanced dancers (AD, n=11). Strength tests were performed using the Biodex System-III Pro Multijoint System isokinetic dynamometer to determine three joint angular velocities (60, 180, 300°/s). RESULTS: During extension, ADs exhibited higher ratios in the HQR (p=0.016) on right leg at 300°/s, IDs generated greater TW (p=0.042), and within groups, there was a significant left-to-right difference in the HQR at 300°/s for ADs (p=0.042). During flexion, within groups, the ADs exhibited significant differences between legs for both PT (p=0.026) and PT%BW (p=0.022) at 300°/s. CONCLUSION: For both groups, the average HQR in all angular velocities was not within the recommended range, which is required to prevent injuries; at the same time, unilateral muscular imbalances existed. Lower extremities of ADs exhibited asymmetric strength patterns at a certain level. Further research should be done to confirm the findings of this pilot study.

Impaired vasomotor function induced by the combination of hypertension and hypercholesterolemia.

Although it is well known that endothelial function is compromised in the presence of either hypertension (HTN) or hypercholesterolemia (HCh), less is known about whether and how the combination of these risk factors (HTN+HCh) results in impaired endothelium-dependent dilation (EDD). The aims of this study were to evaluate the influence of HTN+HCh on vasomotor function and to identify the mechanisms that underlie the altered vascular reactivity elicited by HTN+HCh. Endothelium-dependent and -independent vasomotor responses of aortic vessels were studied in mice with diet-induced HCh and/or HTN induced by chronic administration of either angiotensin II (AngII) or deoxycorticosterone acetate-salt. HTN+HCh elicited an impairment of EDD that appeared between each risk factor alone. Incubation with catalase resulted in more severe EDD impairment. Each risk factor enhanced vascular H2O2 production, but a larger response was noted with HTN+HCh. An attenuated EDD was not observed in AngII type 1a receptor deficient (AT1r(-/-)) mice, but AT1r(-/-) bone marrow chimeras exhibited more profound impairment compared with wild-type. HTN+HCh does not exert an additive effect of vasomotor dysfunction compared with either risk factor alone, and both H2O2 and blood cell-associated AT1r contribute to the impaired EDD responses in mice with HTN+HCh.

The involvement of nitric oxide and endothelin-1 in exercise-induced bronchospasm in young soccer players.

OBJECTIVES: To investigate the levels of nitric oxide (NO) and endothelin-1 (ET-1) in soccer players with exercise-induced bronchospasm (EIB), to test whether these endogenous vasoactive molecules are involved in the development of EIB, and to examine the possible participation of reactive oxygen metabolites in these alterations. DESIGN: Observational study. SETTING: Football club. PARTICIPANTS: Forty-three soccer players (N = 43) aged 16 to 22 years performed maximal exercise test on a treadmill by using Bruce protocol. INTERVENTIONS: Respiratory function tests were evaluated before and after exercise tests. Participants were grouped as control (n = 35) or EIB (n = 8) groups according to the respiratory function test results. MAIN OUTCOME MEASURES: Endothelin-1 (ET-1), nitric oxide (NO), carbonyl, malondialdehyde, and glutathione levels were determined from the blood samples taken before and after exercise tests. RESULTS: In the control group, significant decreases in plasma ET-1 and serum NO levels were determined after exercise. On the other hand, plasma malondialdehyde and carbonyl levels were significantly decreased, whereas glutathione levels were significantly increased after exercise. In the EIB group, blood levels of NO, ET-1, carbonyl, and malondialdehyde after exercise were found to be significantly increased compared with pre-exercise levels. CONCLUSIONS: These findings demonstrate that in young soccer players, EIB is associated with elevated serum NO and plasma ET-1 levels. Moreover, significant increases in lipid peroxidation and protein oxidation and decreases in antioxidant sulfhydryl (RSH) content indicate a significant compromise in the blood antioxidant status and the presence of systemic oxidative stress in young athletes with EIB.

Diet-supported aerobic exercise reduces blood endothelin-1 and nitric oxide levels in individuals with impaired glucose tolerance.

BACKGROUND: Impaired glucose tolerance (IGT) forms an intermediate stage in the natural history of diabetes mellitus. Insulin-resistant states might be associated with dysfunction of the vascular endothelium. OBJECTIVES: To determine the effects of chronic exercise and a low-calorie diet on plasma nitric oxide (NO) and endothelin-1 (ET-1) levels in patients with IGT and to elucidate the relationship between the oxidant stress markers and NO/ET-1 levels of blood before and after exercise. METHODS: Patients with IGT (n = 14) participated in a regular exercise program and exercised for 40 minutes each day, 3 days a week for 12 weeks. Physiological, anthropometric, and biochemical measurements were performed before, during the 6th week, and at the end of the program. RESULTS: There was a significant reduction in body mass index, body fat content, systolic and diastolic blood pressures, as well as NO and ET-1 concentrations after 12 weeks of exercise and diet program. Exercise training significantly elevated subjects' maximum oxygen consumption, whereas the resting metabolic rates of the patients did not change. The formation of thiobarbituric acid reactive substances were significantly reduced, whereas sulfhydryl groups were significantly increased on the 6th week (P < .05) and at the end of program (P < .01). CONCLUSION: Our results demonstrate that exercise, along with low-calorie diet, induced reductions in the plasma of both ET-1 and NO. Beneficial effects were observed on anthropometric measurements and plasma oxidant stress markers, indicating weight loss associated with exercise training and calorie restriction may effectively improve endothelial dysfunction in patients with IGT.

Mediators of glucagon-like peptide 2-induced blood flow: responses in different vascular sites.

The aims of the present study were: to characterize the mechanisms of hemodynamic alterations induced by GLP-2, and, to compare the responses elicited in the superior mesenteric artery (SMA) to other vascular beds. Anesthetized rats were infused at the doses of 0.9, 2.3, 4.6 and 9.3 nmol/kg into the jugular vein for 60 min. Blood flow in the various arteries was measured by the ultrasonic transit time technique. Some animals were pretreated with indomethacin (5 mg/kg, ip), L-NAME (9, 18, 36 and 72 micromol/kg, iv), atropine sulfate (1-2 mg/kg, iv), CCK-1 and CCK-2 receptor antagonists (L-364,718 and L-365,260, 1 mg/kg, iv), exendin (9-39) amide (35 nmol/kg, iv) and lidocaine (74 micromol/kg, iv) prior to the infusion of GLP-2 (4.6 nmol/kg). In another group, capsaicin was applied either systematically (125 mg/kg, sc) or vagally (1 mg/rat). GLP-2 administration at all doses significantly increased the SMA blood flow throughout the experiments. GLP-2 (4.6 nmol/kg) infusion significantly increased blood flow of inferior mesenteric artery and carotid artery but not in any other vessel measured. Only the pretreatments with L-NAME and lidocaine were ineffective in preventing the GLP-2-induced responses. These results implicate that GLP-2-induced blood flow alterations are most significant in the SMA and are not mediated by prostaglandins, muscarinic, GLP-1 or CCK receptors. Our results also suggest that the stimulatory effect of GLP-2 on SMA blood flow is NO-dependent and mediated via intrinsic, non-cholinergic enteric neurons.

Endothelin-3 induced mesenteric vasoconstriction and PMN infiltration in the rat small intestine: role of endothelin receptors.

The objectives of this study were to characterize endothelin (ET)-3-induced alterations in intestinal hemodynamics and to evaluate whether ET-3 administration alters the tissue levels of polymorphonuclear leukocytes (PMNs) and modulates the epithelial barrier function of the small intestine. ET-3 (100 pmol/kg/min) was infused into the superior mesenteric artery (SMA) for 10 min, and tissue samples were obtained 30 min after terminating the infusion. SMA blood flow was significantly decreased throughout the experiment following ET-3 infusion. Pretreatment with bosentan (ET-A and ET-B receptor antagonist), ET-B receptor antagonist BQ-788 or ET-A receptor antagonist BQ-485 completely inhibited the ET-3-induced decrease in the SMA blood flow. Similar results were obtained from the resistance data, in which ET-3-induced increases in SMA resistance were significantly reduced by all ET receptor antagonists. ET-3 administration significantly elevated tissue MPO activity, blood-to-lumen clearance of (51)Cr-EDTA and caused a marked microscopic damage in the intestinal mucosa. ET-3-induced elevations in tissue PMN infiltration and mucosal damage were significantly inhibited by pretreatments with ET-A or ET-B receptor antagonists. Overall, our data indicate that ET-3 causes microscopic damage, PMN infiltration and mucosal dysfunction in the rat small intestine. In addition, ET-3-induced hemodynamic alterations as well as tissue PMN infiltration and mucosal damage are mediated by both ET-A and ET-B receptors.

Endothelin receptor blockers reduce I/R-induced intestinal mucosal injury: role of blood flow.

The aim of the present study was to assess the role of endothelin (ET) in ischemia-reperfusion (I/R)-induced mucosal injury. Mucosal permeability ((51)Cr-EDTA clearance) and tissue myeloperoxidase (MPO) activity were significantly increased after 30 min of ischemia followed by 30 min of reperfusion. The I/R-induced increases in mucosal permeability and polymorphonuclear leukocyte (PMN) infiltration were significantly attenuated by pretreatments with ET(A) (BQ-485) and/or ET(B) (BQ-788) receptor antagonists. Monoclonal antibody (MAb) directed against intercellular adhesion molecule-1 (ICAM-1; MAb 1A29) and superoxide dismutase (SOD) pretreatments significantly attenuated the increased mucosal permeability and PMN infiltration in a similar manner as with ET receptor antagonists. Superior mesenteric artery blood flow was significantly reduced during the reperfusion period. Both ET receptor antagonists caused a significant rise in blood flow compared with an untreated I/R group. In conclusion, our data suggest that ET(A) and/or ET(B) receptors, ICAM-1, and superoxide play an important role in I/R-induced mucosal dysfunction and PMN infiltration. Furthermore, ET is involved in the pathogenesis of post-reperfusion-induced damage and beneficial effects of ET receptor antagonism are related to an improvement of disturbed blood flow during the reperfusion period.