RESUMEN
Patients undergoing chemotherapy with cisplatin commonly present gastrointestinal effects such as constipation and gastric emptying (GE) delay. Both the purinergic system and physical exercise modulate the gastrointestinal (GI) tract. In the current study, we investigated the role of ATP, physical exercise, and P2X7 receptor blocking on GE delay induced by cisplatin in rats. Male rats were divided into the following groups: control (C), cisplatin (Cis), exercise (Ex), Brilliant Blue G (BBG), ATP, Cis+Ex, Cis+ATP, Cis+BBG, Cis+Ex+BBG, Cis+Ex+BBG+ATP, and Cis+ATP+BBG. GE delay was induced by treatment with 1 mg/kg cisplatin (1 time/week for 5 weeks, ip). The moderate physical exercise was swimming (1 h/day, 5 days/week for 5 weeks). At the end of the treatment or exercise and 30 min before the GE assessment, some groups received BBG (50 mg/kg, sc) or ATP (2 mg/kg, sc). Then, GE was assessed after a 10-min postprandial period. Chronic use of Cis decreased GE delay (P<0.05) compared to the control group. Both exercise and ATP prevented (P<0.05) GE delay compared to Cis. The pretreatment with BBG significantly inhibited (P<0.05) the effect of exercise and ATP. On the other hand, the association between exercise and ATP reversed (P<0.05) the effect of the BBG and prevented GE delay. Therefore, we suggest that both exercise and treatment with ATP activate P2X7 receptors and prevent GE delay induced by cisplatin in rats.
Asunto(s)
Adenosina Trifosfato , Antineoplásicos , Cisplatino , Vaciamiento Gástrico , Condicionamiento Físico Animal , Ratas Wistar , Receptores Purinérgicos P2X7 , Animales , Cisplatino/farmacología , Masculino , Adenosina Trifosfato/metabolismo , Vaciamiento Gástrico/efectos de los fármacos , Vaciamiento Gástrico/fisiología , Receptores Purinérgicos P2X7/metabolismo , Condicionamiento Físico Animal/fisiología , Antineoplásicos/farmacología , Ratas , Antagonistas del Receptor Purinérgico P2X/farmacologíaRESUMEN
Patients undergoing chemotherapy with cisplatin commonly present gastrointestinal effects such as constipation and gastric emptying (GE) delay. Both the purinergic system and physical exercise modulate the gastrointestinal (GI) tract. In the current study, we investigated the role of ATP, physical exercise, and P2X7 receptor blocking on GE delay induced by cisplatin in rats. Male rats were divided into the following groups: control (C), cisplatin (Cis), exercise (Ex), Brilliant Blue G (BBG), ATP, Cis+Ex, Cis+ATP, Cis+BBG, Cis+Ex+BBG, Cis+Ex+BBG+ATP, and Cis+ATP+BBG. GE delay was induced by treatment with 1 mg/kg cisplatin (1 time/week for 5 weeks, ip). The moderate physical exercise was swimming (1 h/day, 5 days/week for 5 weeks). At the end of the treatment or exercise and 30 min before the GE assessment, some groups received BBG (50 mg/kg, sc) or ATP (2 mg/kg, sc). Then, GE was assessed after a 10-min postprandial period. Chronic use of Cis decreased GE delay (P<0.05) compared to the control group. Both exercise and ATP prevented (P<0.05) GE delay compared to Cis. The pretreatment with BBG significantly inhibited (P<0.05) the effect of exercise and ATP. On the other hand, the association between exercise and ATP reversed (P<0.05) the effect of the BBG and prevented GE delay. Therefore, we suggest that both exercise and treatment with ATP activate P2X7 receptors and prevent GE delay induced by cisplatin in rats.
RESUMEN
The purinergic system participates in the control of blood pressure. Hypertension promotes the occurrence of gastrointestinal disorders such as intestinal inflammation and gastric emptying delay. This study aimed i) to investigate the participation of the P2X7 receptor blocker Brilliant Blue G (BBG) on gastric emptying of solids and changes in oxidative stress in the gastric fundus, duodenum, and colon of spontaneously hypertensive rats (SHR) and ii) to study the putative relationship of this effect with the renin-angiotensin system. Rats were divided into five groups: Control, SHR, SHR+BBG, SHR+BBG+ATP, and SHR+BBG+ANG II. In the gastrointestinal tract, we assessed gastric emptying (GE) and oxidative stress markers (NOx, MPO, GSH, SOD). We observed a decrease in the GE rate (P<0.05) in SHR vs control rats (21.8±2.0% vs 42.8±3.5%). The decrease in GE was returned (P<0.05) to control levels by BBG in SHR rats (21.8±2.0% vs 41.6±3.2%). Co-administration of ATP or ANG II together with BBG bypassed the effect of the P2X7 antagonist on GE in SHR (P<0.05) (21.9±5.0% vs 25.6±3.0% vs 41.6±3.2%). The MPO activity increased (P<0.05) in the gastric fundus of SHR compared to control rats (6.12±2.26 vs 0.077±0.02 UMPO/mg tissue); this effect was prevented (P<0.05) by BBG (0.55±0.15 vs 6.12±2.26 UMPO/mg tissue). Data demonstrated that blockage of P2X7 receptors with BBG can improve the GE delay and oxidative stress biomarkers in SHR animals. This preventive effect of BBG on GE delay was abrogated by ANG II and ATP, thus prompting crosstalk between renin-angiotensin and the purinergic signaling systems underlying this phenomenon.
Asunto(s)
Enfermedades Gastrointestinales , Antagonistas del Receptor Purinérgico P2X , Ratas , Animales , Ratas Endogámicas SHR , Antagonistas del Receptor Purinérgico P2X/farmacología , Receptores Purinérgicos P2X7 , Adenosina TrifosfatoRESUMEN
The purinergic system participates in the control of blood pressure. Hypertension promotes the occurrence of gastrointestinal disorders such as intestinal inflammation and gastric emptying delay. This study aimed i) to investigate the participation of the P2X7 receptor blocker Brilliant Blue G (BBG) on gastric emptying of solids and changes in oxidative stress in the gastric fundus, duodenum, and colon of spontaneously hypertensive rats (SHR) and ii) to study the putative relationship of this effect with the renin-angiotensin system. Rats were divided into five groups: Control, SHR, SHR+BBG, SHR+BBG+ATP, and SHR+BBG+ANG II. In the gastrointestinal tract, we assessed gastric emptying (GE) and oxidative stress markers (NOx, MPO, GSH, SOD). We observed a decrease in the GE rate (P<0.05) in SHR vs control rats (21.8±2.0% vs 42.8±3.5%). The decrease in GE was returned (P<0.05) to control levels by BBG in SHR rats (21.8±2.0% vs 41.6±3.2%). Co-administration of ATP or ANG II together with BBG bypassed the effect of the P2X7 antagonist on GE in SHR (P<0.05) (21.9±5.0% vs 25.6±3.0% vs 41.6±3.2%). The MPO activity increased (P<0.05) in the gastric fundus of SHR compared to control rats (6.12±2.26 vs 0.077±0.02 UMPO/mg tissue); this effect was prevented (P<0.05) by BBG (0.55±0.15 vs 6.12±2.26 UMPO/mg tissue). Data demonstrated that blockage of P2X7 receptors with BBG can improve the GE delay and oxidative stress biomarkers in SHR animals. This preventive effect of BBG on GE delay was abrogated by ANG II and ATP, thus prompting crosstalk between renin-angiotensin and the purinergic signaling systems underlying this phenomenon.
RESUMEN
Strenuous exercise triggers deleterious effects on the intestinal epithelium, but their mechanisms are still uncertain. Here, we investigated whether a prolonged training and an additional exhaustive training protocol alter intestinal permeability and the putative effect of alanyl-glutamine (AG) pretreatment in this condition. Rats were allocated into 5 different groups: 1) sedentary; 2 and 3) trained (50 min per day, 5 days per week for 12 weeks) with or without 6 weeks oral (1.5 g/kg) AG supplementation; 4 and 5) trained and subjected to an additional exhaustive test protocol with or without oral AG supplementation. Venous blood samples were collected to determine gasometrical indices at the end of the 12-week protocol or after exhaustive test. Lactate and glucose levels were determined before, during, and after the exhaustive test. Ileum tissue collected after all experimental procedures was used for gene expression analysis of Zonula occludens 1 (ZO-1), occludin, claudin-2, and oligopeptide transporter 1 (PepT-1). Intestinal permeability was assessed by urinary lactulose/mannitol test collected after the 12-week protocol or the exhaustive test. The exhaustive test decreased pH and base excess and increased pCO2. Training sessions delayed exhaustion time and reduced the changes in blood glucose and lactate levels. Trained rats exhibited upregulation of PEPT-1, ZO-1, and occludin mRNA, which were partially protected by AG. Exhaustive exercise induced intestinal paracellular leakage associated with the upregulation of claudin-2, a phenomenon protected by AG treatment. Thus, AG partially prevented intestinal training adaptations but also blocked paracellular leakage during exhaustive exercise involving claudin-2 and occludin gene expression.
Asunto(s)
Dipéptidos/administración & dosificación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/fisiopatología , Permeabilidad/efectos de los fármacos , Condicionamiento Físico Animal/fisiología , Animales , Masculino , Modelos Animales , Ratas , Ratas WistarRESUMEN
Strenuous exercise triggers deleterious effects on the intestinal epithelium, but their mechanisms are still uncertain. Here, we investigated whether a prolonged training and an additional exhaustive training protocol alter intestinal permeability and the putative effect of alanyl-glutamine (AG) pretreatment in this condition. Rats were allocated into 5 different groups: 1) sedentary; 2 and 3) trained (50 min per day, 5 days per week for 12 weeks) with or without 6 weeks oral (1.5 g/kg) AG supplementation; 4 and 5) trained and subjected to an additional exhaustive test protocol with or without oral AG supplementation. Venous blood samples were collected to determine gasometrical indices at the end of the 12-week protocol or after exhaustive test. Lactate and glucose levels were determined before, during, and after the exhaustive test. Ileum tissue collected after all experimental procedures was used for gene expression analysis of Zonula occludens 1 (ZO-1), occludin, claudin-2, and oligopeptide transporter 1 (PepT-1). Intestinal permeability was assessed by urinary lactulose/mannitol test collected after the 12-week protocol or the exhaustive test. The exhaustive test decreased pH and base excess and increased pCO2. Training sessions delayed exhaustion time and reduced the changes in blood glucose and lactate levels. Trained rats exhibited upregulation of PEPT-1, ZO-1, and occludin mRNA, which were partially protected by AG. Exhaustive exercise induced intestinal paracellular leakage associated with the upregulation of claudin-2, a phenomenon protected by AG treatment. Thus, AG partially prevented intestinal training adaptations but also blocked paracellular leakage during exhaustive exercise involving claudin-2 and occludin gene expression.
Asunto(s)
Animales , Masculino , Ratas , Permeabilidad/efectos de los fármacos , Condicionamiento Físico Animal/fisiología , Dipéptidos/administración & dosificación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/fisiopatología , Ratas Wistar , Modelos AnimalesRESUMEN
We previously found that acute exercise inhibited the gastric emptying of liquid in awake rats by causing an acid-base imbalance. In the present study, we investigated the involvement of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, vasoactive intestinal peptide (VIP), and corticotropin-releasing factor (CRF) peptide in this phenomenon. Male rats were divided into exercise or sedentary group and were subjected to a 15-min swim session against a load (2.5 or 5% b.w.). The rate of gastric emptying was evaluated after 5, 10, or 20 min postprandially. Separate groups of rats were treated with vehicle (0.9% NaCl, 0.1 mL/100 g, ip) or one of the following agents: atropine (1.0 mg/kg, ip), the NO non-selective inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10.0 mg/kg, ip), or the selective cGMP inhibitor 1H-(1,2,4)oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 5.0 mg/kg, ip), the i-NOS non-specific inhibitor (aminoguanidine; 10.0 mg/kg, ip), the corticotropin-releasing factor receptor antagonist (astressin; 100 µg/kg, ip), or the vasoactive intestinal peptide (VIP) receptor antagonist Lys1, Pro2,5, Arg3,4, Tyr6 (100 µg/kg, ip). Compared to sedentary rats, both the 2.5 and 5% exercise groups exhibited higher (P<0.05) values of blood lactate and fractional gastric dye recovery. Corticosterone and NO levels increased (P<0.05) in the 5% exercised rats. Pretreatment with astressin, VIP antagonist, atropine, L-NAME, and ODQ prevented the increase in gastric retention caused by exercise in rats. Acute exercise increased gastric retention, a phenomenon that appears to be mediated by the NO-cGMP pathway, CRF, and VIP receptors.
Asunto(s)
Hormona Liberadora de Corticotropina/metabolismo , Vaciamiento Gástrico/fisiología , Guanosina Monofosfato/metabolismo , Óxido Nítrico/metabolismo , Condicionamiento Físico Animal/fisiología , Péptido Intestinal Vasoactivo/metabolismo , Animales , Atropina/farmacología , Corticosterona/sangre , Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Hormona Liberadora de Corticotropina/farmacología , Inhibidores Enzimáticos/farmacología , Vaciamiento Gástrico/efectos de los fármacos , Guanosina Monofosfato/antagonistas & inhibidores , Ácido Láctico/sangre , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Periodo Posprandial/efectos de los fármacos , Periodo Posprandial/fisiología , Distribución Aleatoria , Ratas Wistar , Valores de Referencia , Reproducibilidad de los Resultados , Conducta Sedentaria , Factores de Tiempo , Péptido Intestinal Vasoactivo/antagonistas & inhibidoresRESUMEN
Changes in physiological parameters that are induced by acute exercise on a treadmill in healthy military dogs have not been thoroughly investigated, especially with regard to age. This study investigated the effects of acute exercise on a treadmill on cardiovascular function, biochemical parameters and gastric antral motility in military dogs. Thermography was used to assess variations in superficial hindlimb muscle temperature. Nine healthy dogs were distributed into three groups according to their age (Group I: 25 ± 7 months; Group II: 51 ± 12 months; Group III: 95 ± 10 months) and sequentially subjected to running exercise on a treadmill for 12 min (3.2 km/h at 0° incline for 4 min, 6.4 km/h at 0° incline for 4 min and 6.4 km/h at 10° incline for 4 min). Heart rate, systolic and diastolic arterial pressure (DAP), gastric motility, haematocrit and biochemical analyses were performed at rest and after each session of treadmill exercise. Infrared thermographic images of muscles in the pelvic member were taken. Exercise decreased DAP in Group I, increased systolic arterial pressure in Groups II and III and increased mean arterial pressure in Group III (all p < 0.05). After the exercise protocol, plasma creatine kinase and aspartate aminotransferase levels increased only in Group I (p < 0.05). Exercise increased heart rate and decreased the gastric motility of a solid meal at 180 min in all groups (all p < 0.05). Exercise also elevated temperature in the femoral biceps muscles in Group I compared with the older dogs. The results indicate that acute exercise decreased gastric motility in dogs, regardless of age, and caused more pronounced cardiovascular changes in older dogs than in younger dogs. Acute exercise also altered biochemical parameters and superficial hindlimb muscle temperature in younger military dogs.
Asunto(s)
Presión Sanguínea , Temperatura Corporal/fisiología , Perros/fisiología , Motilidad Gastrointestinal/fisiología , Frecuencia Cardíaca , Condicionamiento Físico Animal/fisiología , Animales , Prueba de Esfuerzo/veterinaria , Masculino , Personal Militar , Músculo Esquelético/fisiología , Esfuerzo FísicoRESUMEN
We previously found that acute exercise inhibited the gastric emptying of liquid in awake rats by causing an acid-base imbalance. In the present study, we investigated the involvement of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, vasoactive intestinal peptide (VIP), and corticotropin-releasing factor (CRF) peptide in this phenomenon. Male rats were divided into exercise or sedentary group and were subjected to a 15-min swim session against a load (2.5 or 5% b.w.). The rate of gastric emptying was evaluated after 5, 10, or 20 min postprandially. Separate groups of rats were treated with vehicle (0.9% NaCl, 0.1 mL/100 g, ip) or one of the following agents: atropine (1.0 mg/kg, ip), the NO non-selective inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10.0 mg/kg, ip), or the selective cGMP inhibitor 1H-(1,2,4)oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 5.0 mg/kg, ip), the i-NOS non-specific inhibitor (aminoguanidine; 10.0 mg/kg, ip), the corticotropin-releasing factor receptor antagonist (astressin; 100 µg/kg, ip), or the vasoactive intestinal peptide (VIP) receptor antagonist Lys1, Pro2,5, Arg3,4, Tyr6 (100 µg/kg, ip). Compared to sedentary rats, both the 2.5 and 5% exercise groups exhibited higher (P<0.05) values of blood lactate and fractional gastric dye recovery. Corticosterone and NO levels increased (P<0.05) in the 5% exercised rats. Pretreatment with astressin, VIP antagonist, atropine, L-NAME, and ODQ prevented the increase in gastric retention caused by exercise in rats. Acute exercise increased gastric retention, a phenomenon that appears to be mediated by the NO-cGMP pathway, CRF, and VIP receptors.
Asunto(s)
Animales , Masculino , Hormona Liberadora de Corticotropina/metabolismo , Guanosina Monofosfato/metabolismo , Vaciamiento Gástrico/fisiología , Óxido Nítrico/metabolismo , Valores de Referencia , Atropina/farmacología , Factores de Tiempo , Corticosterona/sangre , Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Hormona Liberadora de Corticotropina/farmacología , Distribución Aleatoria , Ratas Wistar , Inhibidores Enzimáticos/farmacología , Vaciamiento Gástrico/efectos de los fármacosRESUMEN
Preclinical and clinical studies show that gastrointestinal (GI) inflammation can evoke sensory changes occasionally far from the original inflammatory site. Animal models of colitis with either trinitrobenzenesulphonic acid (TNBS) or mustard oil (MO) produce distinct patterns of somatic and visceral sensory changes. We evaluated the effects of four doses of i.v. vincristine 150 µg kg(-1) (total of 600 µg kg(-1) ) treatment on the somatic (thermal nociceptive threshold) and colonic (morphological) changes induced by TNBS or MO in rats. TNBS and MO groups were further submitted to vincristine or saline pretreatments. TNBS induced somatic hypersensitivity, while MO induced somatic hyposensitivity (P < 0.05) when compared to the saline and ethanol control groups. Vincristine per se induced somatic hypersensitivity (P < 0.05). This effect was enhanced by TNBS and reversed by MO treatments. Although vincristine increased the colitis area (colonic weight length(-1) ratio) and the Morris' score in TNBS-treated rats, it did not alter the colitis area and even lowered the Morris' score in MO-treated rats. Compared to the saline (control) group, vincristine did not alter the colonic microscopic pattern. However, such lesions scores are higher (P < 0.05) in colitis groups induced by TNBS and MO, pretreated or not with vincristine. In conclusion, the somatic changes induced by different models of experimental colitis are diverse and modulated differently by vincristine.
Asunto(s)
Colitis/tratamiento farmacológico , Colitis/patología , Colon/efectos de los fármacos , Colon/patología , Umbral del Dolor/efectos de los fármacos , Vincristina/farmacología , Vincristina/uso terapéutico , Animales , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Masculino , Planta de la Mostaza , Aceites de Plantas , Ratas , Índice de Severidad de la Enfermedad , Ácido TrinitrobencenosulfónicoRESUMEN
AIMS: We previously reported that mechanical atrial stretch (AS) by balloon distention increased gastric tonus in anesthetized rats. The present study evaluated the effect of AS on the gastric emptying of a liquid test meal in awake rats and its underlying neural mechanisms. MAIN METHODS: Anesthetized male rats received a balloon catheter into the right atrium and a gastrostomy cannula. The next day, mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP), and cardiac output (CO) were continuously monitored. After the first 20min of monitoring (basal interval), the balloon was either distended or not (control) with 30, 50, or 70µl saline for 5min. Fifteen minutes later, the rats received the test meal (glucose solution with phenol red), and fractional gastric dye retention was determined 10, 20, or 30min later. KEY FINDINGS: Heart rate and CVP values were transiently increased by 50 or 70µl AS but not 30µl AS, whereas gastric emptying was slower after 30, 50, or 70µl AS than after sham distention. Subdiaphragmatic vagotomy or splanchnicotomy+celiac ganglionectomy and capsaicin, ondansetron, hexamethonium, L-NAME, and glibenclamide treatment prevented the AS-induced delay in gastric emptying, whereas atropine and guanethidine treatment failed to prevent it. SIGNIFICANCE: Atrial stretch inhibited the gastric emptying of liquid via non-adrenergic and non-cholinergic pathways that activate nitric oxide-K(+)ATP channels.
Asunto(s)
Función del Atrio Derecho/fisiología , Vaciamiento Gástrico/fisiología , Tránsito Gastrointestinal/fisiología , Atrios Cardíacos/cirugía , Hipovolemia/fisiopatología , Análisis de Varianza , Animales , Atropina/farmacología , Oclusión con Balón/métodos , Presión Sanguínea , Capsaicina/farmacología , Cateterismo Cardíaco/métodos , Cateterismo/métodos , Vaciamiento Gástrico/efectos de los fármacos , Gastrostomía/métodos , Gliburida/farmacología , Guanetidina/farmacología , Frecuencia Cardíaca , Hexametonio/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/sangre , Ondansetrón/farmacología , RatasRESUMEN
In the present study, a practical activity is proposed to adopt an experimental approach to demonstrate the relationship between the equilibrium potential for K(+) and transmembrane electrical potential without glass micropipettes. A conventional setup for recording contractile activity of isolated smooth muscle preparations was used based on the events elegantly described by Somlyo and Somlyo in the 1960s. They showed that, in response to a given stimulus, smooth muscle cells may contract, recruiting electromechanical or pharmacomechanical coupling by mechanisms that involve, or not, changes in transmembrane potential, respectively. By means of contractions and relaxations of a ring-like preparation from the rat mesenteric artery, it is possible to observe the functional consequences of handling K(+) concentration in the extracellular compartment and the effects caused by opening K(+) channels in that preparation, which are significant when the cell membrane establishes an electrical potential difference between intra- and extracellular compartments (driven mainly by K(+) permeability under resting conditions). The effects observed by students fit well with values predicted by Nernst and Goldman-Hodgin-Katz equations, and we demonstrated that the activity is able to improve students' comprehension regarding basic principles of bioelectricity.