RESUMEN
The metabolic syndrome is a cluster of risk factors (central obesity, hyperglycaemia, dyslipidaemia and arterial hypertension), indicating an increased risk of diabetes, cardiovascular disease and premature mortality. The gastrointestinal tract is seldom discussed as an organ system of principal importance for metabolic diseases. The present overview connects various metabolic research lines into an integrative physiological context in which the gastrointestinal tract is included. Strong evidence for the involvement of the gut in the metabolic syndrome derives from the powerful effects of weight-reducing (bariatric) gastrointestinal surgery. In fact, gastrointestinal surgery is now recommended as a standard treatment option for type 2 diabetes in obesity. Several gut-related mechanisms that potentially contribute to the metabolic syndrome will be presented. Obesity can be caused by hampered release of satiety-signalling gut hormones, reduced meal-associated energy expenditure and microbiota-assisted harvest of energy from nondigestible food ingredients. Adiposity per se is a well-established risk factor for hyperglycaemia. In addition, a leaky gut mucosa can trigger systemic inflammation mediating peripheral insulin resistance that together with a blunted incretin response aggravates the hyperglycaemic state. The intestinal microbiota is strongly associated with obesity and the related metabolic disease states, although the mechanisms involved remain unclear. Enterorenal signalling has been suggested to be involved in the pathophysiology of hypertension and postprandial triglyceride-rich chylomicrons; in addition, intestinal cholesterol metabolism probably contributes to atherosclerosis. It is likely that in the future, the metabolic syndrome will be treated according to novel pharmacological principles interfering with gastrointestinal functionality.
Asunto(s)
Tracto Gastrointestinal/metabolismo , Síndrome Metabólico/metabolismo , Animales , Cirugía Bariátrica , Peso Corporal , Comorbilidad , Diabetes Mellitus/epidemiología , Dislipidemias/complicaciones , Tracto Gastrointestinal/microbiología , Humanos , Hiperglucemia/complicaciones , Hipertensión/complicaciones , Inflamación/complicaciones , Síndrome Metabólico/complicaciones , Microbiota , Obesidad/complicaciones , Obesidad/epidemiología , Obesidad/cirugía , Factores de RiesgoRESUMEN
BACKGROUND: Recently it was shown that the classic renin-angiotensin system (RAS) is locally expressed in small intestinal enterocytes and exerts autocrine control of glucose transport. The aim of this study was to investigate if key components for the Angiotensin III (AngIII) and IV (AngIV) formation enzymes and the AngIV receptor, insulin-regulated aminopeptidase (IRAP), are present in the healthy jejunal mucosa. A second aim was to investigate AngIV effects on glucose-induced mucosal transport in vitro. MATERIAL AND METHODS: Enteroscopy with mucosal biopsy sampling was performed in healthy volunteers. ELISA, Western blotting and immunohistochemistry were used to assess the protein levels and localization. The functional effect of AngIV was examined in Ussing chambers. RESULTS: The substrate Angiotensin II, the enzymes aminopeptidases-A, B, M as well as IRAP were detected in the jejunal mucosa. Immunohistochemistry localized the enzymes to the apical brush-border membrane whereas IRAP was localized in the subapical cytosolic compartment in the enterocyte. AngIV increased the glucose-induced electrogenic transport in vitro. CONCLUSION: The present study indicates the presence of substrates and enzymes necessary for AngIV formation as well as the receptor IRAP in the jejunal mucosa. The functional data suggest that AngIV regulates glucose uptake in the healthy human small intestine.
Asunto(s)
Aminopeptidasas/metabolismo , Angiotensina II/análogos & derivados , Cistinil Aminopeptidasa/metabolismo , Células Epiteliales/metabolismo , Glucosa/farmacología , Mucosa Intestinal/metabolismo , Yeyuno/metabolismo , Adolescente , Adulto , Angiotensina II/farmacología , Transporte Biológico/efectos de los fármacos , Western Blotting , Células Epiteliales/efectos de los fármacos , Femenino , Humanos , Inmunohistoquímica , Técnicas In Vitro , Mucosa Intestinal/efectos de los fármacos , Masculino , Sistema Renina-Angiotensina/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND AND AIMS: The prevalence of diabetes is increasing worldwide, and most of the cases are type 2 diabetes mellitus. The relationship between type 2 diabetes mellitus and obesity is well established, and surgical treatment is widely used for obese patients with type 2 diabetes mellitus. The aim was to present current knowledge about the possible mechanisms responsible for glucose control after surgical procedures and to review the surgical treatment results. MATERIAL AND METHODS: Medical literature was searched for the articles presenting the impact of surgical treatment on glycemic control, long-term results, and possible mechanisms of action among obese individuals with type 2 diabetes mellitus. RESULTS: Remission of type 2 diabetes mellitus after bariatric surgery depends on the definition of the remission used. Complete remission rate after surgery with the new criteria is lower than was considered before. Randomized controlled studies demonstrate that surgery is superior to best medical treatment for the patients with type 2 diabetes mellitus. The recurrence of type 2 diabetes mellitus after bariatric surgery is observed in up to 40% of cases with ≥ 5 years of follow-up. Despite the recurrence of type 2 diabetes mellitus in this group, better glycemic control and lower risk of macrovascular complications are present. Incretin effects on glycemic control after bariatric surgery are well described, but the role of other possible mechanisms (bile acids, microbiota, intestinal gluconeogenesis) in humans is unclear. CONCLUSION: Surgery is an effective treatment of type 2 diabetes mellitus in obese patients. The most optimal surgical procedure for the treatment of obese patients with type 2 diabetes mellitus is still to be established. More research is needed to explore the mechanisms of glycemic control after bariatric surgery.
Asunto(s)
Diabetes Mellitus Tipo 2/cirugía , Obesidad/cirugía , Cirugía Bariátrica , Glucemia/análisis , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Obesidad/complicaciones , Obesidad/fisiopatología , Pérdida de Peso/fisiologíaRESUMEN
BACKGROUND: Roux-en-Y gastric bypass may lead to impaired calcium uptake. Therefore, operation-specific effects of gastric bypass and vertical banded gastroplasty on bone mineral density (BMD) were examined in a randomized clinical trial. Bone resorption markers and mechanisms of decreased calcium uptake after gastric bypass were investigated using blood and endoscopic samples from two additional patient cohorts. METHODS: Total BMD and non-weight-bearing skull BMD were measured by dual-energy X-ray absorptiometry at baseline, and 1 and 6 years after gastric bypass or vertical banded gastroplasty in patients who were not receiving calcium supplements. Bone resorption markers in serum and calcium uptake mechanisms in jejunal mucosa biopsies were analysed after gastric bypass by proteomics including radioimmunoassay, gel electrophoresis and mass spectrometry. RESULTS: One year after surgery, weight loss was similar after gastric bypass and vertical banded gastroplasty. There was a moderate decrease in skull BMD after gastric bypass, but not after vertical banded gastroplasty (P < 0·001). Between 1 and 6 years after gastric bypass, skull BMD and total BMD continued to decrease (P = 0·001). C-terminal telopeptide levels in serum had increased twofold by 18 months after gastric bypass. Proteomic analysis of the jejunal mucosa revealed decreased levels of heat-shock protein 90ß, a co-activator of the vitamin D receptor, after gastric bypass. Despite increased vitamin D receptor levels, expression of the vitamin D receptor-regulated calcium transporter protein TRPV6 decreased. CONCLUSION: BMD decreases independently of weight after gastric bypass. Bone loss might be attributed to impaired calcium absorption caused by decreased activation of vitamin D-dependent calcium absorption mechanisms mediated by heat-shock protein 90ß and TRPV6.
Asunto(s)
Densidad Ósea/fisiología , Calcio/metabolismo , Intestino Delgado/metabolismo , Peso Corporal , Resorción Ósea/metabolismo , Canales de Calcio/fisiología , Femenino , Derivación Gástrica/efectos adversos , Gastroplastia/efectos adversos , Humanos , Absorción Intestinal/fisiología , Masculino , Glicoproteínas de Membrana/fisiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/metabolismo , Estudios Prospectivos , Receptores de Calcitriol/fisiología , Canales Catiónicos TRPV/fisiologíaRESUMEN
BACKGROUND: The long-term results of Roux-en-$\hbox{Y}$ gastric bypass (gastric bypass) and vertical banded gastroplasty (VBG) from randomized studies have not been described in detail. METHODS: Patients were randomized to gastric bypass or VBG. Body mass index (BMI), body composition, eating habits and gastrointestinal hormones were reviewed after 6 years. The frequency of reoperation was assessed up to 10 years after surgery. RESULTS: Sixty-six (80 per cent) of the 82 subjects randomized were assessed for weight and BMI 6 years after surgery, 30 (81 per cent) in the gastric bypass group and 36 (80 per cent) in the VBG group. Intention-to-treat analysis demonstrated greater weight loss after gastric bypass compared with VBG, 6 years after surgery: BMI reduced from 41·8 (95 per cent confidence interval 41·3 to 42·3) to 30·3 (28·6 to 32·0) kg/m(2) for gastric bypass and from 42·3 (42·8 to 44·8) to 32·9 (31·3 to 34·5) kg/m(2) for VBG (P = 0·036). Gastric bypass caused a larger loss of fat mass (P = 0·026) and better preservation of lean tissue (P = 0·009). Patients having a gastric bypass had greater postprandial responses to the satiety hormones glucagon-like peptide 1 and peptide YY (P = 0·003 and P = 0·004 respectively). Ghrelin levels did not differ between the groups. Patients with a gastric bypass maintained a lower intake of fat compared with those having VBG (P = 0·013). Some 89 per cent of patients who initially had VBG had undergone, or were scheduled for, conversion to gastric bypass at latest follow-up. CONCLUSION: Gastric bypass was superior to VBG regarding weight loss, body composition, dietary composition and postprandial satiety hormone responses.
Asunto(s)
Derivación Gástrica , Gastroplastia , Índice de Masa Corporal , Ingestión de Alimentos/fisiología , Femenino , Ghrelina/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/sangre , Obesidad Mórbida/cirugía , Péptido YY/sangre , Reoperación , Pérdida de PesoRESUMEN
BACKGROUND: Little is known about eating behaviour and meal pattern subsequent to Roux-en-Y gastric bypass (RYGB), knowledge important for the nutritional care process. The objective of the study was to obtain basic information of how meal size, eating rate, meal frequency and eating behaviour change upon the RYGB surgery. MATERIALS AND METHODS: Voluntary chosen meal size and eating rate were measured in a longitudinal, within subject, cohort study of 43 patients, 31 women and 12 men, age 42.6 (s.d. 9.7) years, body mass index (BMI) 44.5 (4.9) kg m(-2). Thirty-one non-obese subjects, 37.8 (13.6) years, BMI 23.7 (2.7) kg m(-2) served as a reference group. All subjects completed a meal pattern questionnaire and the Three-Factor Eating Questionnaire (TFEQ-R21). RESULTS: Six weeks postoperatively meal size was 42% of the preoperative meal size, (P<0.001). After 1 and 2 years, meal size increased but was still lower than preoperative size 57% (P<0.001) and 66% (P<0.001), respectively. Mean meal duration was constant before and after surgery. Mean eating rate measured as amount consumed food per minute was 45% of preoperative eating rate 6 weeks postoperatively (P<0.001). After 1 and 2 years, eating rate increased to 65% (P<0.001) and 72% (P<0.001), respectively, of preoperative rate. Number of meals per day increased from 4.9 (95% confidence interval, 4.4,5.4) preoperatively to 6 weeks: 5.2 (4.9,5.6), (not significant), 1 year 5.8 (5.5,6.1), (P=0.003), and 2 years 5.4 (5.1,5.7), (not significant). Emotional and uncontrolled eating were significantly decreased postoperatively, (both P<0.001 at all-time points), while cognitive restraint was only transiently increased 6 weeks postoperatively (P=0.011). CONCLUSIONS: Subsequent to RYGB, patients display markedly changed eating behaviour and meal patterns, which may lead to sustained weight loss.
Asunto(s)
Síndrome de Vaciamiento Rápido/prevención & control , Conducta Alimentaria , Derivación Gástrica/métodos , Obesidad Mórbida/cirugía , Adaptación Psicológica , Adulto , Índice de Masa Corporal , Estudios de Cohortes , Síndrome de Vaciamiento Rápido/epidemiología , Conducta Alimentaria/psicología , Femenino , Estudios de Seguimiento , Derivación Gástrica/psicología , Derivación Gástrica/estadística & datos numéricos , Humanos , Estudios Longitudinales , Masculino , Obesidad Mórbida/epidemiología , Obesidad Mórbida/psicología , Periodo Posoperatorio , Encuestas y Cuestionarios , Suecia/epidemiología , Pérdida de PesoRESUMEN
The gastrointestinal (GI) tract is fundamental for the intake of fluid and electrolytes and accommodates a large proportion of bodily hemodynamics and host defence systems. Despite that the renin-angiotensin system (RAS) is a prominent regulatory system for fluid and electrolyte homeostasis its impact on GI physiology is only little explored. Recent data indicate that RAS is well expressed and active in the GI tract although exact physiological roles are to be settled. There are several reports showing influences by RAS and its key mediator angiotensin II (AngII) on intestinal epithelial fluid and electrolyte transport and data are accumulating, suggesting involvement in GI mucosal inflammation and carcinogenesis. Of particular interest is the increasing amount of experimental support for the involvement of AngII formation and actions via the AngII subtype 1 (AT1) receptor in the pathogenesis and treatment of inflammatory bowel disease. The picture of RAS in the GI tract is, however, far from complete. Because RAS is an important application area for reno-cardiovascular diseases, a number of pharmacological agents as well as research technologies already exist and can in the future be used for GI research. A marked expansion of knowledge concerning the role of RAS in GI physiology and pathophysiology is to be expected.
Asunto(s)
Tracto Gastrointestinal/anatomía & histología , Tracto Gastrointestinal/fisiología , Mucosa Intestinal/fisiología , Sistema Renina-Angiotensina/fisiología , Angiotensina II/metabolismo , Animales , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/fisiopatología , Glucosa/metabolismo , Hemodinámica , Humanos , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/fisiopatología , Mucosa Intestinal/patología , Mucosa Intestinal/fisiopatología , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/metabolismoRESUMEN
AIM: Angiotensin II is well known for its contractile effects on smooth muscle cells. This effect is also present in the gut previously shown in animal models. The aim of this study was to clarify expression and localization of angiotensin II receptors in the human small intestine and to explore the pharmacological profile of angiotensin II effects in vitro. METHODS: Strips of jejunal muscle wall from 32 patients undergoing bariatric surgery were used to record isometric tension in vitro in response to angiotensin II (10(-10)-10(-5) M) alone and in the presence of PD123319 (10(-7) M), losartan (10(-7) M), PD123319 (10(-7) M) and losartan (10(-7) M) in combination, tetrodotoxin (TTX) (10(-6) M), atropine (10(-6) M) and guanethidine (3 x 10(-6) M). Western blot, immunohistochemistry and RT-PCR were performed on corresponding muscle samples to identify expression and localization of key components of the renin-angiotensin system. RESULTS: Angiotensin II elicited concentration-dependent contraction in both longitudinal and circular jejunal muscle wall strips; neither TTX, atropine nor guanethidine affected this action. Losartan alone and in combination with PD123319 shifted the concentration-response curve to the right. Transcription of angiotensinogen, ACE and angiotensin II types 1 and 2 receptor RNA was detected in all patients. Immunohistochemistry detected angiotensin II type 1 receptors in the musculature; both angiotensin II types 1 and type 2 receptors were found in the myenteric plexus. CONCLUSION: This pharmacological analysis indicates that the contractile action elicited by angiotensin II on jejunal wall musculature is primarily mediated through the angiotensin II type 1 receptor located on the musculature.
Asunto(s)
Angiotensina II/farmacología , Yeyuno/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Adulto , Anciano , Western Blotting , Relación Dosis-Respuesta a Droga , Humanos , Yeyuno/metabolismo , Yeyuno/fisiología , Persona de Mediana Edad , Contracción Muscular/fisiología , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Músculo Liso/fisiología , ARN Mensajero/genética , Receptor de Angiotensina Tipo 1/biosíntesis , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 2/biosíntesis , Receptor de Angiotensina Tipo 2/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Técnicas de Cultivo de TejidosRESUMEN
BACKGROUND: Angiotensin II (Ang II) is a well-known activator of smooth muscle in the vasculature but has been little explored with regard to intestinal wall muscular activity. This study investigates pharmacological properties of Ang II and expression of its receptors in small-intestinal smooth muscle from rats and humans. METHODS: Isometric recordings were performed in vitro on small intestinal longitudinal muscle strips. Protein expressions of Ang II typ 1 (AT1R) and typ 2 (AT2R) receptors were assessed by Western blot. RESULTS: Ang II elicited concentration-dependent contractions of rat jejunal and ileal muscle preparations. The concentration-response curve (rat ileum, EC(50): 1.5 +/- 0.9 x 10(-8) M) was shifted to the right by the AT1R receptor antagonist losartan (10(-7) M) but was unaffected by the AT2R antagonist PD123319 (10(-7) M) as well as by the adrenolytic guanethidine (3 x 10(-6) M) and the anticholinergic atropine (10(-6) M). Human duodenal, jejunal and ileal longitudinal muscle preparations all contracted concentration-dependently in response to Ang II. The concentration-response curve (human jejunum, EC(50): 1.5 +/- 0.8 x 10(-8) M) was shifted to the right by losartan (10(-7) M) but was unaffected by PD123319 (10(-7) M). Both AT1R and AT2R were detected in all segments of the rat small intestinal wall musculature, whereas only AT1R was readily detectable in the human samples. CONCLUSION: Ang II elicits contractions of small-intestinal longitudinal muscle preparations from the small intestine of rats and man. The pharmacological pattern and protein expression analyses indicate mediation via the AT1R.
Asunto(s)
Angiotensina II/farmacología , Intestino Delgado/fisiología , Músculo Liso/fisiología , Antagonistas Adrenérgicos/farmacología , Adulto , Anciano , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 2 de Angiotensina II , Animales , Atropina/farmacología , Western Blotting/métodos , Antagonistas Colinérgicos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Guanetidina/farmacología , Humanos , Imidazoles/farmacología , Técnicas In Vitro , Intestino Delgado/efectos de los fármacos , Losartán/farmacología , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Músculo Liso/química , Músculo Liso/efectos de los fármacos , Piridinas/farmacología , Ratas , Receptor de Angiotensina Tipo 1/análisis , Receptor de Angiotensina Tipo 2/análisis , Especificidad de la EspecieRESUMEN
Activation of angiotensin II type 2 receptors (AT2R) has been shown to stimulate duodenal mucosal alkaline secretion (DMAS) in Sprague-Dawley rats (S-D). This finding could not be confirmed in another line of S-D, and the present study investigates whether the level of AT2R expression determines the response to the AT2R agonist CGP42112A. DMAS was measured in anaesthetized rats using in situ pH-stat titration. Real-time PCR and Western blot were used to assess AT1R and AT2R RNA and protein expression, respectively. CGP42112A (0.1 microg kg(-1)min(-1) I.V.) elicited a 45% net increase in DMAS in the previous S-D line studied, whereas no change occurred in the new S-D line. Luminal administration of prostaglandin E2 (10(-5) M) increased DMAS similarly in both S-D lines. AT2R protein expression was significantly higher in tissue from the previous line compared to the new line. Individual AT1R to AT2R ratios (RNA and protein) were significantly higher in the new line compared to the previous S-D line. In the new S-D line intravenous infusion of angiotensin II (Ang II; 10 microg kg(-1) h(-1)) over 120 min significantly lowered the duodenal AT1aR to AT2R RNA ratio. Prolonged Ang II infusion over 240 min increased AT2R protein expression and evoked a 42% stimulatory response in DMAS to CGP42112A. The level of local AT2R expression determines the effect of the AT2R agonist CGP42112A on rat duodenal mucosal alkaline secretion. AT2R expression should be confirmed before interpreting the experimental effects of pharmacological interferences with this receptor.
Asunto(s)
Duodeno/metabolismo , Mucosa Intestinal/metabolismo , ARN Mensajero/metabolismo , Receptor de Angiotensina Tipo 2/agonistas , Angiotensina II/farmacología , Animales , Dinoprostona/farmacología , Duodeno/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Masculino , Oligopéptidos/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/genética , Receptor de Angiotensina Tipo 2/metabolismoRESUMEN
BACKGROUND: Patients with cystic fibrosis (CF) have a high incidence of gastroesophageal reflux disease, but few cases of mucosal injury are reported. Duodenogastric reflux has not been studied in CF but has been suggested to have a pathogenic role in producing alkaline injury to the esophageal mucosa. The aim of this study was to analyze the presence of duodenogastric reflux in patients with CF. PATIENTS AND METHODS: Ten patients with CF and 7 healthy volunteers participated in the study. Gastroduodenal manometry and intragastric perfusion were performed in all subjects. Gastric perfusate was analyzed for bilirubin and bile acids. Only patients and controls exhibiting normal migrating motor complexes were evaluated. RESULTS: Eight patients with CF had normal motility recordings and had significantly higher gastric bilirubin levels compared with healthy subjects (P = 0.003). The bilirubin concentration was associated with bile acid regurgitation in five patients with CF. All bile acids were conjugated with a high glycine/taurine ratio and low levels of secondary bile acids. Small amounts of keto bile acids were found in two patients. CONCLUSION: The patients with CF had an increased incidence of duodenogastric reflux compared with healthy subjects. The bile acid composition was typical for CF with low levels of secondary bile acids. Although high bile acid concentration was found in the duodenogastric reflux in most patients with CF, the less toxic profile of the bile acids might possibly contribute to the low frequency of Barrett's esophagus in CF.
Asunto(s)
Ácidos y Sales Biliares/análisis , Bilirrubina/análisis , Fibrosis Quística/complicaciones , Reflujo Duodenogástrico/epidemiología , Adulto , Estudios de Casos y Controles , Reflujo Duodenogástrico/etiología , Femenino , Ácido Gástrico/química , Motilidad Gastrointestinal , Humanos , Masculino , Manometría , Persona de Mediana Edad , Suecia/epidemiologíaRESUMEN
BACKGROUND: Blockade of the angiotensin II type 1 (AT1) receptor has been demonstrated to ameliorate splanchnic hypoperfusion in acute experimental circulatory failure. This study focused on hemodynamic changes and survival in pigs treated with AT1 blockade prior to or during acute endotoxinemia. METHODS: Escherichia coli lipopolysaccharide endotoxin was infused in anesthetized and mechanically ventilated pigs. Systemic, renal, mesenteric and jejunal mucosal perfusion as well as systemic oxygen and acid-base balance were monitored. The selective AT1 receptor blocker candesartan was administered prior to as well as during endotoxinemia. Control animals received the saline vehicle. RESULTS: Pre-treatment with candesartan resulted in higher survival rate (83%, 10 out of 12 animals) compared with 50% (6 of 12) in control animals and 27% (3 of 11) in animals treated during endotoxinemia. Pre-treatment with candesartan resulted in higher cardiac output, mixed venous oxygen saturation, arterial standard base-excess, portal venous blood flow during endotoxin infusion compared with controls and animals treated during endotoxinemia. No adverse effects were found on neither systemic nor renal circulation. CONCLUSION: The favorable results of AT1 receptor blockade prior to endotoxinemia are lost when blockade is established during endotoxinemia demonstrating the importance of the renin-angiotensin system and its dynamic involvement in acute endotoxinemic shock.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Bencimidazoles/farmacología , Endotoxemia/tratamiento farmacológico , Circulación Esplácnica/efectos de los fármacos , Tetrazoles/farmacología , Enfermedad Aguda , Animales , Compuestos de Bifenilo , Gasto Cardíaco/efectos de los fármacos , Endotoxemia/mortalidad , Endotoxemia/fisiopatología , Femenino , Masculino , Oxígeno/sangre , Sistema Renina-Angiotensina/fisiología , Tasa de Supervivencia , PorcinosRESUMEN
BACKGROUND/AIMS: High concentrations of nitric oxide (NO), derived from dietary nitrite in an acid environment, have been demonstrated in the gastric fundus and in the oesophagus. The aim of this study was to investigate whether luminal NO can influence oesophageal smooth muscle performance, lower oesophageal sphincter (LOS) function or gastric and oesophageal acid exposure. METHODS: Eleven healthy volunteers and 9 patients with chronic gastro-oesophageal reflux disease (GORD) received a diet deprived of nitrate/nitrite but supplemented with placebo or potassium nitrate for 4 days in a randomised order. On day 4 in each trial period, manometry was performed including a sleeve sensor registration of the LOS followed by a simultaneous 24-hour intra-gastric and oesophageal pH registration. RESULTS: Nitrate supplementation increased the proportion of effective peristalsis when analysed for the entire study population. No other significant effects of dietary nitrate were found on oesophageal motor variables, on the sphincter resting tone or on the number or duration of transient sphincter relaxations. No effect was found on either gastric acidity or gastro-oesophageal reflux variables. Major reflux symptoms were not influenced by nitrate administration. CONCLUSION: Dietary nitrate did not significantly affect oesophageal motor or LOS function, gastro-oesophageal acid reflux or reflux symptomatology either in healthy volunteers or in GORD patients.
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Esófago/fisiología , Reflujo Gastroesofágico/metabolismo , Nitratos/administración & dosificación , Óxido Nítrico/metabolismo , Adulto , Estudios Cruzados , Dieta , Método Doble Ciego , Unión Esofagogástrica/fisiología , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Nitratos/farmacología , Compuestos de Potasio/farmacologíaRESUMEN
BACKGROUND: Interference with the L-arginine/nitric oxide pathway may be a virulence strategy for the gastric pathogen Helicobacter pylori. This study evaluates a bioassay for such inhibitory actions on nitric oxide synthase. METHODS: Cultured murine macrophages were stimulated by lipopolysaccharide and interferon-gamma. Nitric oxide synthesis and the expression of inducible nitric oxide synthase (iNOS) at increasing concentrations of L-arginine were analysed using chemiluminescence and Western blotting, respectively. RESULTS: The bioassay was evaluated against nitrite accumulation and two established NOS inhibitors. Bacterial extracts or whole cells of one H. pylori strain inhibited nitric oxide production at low L-arginine concentrations (2-20 microM). A higher concentration of L-arginine (200 microM) was not associated with such inhibition. The iNOS expression was not affected by any of the additives compared to stimulated controls. CONCLUSIONS: This bioassay is a reliable and simple method for analysing iNOS inhibition, resolving effects on enzyme activity or enzyme expression. H. pylori water extract and whole cells exert an L-arginine-dependent NOS inhibition, not influencing iNOS expression.
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Bioensayo , Infecciones por Helicobacter/enzimología , Helicobacter pylori , Macrófagos/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Arginina/metabolismo , Ratones , Óxido Nítrico/biosíntesisRESUMEN
BACKGROUND: The present study explores some aspects of the triggering of the acid-induced oesophago-salivary reflex. In addition to hydrogen ions, there are two acid-dependent molecules with messenger potential in the oesophageal lumen: CO2 and NO. The aim of this study was to clarify whether oesophageal NO and CO2 participate in the regulation of salivary neutralizing capacity in response to acid exposure. METHODS: Healthy volunteers received oesophageal acidification composed of HCl, with NO3-, or HCO3- or NO3- and HCO3- in combination. In a second series of experiments, the exposure period was divided into 2 separate 10-min events. Saliva volume and titratable buffering capacity were used to calculate alkaline secretion. RESULTS: Salivary alkaline secretion increased markedly following 20 min intraluminal exposure to HCl. The initial part of this response was 22% +/- 2.2% larger (P < 0.05) if NO3- was present. When HCO3- was added, or if NO3- and HCO3- were given simultaneously, the secretory response tended to be lower. The accumulated responses over 70 min to 2 short HCl exposures (10 min each separated by a 30 min 'rest') compared to one long one lasting 20 min were similar regardless of the presence of NO3-. CONCLUSION: The data suggest that oesophageal intraluminal NO facilitates initiation of the oesophago-salivary reflex. CO2 seems to have a negligible effect on alkaline salivation, and repeated stimulation does not influence the magnitude of the response over time.
Asunto(s)
Esófago/metabolismo , Esófago/fisiopatología , Reflujo Gastroesofágico/etiología , Reflujo Gastroesofágico/fisiopatología , Óxido Nítrico/metabolismo , Saliva/metabolismo , Adulto , Femenino , Reflujo Gastroesofágico/metabolismo , Humanos , Ácido Clorhídrico/administración & dosificación , Ácido Clorhídrico/metabolismo , Masculino , Óxido Nítrico/administración & dosificación , Valores de Referencia , Reflejo/fisiología , Saliva/fisiología , Salivación/efectos de los fármacos , Salivación/fisiología , Factores de TiempoRESUMEN
BACKGROUND: The aim of the present study was to assess luminal nitric oxide (NO) levels in the oesophagus during baseline and acidic conditions and to clarify the sources of such oesophageal NO formation. METHODS: Healthy volunteers received an intra-oesophageal infusion of either HCl (100 mM) or NaCl (50 mM) on two separate study days. After a low nitrate diet, nitrate load or no dietary restrictions/pretreatment, direct intraluminal measurements of NO formation were performed using a tonometric technique. Endoscopy was performed and mucosal biopsies were taken and analysed by means of immunohistochemistry, Western blot and RT-PCR. RESULTS: No intra-oesophageal NO was detected during baseline conditions with pH neutrality. During the infusion of HCI the NO levels rose dramatically to around 12000 ppb. This high rate of NO formation fell by 95% following deviation of saliva. NO formation after an acute nitrate load was almost doubled during acid perfusion compared to control. Immunohistochemistry demonstrated distinct staining for iNOS in the oesophageal squamous epithelial cells, and Western blot and RT-PCR confirmed the presence of iNOS. CONCLUSION: Two sources exist for intra-oesophageal NO formation, both dependent on the luminal acidity: 1) chemical reduction of salivary nitrite, a mechanism related to dietary intake of nitrate, and 2) NO formation within the oesophageal mucosal epithelium by enzymatic degradation of L-arginine. In the latter case, the NO synthase has antigenic characteristics, indicating the inducible isoform, although a functional behaviour suggests an unconventional subtype.
Asunto(s)
Esófago/patología , Ácido Clorhídrico/farmacología , Óxido Nítrico/biosíntesis , Cloruro de Sodio/farmacología , Adolescente , Adulto , Secuencia de Bases , Biopsia con Aguja , Western Blotting , Esofagoscopía , Esófago/metabolismo , Femenino , Humanos , Inmunohistoquímica , Inyecciones Intralesiones , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Óxido Nítrico/análisis , Estudios Prospectivos , Valores de Referencia , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Inducible NO synthase expression is upregulated in H. pylori-infected gastric mucosa, suggesting increased NO synthesis as part of a host defense reaction. This study investigates actual NO production in the human antrum in situ. METHODS: Gastroscopy with antral biopsy sampling and intragastric tonometric NO assessments were performed on H. pylori-positive and -negative volunteers. The antral mucosal specimens were analyzed with regard to inducible NO synthase (Western blotting) and the presence of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) as well as L-arginine. RESULTS: Mucosal expression of inducible NO synthase was markedly increased in H. pylori infected subjects compared to noninfected ones. The ratio between the tissue contents of L-arginine and asymmetric dimethylarginine was considerably lower in the infected group. Antral output of NO was similar in the two groups during baseline conditions. Following intragastric L-arginine exposure. the antral NO production in controls was unaltered (from 442 ppb +/- 104 to 286 ppb +/- 94), whereas it increased (from 524 ppb +/- 162 to 1066 ppb +/- 274) in the infected individuals. CONCLUSIONS: The study confirms that NO synthase expression is increased in H. pylori-infected antral mucosa. However, NO synthesis is restricted owing to the presence of pathogen-induced competitive NO synthase inhibitors such as methylated arginines.
Asunto(s)
Arginina/análogos & derivados , Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/metabolismo , Helicobacter pylori , Óxido Nítrico/biosíntesis , Adolescente , Adulto , Anciano , Arginina/análisis , Biopsia con Aguja , Western Blotting , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo II , Antro Pilórico/metabolismo , Regulación hacia ArribaRESUMEN
It has previously been shown that mucosal nitric oxide synthase (NOS) is involved in acid-induced duodenal mucosal alkaline secretion. The primary aim of the present study was to elucidate which isoform of NOS is responsible in rats. Immunohistochemistry showed that inducible NOS (iNOS) was constitutively expressed in villous epithelial cells. Exposing the duodenal mucosa to 10 mM HCl resulted in an increased duodenal mucosal alkaline secretion. This response was totally inhibited by intraluminal administration of a selective inhibitor of iNOS (L-N6-1-iminoethyl-lysine). One hour after the acid exposure, western blot technique showed a marked increase in mucosal iNOS expression. A second acid exposure resulted in a further stimulation of alkaline secretion. These data suggest that exposure of the duodenal mucosa to HCI initiates an increased mucosal alkaline secretion, via NO synthesis mediated by iNOS located in the epithelial cells of the villi. In addition, luminal acid stimulates expression of iNOS.
Asunto(s)
Bicarbonatos/metabolismo , Duodeno/metabolismo , Ácido Clorhídrico/farmacología , Mucosa Intestinal/metabolismo , Óxido Nítrico Sintasa/fisiología , Animales , Western Blotting , Duodeno/enzimología , Inmunohistoquímica , Mucosa Intestinal/enzimología , Lisina/análogos & derivados , Lisina/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/farmacología , Óxido Nítrico Sintasa de Tipo II , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Gastrointestinal symptoms in cystic fibrosis are frequent, but little is known about the underlying pathophysiology. Mucosal secretion of IgA is important for the immunologic function in the human gastrointestinal tract but has not been studied in cystic fibrosis. The aim of this study was to quantify the release of IgA by the gastric mucosa in relation to interdigestive motor activity in patients with cystic fibrosis with different genotypes. METHODS: The study included 7 healthy adult volunteers and 10 adult patients with cystic fibrosis, all Helicobacter pylori-negative. All patients had pathological sweat tests and clinical symptoms and signs of cystic fibrosis. All but one were colonized with Pseudomonas aeruginosa. Three patients were pancreatic sufficient. The investigation was performed using intragastric perfusion and gastroduodenal manometry. RESULTS: During the investigation, 8 of 10 patients with cystic fibrosis showed the characteristic pattern of interdigestive motility. The patients had significantly lower levels of gastric IgA compared to healthy subjects during phases II and III of migrating motor complex, median (range) 120 (67-442) and 36 (6-299) microg/5 min. 382 (40-1176) and 56 (4-398) (P = 0.03 and P = 0.04), respectively. Only one patient with genotype R668C/unknown showed IgA levels within the normal range. There was no correlation to gastric presence of duodenogastric reflux markers. CONCLUSION: The interdigestive motility pattern was normal in most patients with cystic fibrosis. The low levels of IgA released from the gastric mucosa in the patients might indicate a defective gastric transmucosal IgA transport in cystic fibrosis.