La dexametasona, un inhibidor de la expresion de la óxido nítrico sintasa inducible, no modifica el estado hiperdinámico en ratas cirróticas. / [Dexamethasone, an inhibitor of the expression of inducible nitric oxide synthase, does not modify the hyperdynamic state in cirrhotic rats]

Increased nitric oxide formation has been shown to be involved in the hyperdynamic circulation of portal hypertension. It has been proposed that it could be related to stimulation of the inducible nitric oxide synthase by endotoxin. Therefore, the aim of the present study was to evaluate whether dexamethasone treatment, an inhibitor of the expression of the inducible enzyme, ameliorates the hyperdynamic circulation observed in cirrhotic rats due to chronic bile duct ligation. Systemic and splanchnic hemodynamic parameters were measured after administration of dexamethasone (3 mg/kg/day during 3 days, i.p.) or its vehicle. In cirrhotic rats dexamethasone treatment caused a mild but not significantly higher mean arterial pressure in comparison with vehicle while similar values of cardiac output, peripheral vascular resistance, portal blood flow and portal pressure were observed in both group of animals. A significant body weight loss over the three days of treatment was observed in rats receiving dexamethasone. In sham-operated rats, dexamethasone administration caused similar changes as observed in cirrhotic animals. Endotoxemia was observed in five of six cirrhotic rats while it was not detected in the control group. Our results show that dexamethasone administration does not modify systemic and splanchnic hemodynamic parameters in endotoxemic cirrhotic rats. This finding suggests that stimulation of the inducible nitric oxide synthase may not play a role in the increased nitric oxide production in portal hypertension.

Effect of loperamide and bisacodyl on intestinal transit time, fecal weight and short chain fatty acid excretion in the rat

En esta experiencia se estudió el efecto de drogas que modifican la motilidad colónica sobre el tiempo de tránsito intestinal (TTI), (medidos con marcadores radiopacos) el peso fecal (PF) y la concentración fecal de ácidos grasos de cadena corta (AGCC) (medidos por cromatografía gaseosa) en un grupo de 8 ratas durante 4 semanas mantenidad con una dieta convencional. Para acortar el TTI se usó bisacordyl y para alargar el TTI se usó loperamida. La primera y la tercera semana fueron períodos controles sin administración de drogas. El valor promedio de estos períodos fue, para el TTI: 28,9 ñ 1,9 h, para el PF: 9,2 ñ 1,2 g/24h, para la concentración fecal de AGCC: 60,6 ñ 17,9 mmoles/g. Durante la administración de loperamida (2da semana) se observó un incremento del TTI con respecto al período control: 40,4 ñ 8,0h una disminución en el PF: 4,8 ñ 3,6g/24h y en la concentración fecal de AGCC: 32,2 ñ 5,8 mmoles/g. Con la adminstración de Bisacodyl (4ta semana) se obtuvo una disminución en TTI: 24,8 ñ 2,5h un incremento en el PF: 27,5 ñ 3,7g/24h, y un incremento de la concentración fecal de AGCC: 108,2 ñ 39,9 mmoles/g. Se observó una correlación negativa entre el TTI y el PF (R=0,67 p < 0,01) y una correlación positiva entre la concentración de AGCC y el PF (R=0,71 p < 0,01). El análisis individual de los AGCC fecales muestra una correlación positiva del ácido acético, propiónico y butírico con el PF y una correlación negativa para el ácido isovalérico y caproico. Los resultados de este trabajo muestan que el PF y la concentración de AGCC fecales pueden ser influenciados por modificaciones del tránsito intestinal (AU)

Effect of loperamide and bisacodyl on intestinal transit time, fecal weight and short chain fatty acid excretion in the rat.

We analyzed the effect of drugs that modify the colonic motility on rat intestinal transit time (ITT) (measured with radiopaque markers), fecal weight (FW) and fecal concentration of short chain fatty acids (FSCFA) (assayed by gas liquid chromatography), over a four-week period. Bisacodyl was used to accelerate and Loperamide to retard the intestinal transit in rats maintained on a conventional diet. The first and 3rd week were drug-free control periods. The mean values of these periods were: ITT = 28.9h +/- 1.9 FW: 9.2 +/- 1.2 g/24 h and FSCFA = 60.6 +/- 17.9 mmol/g. After loperamide administration, we observed an increase in the mean ITT as compared to the control period (40.4 +/- 8.0h) and decrease in FW (4.8 +/- 3.6 g/24h) and in FSCFA = 32.2 +/- 5.6 mmol/g). After bisacodyl administration, we found a shorter ITT in relation to controls (24.8 +/- 2.5h), and increases in FW (27.5 +/- 3.6g/24h) and in FSCFA (108.2 +/- 39.9 mmol/g). There was a negative correlation between ITT and FW (R = 0.67 p less than 0.01) and a positive correlation between total SCFA concentration and FW (R = 0.71 p less than 0.01). The concentration of acetic, propionic and butyric acids increased with progressive increments in fecal weight, whereas concentrations of isovaleric and caproic acids decreased. The results of this study show that the FW and the FSCFA may be influenced by modifications in the intestinal transit time.

Stimulation of inflammatory mediators secretion by chemotactic peptides in rat colitis model

Colonic inflammation was produced in rats by chemotactic peptides acting on polymorphonuclear leucocytes. Instillation during one hour of formylated tripeptide: formylmethionyl-leucy-phenylalanine (FMLP) and a tetrapeptide: alanine-glycine-sefine-glutamine (AGSG) into rat colon caused erosions and exulcerations. Neutrophils increased secondary to instillation, predominantly with FMLP, and mucus depletion was marked in the cecum. Chloride ion secretion and mucosal permeability were significatively greater in the colonic lumen with the chemotactic peptides. Histamine and serotonin concentration were greater in the colonic fluid in animals treated with the peptides. These observations could suggest that the presence of chemotactic peptides at the colonic lumen produce changes at the mucosal wall, that would participate in generation and perpetuation of the colonic inflammation. (AU)

Papel del óxido nítrico en las alteraciones de la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal / Role of nitric oxide in the alterations of the systemic and splanchnic hemodynamics in a experimental model of portal hypertension

Se evaluó el efecto de la Nw-Nitro-L-arginina (L-NNA), un inhibidor específico de la síntesis de óxido nítrico, sobre la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal (ligadura parcial de la vena porta). La administración de L-NNA en los animales con hipertensión portal ocasionó un aumento significativo de la presión arterial media, una reducción del gasto cardíaco y un aumento de la resistencia vascular periférica. A nível de la hemodinámica esplácnica la L-NNA ocasionó un marcado incremento de la resistencia vascular esplácnica con la consecuente disminución del flujo sanguíneo portal. No se observaron cambios singnificativos en la presión portal. El pretratamiento con L-arginina inhibió los efectos hemodinámicos de la L-NNA. Similares niveles plasmáticos de endotoxina se detectaron en ambos grupos de animales. En el grupo control La L-NNA produjo un aumento de la presión arterial media; sin embargo, y a diferencia de lo observado en los animales on hipertensión portal, la administración de L-NNA no se acompaño de cambios significativos en el gasto cardíaco, flujo sanguíneo portal ni resistencia vascular esplácnica. Nuestros resultados sugieren que las alteraciones, tanto de la hemodinámica sistémica como esplácnica, asociadas a la hipertensión portal, pueden ser atenuadas mediante la administración de L-NNA. Asimismo, el aumento de la síntesis de óxido nítrico puede jugar un papel importante en la fisiopatogenia de estos trastornos hemodinámicos (AU)

Influence of pirenzepine on colonic serotonin changes induced by short chaim fatty acid

En este trabajo hemos la influencia de un ácido graso de cadena corta (acetato) sobre el número de células enterocromafines (EC) conteniendo serotonina (5HT) a dos diferentes pH (pH 6.9, estímulo absortivo y pH 2.9 estímulo secretor) infundido durante una hora en el colon. El número de células EC disminuye significativament con una solución infundida a pH 2.9, especialmente en el ciego. La acción de la pirencepina en prevenir esta reducción demuestra que el mecanismo se efectúa parcialmente a través de receptores colinérgicos. Por parte, se observa una disminución de la liberación de 5HT, a través de un mecanismo colinérgico, como lo indica la inhibición observada con la droga antimuscarínica (AU)

Papel del óxido nítrico en las alteraciones de la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal. / [Role of nitric oxide in alterations of the systemic and splanchnic hemodynamics in a experimental model of portal hypertension]

Recent experimental studies have suggested that an increase in the synthesis of nitric oxide, a powerful vasodilator secreted by endothelial cells, plays a role in the hemodynamic disturbances associated to portal hypertension. The present study was addressed to investigate the effects of L-NNA (a specific inhibitor of nitric oxide) on systemic and splanchnic hemodynamics in portal hypertensive rats, induced by partial portal vein ligation. Intravenous infusion of L-NNA (50 ug/kg/min) significantly increased systemic blood pressure and decreased cardiac output as measured by radiolabeled microspheres. A significant increase in systemic and splanchnic vascular resistance was also observed in L-NNA-treated rats; whereas portal blood flow decreased significantly, L-NNA did not modify portal pressure. Pretreatment with L-arginine (300 mg/Kg, i.v.) prevented the hemodynamic changes induced by L-NNA. Similar values of endotoxin levels were detected in both groups of animals. In the control group, L-NNA caused a mild but significant increase of mean arterial pressure; no significant changes on the other hemodynamic parameters were observed. These results suggest that an increase in endogenous synthesis of nitric oxide may play an important role in hemodynamic disturbances associated with chronic portal hypertension.

Influence of pirenzepine on colonic serotonin changes induced by short chain fatty acid.

In this work we have demonstrated the influence of a short chain fatty acid (acetate) on the number of enterochromaffin (EC) cells containing serotonin (5HT), at two different pH (pH 6.9 absorptive stimuli, and pH 2.9 secretory stimuli), infused into the colon during one hour. The number of EC cells decrease significatively, specially in the cecum with a solution of low pH (2.9). The action of piprenzepine in preventing this reduction demonstrated that was partly mediated by a cholinergic receptor mechanism. On the other hand, a decrease on the release of 5HT to the lumen was a observed under the influence of pirenzepine. We conclude that the short chain fatty acid acetate, at a low pH induces the release of serotonin through a cholinergic mechanisms indicated by the inhibition observed with antimuscarinic drug.