RESUMEN
Nonlinear optical response of the cybotactic nematic phase of a bent-core mesogen has been investigated for the first time through self-phase modulation induced by a Gaussian beam. The material exhibits a high nonlinear response achieving a nonlinear index n(2)≈5×10(-5) cm(2)/W and an unconventional behavior characterized by two different regimes. While the high-intensity regime can be easily explained in terms of a thermal indexing effect, the low-intensity regime is metastable and characterized by an unusual dependence on the irradiation energy. It is suggested that a change of the director configuration, possibly due to a light-induced modification of surface anchoring, is responsible for the observed behavior.
RESUMEN
The present study aimed to investigate, whether short-term experimental exposure to high levels of welding fumes would be capable of exerting acute effects in healthy subjects. Specifically, we assessed cardiovascular function in terms of heart rate variability (HRV) as well as the concentrations of inflammatory mediators and hemostatic proteins in blood as outcome measures. Twenty subjects without a history of airway and cardiovascular diseases were exposed to either control air or welding fume for 1 h on 2 separate days under standardized conditions. The median concentration of the alveolar particle fraction during welding was 3.5 mg/m(3 )(quartiles: 1.4-6.3 mg/m(3); range 1.0-25.3 mg/m(3)). Five hours later a panel of clinical assessments was performed, including HRV measurement and drawing of blood samples. There were no changes in symptom ratings or lung function after welding fume exposure. Exposures did also not differ regarding effects on time- and frequency-domain parameters of HRV. Similarly, blood leukocyte numbers, cell differentials and the blood levels of fibrinogen, C-reactive protein, antithrombin III, factor VIII, von Willebrand factor, ristocetin cofactor, sICAM-1, tumor necrosis factor alpha, interleukin 6, interleukin 8 and epithelial neutrophil activating peptide 78 were not altered by welding fume inhalation. However, there was a significant fall in the level of endothelin-1 (P < 0.01). In conclusion, the data did not indicate effects of clinical significance of a short-term high-level exposure to welding fumes on HRV or a set of blood hemostatic and acute inflammatory parameters in healthy subjects. The small but statistically significant effect on endothelin levels demonstrated that measurable effects could be elicited even in these individuals. Overall, welding fumes are not likely to exert acute cardiovascular effects in healthy individuals.
Asunto(s)
Contaminantes Ocupacionales del Aire/efectos adversos , Frecuencia Cardíaca/efectos de los fármacos , Exposición por Inhalación/efectos adversos , Exposición Profesional/efectos adversos , Soldadura , Adulto , Femenino , Hemostasis/efectos de los fármacos , Humanos , Inmunidad Innata/efectos de los fármacos , Masculino , Material Particulado/efectos adversosRESUMEN
A 6 year old girl presented with flat-topped, skin-colored, partly grouped papules with slightly roughened surface on the left side of the forehead and around the left orbit. In an off-label use imiquimod 5% cream was applied twice a week before bedtime and was rinsed off in the morning. After four weeks of treatment the lesions had vanished completely. We suggest imiquimod 5% cream as a treatment option for juvenile plane warts even in children and in the face.
Asunto(s)
Aminoquinolinas/administración & dosificación , Dermatosis Facial/tratamiento farmacológico , Dermatosis Facial/patología , Verrugas/tratamiento farmacológico , Verrugas/patología , Adyuvantes Inmunológicos/administración & dosificación , Administración Tópica , Niño , Fármacos Dermatológicos/administración & dosificación , Femenino , Humanos , Imiquimod , Resultado del TratamientoRESUMEN
In ruminants large amounts of nucleic acids associated with the microbial cell mass leaving the fore-stomach system via the abomasum enter the small intestine. In dairy cows this amounts to 100-200 g microbial nucleic acids per day. These nucleic acids are very efficiently digested in the small intestine whereby nucleosides were found to be the main degradation products. Therefore, this review centers mainly on the mechanisms of intestinal absorption of nucleosides and their role in nucleic acid digestion. Furthermore, metabolism of nucleosides in intestinal epithelial cells and its bearing for nucleoside absorption and salvage of nucleosides for nucleic acid synthesis in various tissues is considered. According to own studies using isolated intestinal brush-border membrane (BBM) vesicles (BBMV) from dairy cows purine and pyimidine nucleosides are transported actively by two separate Na+ co-transport systems (N1 and N2) across the bovine BBM, whereby transport activity in the small intestine decreases from proximal to distal. Guanosine and inosine appeared to be transported exclusively by N1 while thymidine and cytidine appeared to be transported exclusively by N2. Uridine and adenosine had an affinity to both transporters. In comparison to findings in man and rabbit, transport capacity (Vmax) of N1 and N2 in the BBM of cows was more than 10-fold higher. Similar findings were obtained in BBMV isolated from the small intestine of veal calves with rudimentary forestomach development in regard to nucleoside transport. Therefore, the high intestinal transport activity for nucleosides seems to be a genetically fixed property in the bovine, which is not related to a functional fore-stomach system.
Asunto(s)
Bovinos/metabolismo , Absorción Intestinal/fisiología , Intestino Delgado/metabolismo , Nucleósidos/farmacocinética , Animales , Transporte Biológico , Transporte Biológico Activo , Industria Lechera , Digestión , Femenino , Nucleósidos/metabolismoRESUMEN
Alpha-cyano-4-hydroxycinnamic acid (4-CIN, 100-200 mg/kg b.wt.), which impairs glucose oxidation by inhibiting pyruvate transport across the mitochondrial membrane, stimulated feeding in rats following intraperitoneal injection without affecting blood glucose level. Like 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, 4-CIN probably acts mainly on the CNS through activation of alpha(2)-adrenergic receptors, because the feeding response to 4-CIN was eliminated by phentolamine or yohimbine. Unlike feeding elicited by 2-DG, 4-CIN-induced feeding was eliminated by total abdominal (but not hepatic branch) vagotomy. Since peripheral atropinization also blocked 4-CIN-induced feeding, activation of central parasympathetic neurons seems to be involved in 4-CIN-induced feeding. The feeding response to 4-CIN was diminished in rats fed a high-fat diet, probably because metabolic sensors sensing fatty acid oxidation counteract the feeding response to 4-CIN. The results suggest that inhibition of glucose oxidation by blocking pyruvate entry into mitochondria stimulates feeding in rats in particular when fed a high-carbohydrate diet.
Asunto(s)
Glucemia/metabolismo , Ácidos Cumáricos/farmacología , Conducta Alimentaria/efectos de los fármacos , Proteínas de Transporte de Monosacáridos/antagonistas & inhibidores , Ácido Pirúvico/antagonistas & inhibidores , Antagonistas Adrenérgicos alfa/farmacología , Animales , Atropina/farmacología , Desoxiglucosa/metabolismo , Carbohidratos de la Dieta/metabolismo , Grasas de la Dieta/metabolismo , Regulación hacia Abajo , Interacciones Farmacológicas , Ingestión de Alimentos/efectos de los fármacos , Masculino , Proteínas de Transporte de Monosacáridos/metabolismo , Oxidación-Reducción , Parasimpatolíticos/farmacología , Fentolamina/farmacología , Ácido Pirúvico/metabolismo , Ratas , Ratas Sprague-Dawley , Vagotomía , Yohimbina/farmacologíaRESUMEN
The properties of hypoxanthine transport were investigated in purified brush border membrane vesicles isolated from calf proximal and distal jejunum. Hypoxanthine uptake in the vesicles was stimulated by a transmembrane Na(+) gradient and an inside negative potential resulting in a transient accumulation of intravesicular hypoxanthine, especially in the proximal jejunum. Na(+)-dependent hypoxanthine uptake at this site seemed to occur by two saturable transport systems, a high affinity (K(m)=0.33 micromol/l) and a low affinity (K(m)=165 micromol/l) transporter. Guanine, hypoxanthine, thymine and uracil inhibited intravesicular hypoxanthine uptake, whereas adenine and the nucleosides inosine and thymidine were without effect. These findings represent the first demonstration of active Na(+) gradient-dependent nucleobase transport in intestinal brush border membrane vesicles.
Asunto(s)
Hipoxantina/farmacocinética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/ultraestructura , Sodio/metabolismo , Animales , Transporte Biológico Activo/fisiología , Bovinos , Técnicas In Vitro , Transporte Iónico , Yeyuno/metabolismo , Microvellosidades/metabolismo , Proteínas de Transporte de Nucleobases/fisiologíaRESUMEN
Previous studies indicated that amylin contributes to the anorectic effects of cholecystokinin (CCK) and bombesin (BBS), possibly by enhancing the release of pancreatic amylin or by modulating their anorectic actions within the central nervous system (CNS). To elucidate the interaction between amylin and CCK or BBS, respectively, we investigated the influence of an IP injection of CCK or BBS on feeding in amylin-deficient mice (IAPP(-/-)). The anorectic effects of CCK and BBS were nearly abolished in IAPP(-/-) mice compared to wildtype (WT) mice (e.g. 20 microg/kg CCK, 1-h food intake: WT/NaCl 0.53 +/- 0.03 g; WT/CCK 0.16 +/- 0.03 g (P < 0.001); IAPP(-/-)/NaCl 0.49 +/- 0.05 g; IAPP(-/-)/CCK 0.39 +/- 0.04 g). Acute amylin replacement restored the anorectic effect of CCK in IAPP(-/-) mice. To find out whether CCK or BBS enhance the feeding-induced release of pancreatic amylin, we injected rats with CCK-8 (0.5-50 microg/kg) or BBS (5 microg/kg) and measured plasma amylin levels after injections. Neither CCK nor BBS increased the plasma amylin level in rats. We suggest that the mediation of the anorectic effects of CCK and BBS by amylin is not dependent on a CCK- or BBS-induced release of pancreatic amylin, but may rather be due to a modulation of their effects by amylin within the CNS.
Asunto(s)
Amiloide/fisiología , Anorexia/fisiopatología , Bombesina/fisiología , Colecistoquinina/fisiología , Amiloide/genética , Animales , Anorexia/etiología , Polipéptido Amiloide de los Islotes Pancreáticos , Ratones , Ratones Endogámicos C57BLAsunto(s)
Contaminación del Aire Interior/efectos adversos , Trasplante de Pulmón/fisiología , Pulmón/patología , Enfermedades Profesionales/etiología , Fibrosis Pulmonar/cirugía , Soldadura , Adulto , Humanos , Masculino , Infecciones por Mycobacterium/etiología , Infecciones por Mycobacterium/cirugía , Enfermedades Profesionales/patología , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/patologíaRESUMEN
In previous work, a comparatively high capacity for Na(+)-dependent transport of nucleosides across the intestinal brush border membrane (BBM) was observed in dairy cows, which might be related to digestion of the large amount of nucleic acids present in ruminal microorganisms in the ruminant small intestine. If this were the case, the capacity for Na(+)-dependent intestinal nucleoside transport should be much lower in veal calves, in which only small amounts of nucleic acids, nucleotides, and nucleosides reach the small intestine via the milk replacer. To test this hypothesis, we investigated Na(+)-dependent transport of 3H-labeled thymidine and guanosine across the BBM using BBM vesicles (BBMV) isolated from the small intestine of veal calves. In the presence of a transmembrane Na+ gradient both substrates were transported against a concentration gradient. Inhibitory studies showed that thymidine and guanosine are transported by two different transporters with overlapping substrate specificity, one accepting predominantly pyrimidine nucleosides (N2) and one accepting particularly purine nucleosides (N1). Nucleoside transport was inhibited by glucose along the whole small intestine. Maximal transport rates similar to those in dairy cows were obtained for the proximal, mid-, and distal small intestine. These findings suggest that the high absorptive capacity for nucleosides is a genetically fixed property in the bovine small intestine, which is already present in the preruminant state of veal calves. It may contribute to the high digestibility of nucleic acids observed by others in veal calves receiving milk replacer supplemented with RNA. Its main function may be the efficient absorption of nucleosides resulting from the digestion of nucleic acids associated with desquamated enterocytes. Due to the limited de novo synthesis of nucleotides in enterocytes intracellular uptake of nucleosides across the BBM may contribute to nucleic acid synthesis in enterocytes and thus may have a trophic effect on the intestinal epithelium.
Asunto(s)
Bovinos/metabolismo , Absorción Intestinal , Intestino Delgado/ultraestructura , Microvellosidades/metabolismo , Nucleósidos/farmacocinética , Sodio/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Glucosa/farmacología , Guanosina/farmacocinética , Cinética , Timidina/farmacocinética , TritioRESUMEN
Leptin decreases food intake and increases energy expenditure in rodents by inhibiting neurones in the hypothalamic arcuate nucleus. The growth hormone secretagogue (GHS) ghrelin is known to stimulate food intake and to be the endogenous ligand for the GHS-receptor, which is strongly expressed in the arcuate nucleus, like the leptin receptor (Ob-R). In this study, we analysed the effect of systemic ghrelin administration on Fos expression in the arcuate nucleus on neurones expressing Ob-R. Injection of ghrelin (0.2 mg/kg, i.p) significantly increased the number of neurones expressing Fos protein in the ventromedial arcuate nucleus. Fifty-seven percent of all Fos-positive cells in the ventromedial arcuate nucleus were also positive for Ob-R staining. Furthermore, we investigated electrophysiologically the effect of ghrelin and leptin on the activity of arcuate neurones in an in-vitro slice preparation. Ghrelin stimulated the electrical activity dose-dependently in 80% of all cells tested (n=49) with a threshold concentration of 10(-11) M; only 8% were inhibited and 12% did not respond. The effect of ghrelin (10(-7) M) was weakly antagonized by the peptidic GHS-receptor antagonist (D-Lys3)-GHRP-6 (10(-4) M), which also showed a much weaker affinity (IC(50), 0.9 x 10(-6) M) to the GHS-receptor than ghrelin (IC(50), 0.3 x 10(-9) M). Ghrelin increased the electrical activity in 76% of all cells which were inhibited by leptin (n=17). These data show that ghrelin interacts with the leptin hypothalamic network in the arcuate nucleus. The opposite effect of leptin and ghrelin on neurones in the arcuate nucleus may serve as a neurophysiological correlate of the orexigenic and anorectic effects of ghrelin and leptin.
Asunto(s)
Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Leptina/fisiología , Neuronas/efectos de los fármacos , Hormonas Peptídicas , Péptidos/farmacología , Animales , Núcleo Arqueado del Hipotálamo/citología , Unión Competitiva , Electrofisiología , Ghrelina , Inmunohistoquímica , Neuronas/química , Neuronas/fisiología , Oligopéptidos/farmacología , Proteínas Proto-Oncogénicas c-fos/análisis , Ensayo de Unión Radioligante , RatasRESUMEN
It was recently demonstrated that ammonia inhibits sodium absorption in the proximal colon of rats. In order to investigate the effect of luminal ammonia in the distal colon, sodium and chloride transport were measured in Ussing chambers. Under short-circuit conditions, distal colon absorbed sodium and chloride. When luminal ammonia (30 mmol l(-1)) was present, sodium and chloride absorption was diminished. Inhibition of the two Na(+)-H(+) exchanger isoforms NHE2 and NHE3, which are known to be located in the apical membrane of the distal colon epithelium, failed to influence the effect of ammonia on transepithelial sodium and chloride fluxes. The inhibitory effect of ammonia was eliminated under the following conditions: after block of carbonic anhydrases with acetazolamide, in the presence of an unspecific blocker of Na(+)-H(+) exchangers, and under chloride-free conditions. Ammonia did not alter electrogenic sodium absorption. These results demonstrate that luminal ammonia inhibits sodium and chloride absorption in rat distal colon. We suggest that ammonia inhibits NaCl absorption by interfering with a Na(+)-H(+) exchanger that is not NHE2 or NHE3
Asunto(s)
Amoníaco/farmacología , Cloruros/metabolismo , Colon/metabolismo , Absorción Intestinal/efectos de los fármacos , Sodio/metabolismo , Animales , Tampones (Química) , Colon/efectos de los fármacos , Electrofisiología , Guanidinas/farmacología , Técnicas In Vitro , Masculino , Metacrilatos/farmacología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Soluciones , Especificidad de la Especie , Sulfonas/farmacologíaRESUMEN
In the present study, the effects of peripherally administered amylin and of the amylin-related peptide salmon calcitonin (sCT) on food and water intake was tested for the first time in pygmy goats. In the first series of experiments, the effect of amylin on food (0.5, 1.0 and 2.0 microg/kg b.wt.) and water (2.0 microg/kg) intake was tested. In the second series of experiments, the effect of sCT on food intake (1.0 microg/kg) was tested under ad libitum feeding conditions or after 14 h food deprivation. The relationship of dose on the effect of sCT (0.1, 0.5 and 1.0 microg/kg) on food and water intake was also tested. Finally, the effect of a low dose (0.1 sCT microg/kg) on water intake was also investigated during food withdrawal. We showed for the first time an anorexigenic effect of the satiety peptide amylin (2.0 microg/kg) in ruminants, which was characterized by a reduction in meal size. In pygmy goats, the administration of the three doses of sCT induced an anorexigenic effect, which was larger and of longer duration when compared with amylin, although the anorexigenic effect of the lowest dose never reached significance. This effect was not dose dependent and was partly due to a reduction in meal size and partly to a prolongation of the interval between meals. The anorexigenic effect of sCT was accompanied by a reduced water intake, probably due to reduced prandial drinking. Furthermore, the low dose of sCT (0.1 microg/kg) was dipsogenic during food withdrawal.
Asunto(s)
Amiloide/administración & dosificación , Antiulcerosos/administración & dosificación , Calcitonina/administración & dosificación , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Animales , Anorexia/inducido químicamente , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Conducta de Ingestión de Líquido/fisiología , Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/fisiología , Privación de Alimentos , Cabras , Polipéptido Amiloide de los Islotes Pancreáticos , Salmón , Órgano Subfornical/efectos de los fármacos , Órgano Subfornical/fisiologíaRESUMEN
Since the capacity of nucleic acid digestion and absorption appears to be comparatively high in the pig, we investigated the properties of transport of (3)H-labelled nucleosides across the porcine intestinal brush border membrane (BBM) using BBM vesicles isolated from the small intestine of slaughter pigs. In the presence of a transmembrane Na(+) gradient, uridine, thymidine and guanosine transiently accumulated in the vesicular lumen beyond the equilibrium (60 min) value suggesting the presence of Na(+)/nucleoside cotransporters in the BBM. The findings of inhibitory studies are consistent with the presence of two Na(+)-dependent nucleoside transporters with overlapping substrate specificity, one for pyrimidine nucleosides (N2) and one for purine nucleosides (N1). Guanosine appeared to be a specific substrate for N1, while this applies to thymidine for N2. Transport of thymidine and guanosine were also inhibited by 2 mmol/l D-glucose and alpha-methyl-D-glucoside. The maximal transport capacity (V(max)) for Na(+)-dependent thymidine and guanosine transport were much higher than reported for other monogastric species. Unlike in other species tested, there was no proximal-to-distal gradient, neither in nucleoside transport activity nor in the inhibition of nucleoside transport by monosaccharides in the porcine small intestine. The high intestinal nucleoside transport activity may contribute to the high digestive capacity for nucleic acids in the pig.
Asunto(s)
Mucosa Intestinal/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Nucleósidos/farmacocinética , Sodio/metabolismo , Porcinos/metabolismo , Animales , Glucosa/metabolismo , Guanosina/farmacocinética , Cinética , Microvellosidades/metabolismo , Timidina/farmacocinética , Tritio , Uridina/farmacocinéticaRESUMEN
Large amounts of nucleic acids associated with rumen microorganisms are digested in the proximal part of the small intestine of ruminants. We studied how the proximal-distal gradient in nucleic acid digestion is related to activity of Na(+)-nucleoside transporters in brush border membrane vesicles isolated from the proximal and distal small intestine of cows. Two Na(+)-dependent nucleoside transporters with overlapping substrate specificity were shown to be present at the two intestinal sites, one for pyrimidine nucleosides and one for purine nucleosides. Affinity constants (K(m)-values) for both thymidine and guanosine transport were similar at the two intestinal sites, while transport capacity (V(max)) was 2-3 times higher in the proximal than in the distal small intestine. Glucose and alpha-methyl-D-glucoside (0.1 mmol/l or 2 mmol/l) inhibited transport of thymidine and guanosine markedly only in the proximal small intestine. It is concluded that absorption of nucleosides by the two Na(+)-nucleoside transporters reflects the proximal-distal gradient in nucleic acid digestion.
Asunto(s)
Intestino Delgado/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Animales , Transporte Biológico/fisiología , Bovinos , Femenino , Guanosina/farmacocinética , Microvellosidades/metabolismo , Monosacáridos/metabolismo , Timidina/farmacocinética , TritioRESUMEN
We investigated the role of histamine H1 receptors in mediating the anorectic effect of intraperitoneally injected amylin (5 and 20 microg/kg), the amylin agonist salmon calcitonin (sCT; 10 microg/kg), leptin (1.3 mg/kg), and cholecystokinin (CCK; 20 microg/kg). The experiments were performed with mice lacking functional H1 receptors (H1Rko) and wild-type (WT) controls. The mice were also injected with the H3 antagonist thioperamide (20 mg/kg), which reduces feeding by enhancing the release of endogenous histamine through presynaptic H3 receptors. The feeding-suppressive effect of thioperamide was abolished in H1Rko mice. The anorectic effects of amylin and sCT were significantly reduced in 12-h food-deprived H1Rko mice compared with WT mice [1-h food intake: WT-NaCl 0.51 +/- 0.05 g vs. WT-amylin (5 microg/kg) 0.30 +/- 0.06 g (P < 0.01); H1Rko-NaCl 0.45 +/- 0.05 g vs. H1Rko-amylin 0.40 +/- 0.04 g; WT-NaCl 0.40 +/- 0.09 g vs. WT-sCT (10 microg/kg) 0.14 +/- 0.10 g (P < 0.05); H1Rko-NaCl 0.44 +/- 0.08 g vs. H1Rko-sCT 0.50 +/- 0.06 g]. The anorectic effect of leptin was absent in ad libitum-fed H1Rko mice, whereas CCK equally reduced feeding in WT and H1Rko animals. This suggests that the histaminergic system is involved in mediating the anorectic effects of peripheral amylin and sCT via histamine H1 receptors. The same applies to leptin but not to CCK. H1Rko mice showed significantly increased body weight gain compared with WT mice, supporting the role of endogenous histamine in the regulation of feeding and body weight.
Asunto(s)
Amiloide/farmacología , Ingestión de Alimentos/efectos de los fármacos , Receptores Histamínicos H1/metabolismo , Animales , Anorexia/metabolismo , Peso Corporal , Calcitonina/farmacología , Colecistoquinina/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Polipéptido Amiloide de los Islotes Pancreáticos , Leptina/farmacología , Masculino , Ratones , Ratones Noqueados , Páncreas/química , Piperidinas/farmacología , Receptores Histamínicos H1/genéticaRESUMEN
The pancreatic hormone glucagon hyperpolarizes the liver cell membrane under various conditions. Here we investigated the physiological relevance of this effect by testing the influence of infusions of glucagon antiserum on the liver cell membrane potential in vivo. Intracellular microelectrode recordings of liver cells (up to 60/rat over 2 h) were done in anesthetized male rats. Livers were fixed in place, and recordings were done 10-30 min after intraperitoneal injections of glucagon or hepatic portal vein infusions of glucagon or specific polyclonal glucagon antibodies raised in rabbits. The isotonic lactose vehicle was used as a control for glucagon, and equal amounts of nonimmunized rabbit IgG were used as a control for glucagon antibodies. Intraperitoneal glucagon (400 microg/kg) hyperpolarized the liver cell membrane up to 12 mV, and intraportal glucagon (10 or 60 microg/kg) dose dependently hyperpolarized the liver cell membrane by 3-7 mV. Intraportal infusion of glucagon antiserum (in vitro binding capacity of 4 ng glucagon/rat) significantly depolarized the liver cell membrane by approximately 2.5 mV. The effects of both glucagon and glucagon antiserum reversed after 60-90 min. We conclude that glucagon is a physiologically important modulator of the liver cell membrane potential.
Asunto(s)
Glucagón/fisiología , Hepatocitos/fisiología , Animales , Anticuerpos/inmunología , Glucagón/administración & dosificación , Glucagón/inmunología , Glucagón/farmacología , Hepatocitos/efectos de los fármacos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Microelectrodos , Ratas , Ratas Sprague-DawleyRESUMEN
The plant polyphenol quercetin was shown to induce a significant CI- secretion in intestinal epithelium. In order to elucidate the structural requirements of quercetin and related flavonoids for this activity, we tested the ability of further flavonols and other flavonoids found in edible plants to induce CI- secretion which was measured as an increase in short-circuit current (I(SC)) in rat colon. Whereas several flavonols and the flavon luteolin increased I(SC), other flavonoids such as flavanones, flavans, flavanols, and anthocyanidins failed to do so. Two glycosides of quercetin, spiraeosid, and isoquercitrin, as well as two methoxylated quercetin metabolites, isorhamnetin and tamarixetin, were also able to increase I(SC). We conclude that a 2,3-double bond in conjunction with the 4-oxo group in the C ring and a hydroxylated B ring are necessary for the secretory activity of flavonoids. This activity requires different structural features than those mandatory for the antioxidative properties of flavonoids. Glucosidation and methoxylation of several hydroxyl groups does not necessarily abolish the secretory potential.
Asunto(s)
Cloruros/metabolismo , Colon/efectos de los fármacos , Flavanonas , Flavonoides/farmacología , Animales , Colon/metabolismo , Técnicas In Vitro , Isoflavonas/farmacología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Metformin (1,1-dimethylbiguanide; MET) is used in the treatment of type 2 diabetes mellitus. MET's antihyperglycemic action depends at least in part on its inhibitory effect on hepatic gluconeogenesis. As to gluconeogenesis from amino acids (e.g. L-alanine), this is associated with an inhibition of L-alanine uptake into hepatocytes. Since this uptake is mediated by an electrogenic transport mechanism, the aim of the present study was to investigate whether MET has an influence on the liver cell membrane potential which might explain its inhibitory effect on L-alanine uptake. The experiments were performed in vivo in anesthetized rats and in vitro using superfused mouse liver slices with the conventional microelectrode technique. In vivo, MET (160 mg/kg intraperitoneally (i.p.)) significantly depolarized (dV) the liver cell membrane by 6 mV. MET (1 mmol/l) also depolarized the liver cell membrane in vitro (e.g. 15 min after start of superfusion: dV=8 mV). MET's effect was at least partly reversible. Glucagon (10(-7) mol/l), which hyperpolarized the liver cell membrane, abolished MET's effect. Further, the MET-induced depolarization was completely absent during superfusion with low Cl(-) ([Cl(-)]=27 mmol/l) medium, and significantly attenuated by the Cl(-) channel blocker NPPB (25 micromol/l). While MET's effect was only somewhat attenuated by blockade of the Na(+)/K(+)/2Cl(-) cotransporter or by superfusion with (HCO(-)(3)-free) HEPES buffer, the carboanhydrase blocker acetazolamide (1 mmol/l) or blockade of the HCO(-)(3)/Cl(-) exchanger by DIDS (100 micromol/l), which, however, also blocks Cl(-) channels, abolished its effect. The depolarization of the liver cell membrane by MET was unaffected by a blockade of K(+) channels with Ba(2+), a blockade of the Na(+)/K(+) pump or superfusion with low Na(+) medium ([Na(+)]=26 mmol/l). According to these results, the MET-induced depolarization of the liver cell membrane could be due to an activation of the Cl(-)/HCO(-)(3) exchanger and thus depend on intracellular HCO(-)(3) formation. This activation could then lead to a disturbance of the equilibrium between intra- and extracellular Cl(-) and therefore to an enhanced Cl(-) efflux via Cl(-) channels. It is plausible that the depolarizing effect induced by MET is associated with its inhibitory effect on gluconeogenesis by inhibiting uptake of L-alanine and other amino acids into hepatocytes.
Asunto(s)
Hipoglucemiantes/farmacología , Hígado/efectos de los fármacos , Metformina/farmacología , Animales , Tampones (Química) , Membrana Celular/química , Membrana Celular/efectos de los fármacos , Glucagón/farmacología , Gluconeogénesis/efectos de los fármacos , Técnicas In Vitro , Inyecciones Intraperitoneales , Hígado/química , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratones , Microelectrodos , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Neurons in the area postrema/nucleus of the solitary tract (AP/NTS) region mediate amylin's anorectic effect elicited by a single intraperitoneal (i.p.) injection of a low dose (5 microg/kg). Here, we tested if a sustained elevation in amylin levels which was achieved by chronic amylin infusion reduces food intake by acting in the AP/NTS region or, possibly, at other brain sites. Further, we tested the role of the AP/NTS region in mediating the anorectic effects of high doses of amylin and its receptor agonist salmon calcitonin (sCT) after an acute single injection. DESIGN: Amylin (2 microg/kg/h) was chronically infused i.p. by osmotic minipumps in AP/NTS-lesioned (AP-X) or sham-lesioned (SHAM) rats. For the acute experiments, amylin or sCT was injected i.p. at doses of 0.5 (only sCT), 5 or 50 microg/kg. Food intake was measured by a computerized system. Body weight was assessed by manually weighing the rats. RESULTS: Amylin significantly reduced cumulative food intake for about 7 days in SHAM but not in AP-X rats. Amylin's effect in SHAM rats was mainly due to a reduction of the size of nocturnal meals (eg average meal size during the first four dark phases; SHAM, NaCl 4.1+/-0.6 vs amylin 2.6+/-0.4 g; n=6, P<0.05; AP-X, 2.6+/-0.3 vs 3.7+/-0.3) while light phase food intake was unaffected. Body weight gain over the whole 14 day infusion period was reduced by amylin in SHAM (NaCl 61+/-6 vs amylin 46+/-4 g; P<0.05) but not in AP-X rats (54+/-4 vs 62+/-4). After single injection, the anorectic effect of high doses of amylin and sCT (50 microg/kg) was attenuated, but not abolished, in AP-X rats. CONCLUSION: We conclude that, under our experimental conditions, neurons in the AP/NTS region are necessary for chronically elevated peripheral amylin to reduce food intake in rats. High doses of amylin, however, may be able to overrun these receptors and reduce feeding by acting at other brain sites.
Asunto(s)
Amiloide/farmacología , Anorexia/inducido químicamente , Ingestión de Alimentos/efectos de los fármacos , Núcleo Solitario/lesiones , Núcleo Solitario/fisiología , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Animales , Anorexia/fisiopatología , Calcitonina , Ingestión de Alimentos/fisiología , Infusiones Parenterales , Polipéptido Amiloide de los Islotes Pancreáticos , Masculino , Ratas , Ratas Sprague-Dawley , Núcleo Solitario/efectos de los fármacosRESUMEN
The anorectic effect of the pancreatic peptide amylin has been established in numerous studies. Here, we investigated the influence of a pretreatment with dopamine (DA) D(1)- and D(2)-receptor antagonists on the anorectic effect of intraperitoneally injected amylin in rats fed a medium-fat (18% fat) diet. In 24-h food-deprived rats, pretreatment with the DA D(2)-receptor antagonist raclopride [100 microg/kg (0.2 micromol/kg) ip] significantly attenuated amylin's (5 microg/kg ip) anorectic effect, whereas raclopride alone had no effect on food intake [i.e., food intakes 1 h after injection were (n = 12): NaCl/NaCl 7.3 +/- 0.5 g; NaCl/amylin 3.9 +/- 0.6; raclopride/NaCl 7.7 +/- 0.7; raclopride/amylin 5.6 +/- 0.7]. Pretreatment with another DA D(2) receptor antagonist, sulpiride [50 mg/kg (154 micromol/kg) ip], similarly reduced amylin's satiety effect, whereas pretreatment with the DA D(1)-receptor antagonist SCH-23390 [10 microg/kg (0.03 micromol/kg) ip] did not influence amylin's effect. SCH-23390, however, completely blocked the anorexia induced by D-amphetamine (0.3 mg/kg ip). These results suggest that, under the present feeding conditions, the dopaminergic system mediates part of amylin's inhibitory effect on feeding in rats when administered intraperitoneally. This seems to involve DA D(2) receptors but not D(1) receptors.