RESUMEN
Dietary proteins are mostly absorbed as di- and tripeptides by the intestinal proton-dependent transporter PepT1. We have examined the effects of leptin on PepT1 function in rat jejunum and in monolayers of the human enterocyte-like 2 cell Caco-2. Leptin is produced by the stomach and secreted in the gut lumen. We show here that PepT1 and leptin receptors are expressed in Caco-2 and rat intestinal mucosal cells. Apical (but not basolateral) leptin increased Caco-2 cell transport of cephalexin (CFX) and glycylsarcosine (Gly-Sar), an effect that was associated with increased Gly-Sar uptake, increased membrane PepT1 protein, decreased intracellular PepT1 content, and no change in PepT1 mRNA levels. The maximal velocity (Vmax) for Gly-Sar transport was significantly increased by leptin, whereas the apparent Michaelis-Menten constant (Km) did not change. Furthermore, leptin-stimulated Gly-Sar transport was completely suppressed by colchicine, which disrupts cellular translocation of proteins to plasma membranes. Intrajejunal leptin also induced a rapid twofold increase in plasma CFX after jejunal perfusion with CFX in the rat, indicating enhanced intestinal absorption of CFX. These data revealed an unexpected action of gastric leptin in controlling ingestion of dietary proteins.
Asunto(s)
Proteínas Portadoras/fisiología , Cefalexina/metabolismo , Dipéptidos/metabolismo , Intestino Delgado/fisiología , Leptina/fisiología , Receptores de Superficie Celular , Simportadores , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Transporte Biológico , Brefeldino A/farmacología , Células CACO-2 , Proteínas Portadoras/metabolismo , Colchicina/farmacología , Cartilla de ADN , Dipéptidos/química , Humanos , Intestino Delgado/metabolismo , Datos de Secuencia Molecular , Transportador de Péptidos 1 , Ratas , Receptores de LeptinaRESUMEN
The purpose of this work was to determine the mechanism of the antisecretory effect of peptide YY in the rat colon and whether this effect is physiological. In this prospect, doses of exogenous peptide YY producing physiological and supraphysiological plasma levels were intravenously infused in rats provided with colonic and jejunal ligated loops in vivo, under secretory stimulation by vasoactive intestinal peptide. Peptide YY decreased the secretory effect of VIP in a dose-related fashion. The effect of peptide YY was blocked or strongly decreased by tetrodotoxin, hexamethonium, idazoxan, haloperidol, and the sigma antagonist BMY 14, 802 in both the colon and jejunum. We conclude that peptide YY decreases water and electrolyte secretion in the colonic mucosa by a complex neural mechanism involving at least two neurons connected through a nicotinic synapse, alpha-2 adrenoceptors and sigma receptors, and that this effect can occur with physiological doses of peptide YY.
Asunto(s)
Colon/efectos de los fármacos , Colon/metabolismo , Péptido YY/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Agua Corporal/efectos de los fármacos , Agua Corporal/metabolismo , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Haloperidol/farmacología , Hexametonio/farmacología , Idazoxan/farmacología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Yeyuno/efectos de los fármacos , Yeyuno/metabolismo , Masculino , Antagonistas Nicotínicos/farmacología , Péptido YY/administración & dosificación , Péptido YY/fisiología , Ratas , Ratas Wistar , Bloqueadores de los Canales de Sodio , Tetrodotoxina/farmacología , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
Several Y receptor subtypes have been cloned and/or pharmacologically characterized that mediate the effects of the regulatory peptides peptide YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP). These peptides possess antisecretory properties on the intestine. This effect can be blocked in vivo by neural antagonists, suggesting the intervention of neural receptors, although epithelial PYY-preferring receptors have been evidenced on jejunal crypt cells. The purpose of the present experiments was to compare the antisecretory properties in vivo of a series of PYY and NPY derivatives with various affinities for different Y receptor subtypes, in order to determine which subtypes were involved. A model of VIP-stimulated secretion by rat jejunal loops was used. The results were compared with the binding affinities for PYY-preferring receptors determined on rat jejunal crypt cell membranes. Full-length PYY(1-36) was about three times more potent than NPY(1-36), and 10 times more potent than PP in the low dose range. PP, however, had a low efficacy limited to about 50% inhibition of VIP effect. Both Y1 agonists ([Leu31, Pro34]PYY and [Leu31,Pro34]NPY), and Y2 agonists [C-terminal fragments ranging from PYY (3-36) and NPY(3-36) to PYY(22-36) to NPY(22-36)] displayed potent antisecretory properties. PYY derivatives and fragments were always more potent than their respective NPY counterparts. In contrast, Y1 derivatives and PP had very low affinity for the epithelial PYY receptor as measured in vitro by radioreceptor assay. These data suggest that the antisecretory effect of PYY/NPY/PP peptides in vivo involves the effects of several receptors: a Y2-like, PYY-preferring receptor identical to the epithelial receptor, a Y1-like receptor, and a third receptor with high affinity for PP.
Asunto(s)
Líquidos Corporales/metabolismo , Yeyuno/efectos de los fármacos , Neuropéptidos/farmacología , Animales , Membrana Celular/efectos de los fármacos , Técnicas In Vitro , Yeyuno/metabolismo , Masculino , Neuropéptido Y/farmacología , Polipéptido Pancreático/farmacología , Péptido YY , Péptidos/farmacología , Ratas , Ratas Wistar , Tasa de Secreción/efectos de los fármacos , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
The intracerebroventricular (i.c.v.) administration of prostaglandin E2 (PGE2) inhibits gastric secretion at doses that are inactive by i.v. administration in the rat. The present study was undertaken to examine the central and peripheral effects of enprostil, a potent synthetic PGE2 analogue, on gastric acid secretion as compared to those of PGE2. We used conscious rats equipped with a chronic gastric fistula and a cannula to allow injection into the third ventricle of the brain. Gastric acid output was measured under basal interdigestive conditions and during stimulation with submaximal doses of pentagastrin and histamine. Total inhibition of basal and stimulated gastric acid output was obtained after i.c.v. PGE2 and after i.c.v. or i.v. enprostil administration. After i.v. PGE2, the maximal observed inhibition was not greater than 50%. The ratio of ED50 values for i.v. administered to i.c.v. administered PGE2 was 64 or more, whereas the ratio of ED50 values for i.v. enprostil to i.c.v. enprostil was 9 to 13. Under all conditions studied, enprostil was more potent than PGE2 and this greater potency was more prominent after i.v. administration (ratio 250 to 2500) than after i.c.v. administration (ratio 10 to 400). The blockade of alpha 2-adrenoceptors by idazoxan did not suppress the inhibition of gastric secretion produced by i.c.v. PGE2 or enprostil. It is concluded that low doses of PGE2 inhibit gastric acid output mainly through a central mechanism, whereas low doses of enprostil potently inhibit gastric acid output through both a central and a peripheral mechanism. alpha 2-Adrenoceptors are not essential for the effect of i.c.v. prostanoids on gastric acid secretion.
Asunto(s)
Sistema Nervioso Central/efectos de los fármacos , Dinoprostona/farmacología , Ácido Gástrico/metabolismo , Nervios Periféricos/efectos de los fármacos , Prostaglandinas E Sintéticas/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Dinoprostona/administración & dosificación , Dioxanos/farmacología , Enprostilo , Histamina/farmacología , Idazoxan , Inyecciones Intravenosas , Inyecciones Intraventriculares , Masculino , Pentagastrina/farmacología , Prostaglandinas E Sintéticas/administración & dosificación , Ratas , Ratas Endogámicas , Estimulación QuímicaRESUMEN
Prostaglandin E2 (PGE2) has been reported to exert some centrally mediated effects on intestinal motility and secretion and on gastric secretion, but it is not known whether such central effects exist on pancreatic secretion. The central and peripheral effects of PGE2 and enprostil, a long-acting, potent PGE2 analogue, were studied in conscious and anesthetized rats fitted with pancreatic fistulae. In chronically implanted, conscious rats, PGE2 inhibited the secretion of fluid, bicarbonate, and total protein in the pancreatic juice, both after i.v. or intracerebroventricular (icv) injections. The maximal inhibition was similar after both injection procedures (about 45% for fluid and bicarbonate and 60% for protein), but the potency of PGE2 was three to 10 times greater by the icv than the i.v. route. Enprostil also inhibited pancreatic secretion in a dose-related way. The maximal inhibition was larger than after PGE2 injection (about 70% for fluid and bicarbonate and 90% for protein). The potency of enprostil was five to 10 times lower by the icv than by the i.v. route. The diversion of gastric secretion suppressed the effect of icv PGE2 on fluid and bicarbonate output but not on protein and did not change the effect of enprostil on all the variables of pancreatic secretion. Adrenergic antagonists did not suppress the effect of icv PGE2 or enprostil on pancreatic secretion. In anesthetized rats, i.v. PGE2 inhibited hormone-stimulated protein secretion but did not change fluid and bicarbonate output, while i.v. enprostil inhibited cholecystokinin-stimulated fluid, bicarbonate, and protein output in the pancreatic juice.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Dinoprostona/farmacología , Jugo Pancreático/metabolismo , Prostaglandinas E Sintéticas/farmacología , Animales , Dioxanos/farmacología , Relación Dosis-Respuesta a Droga , Enprostilo , Idazoxan , Inyecciones Intraventriculares , Masculino , Páncreas/efectos de los fármacos , Prazosina/farmacología , Ratas , Ratas Endogámicas , Nervio Vago/fisiología , Yohimbina/farmacologíaRESUMEN
The endocrine and neural peptide, peptide YY, inhibits intestinal secretion of water and electrolytes in several animal species and in man. Peptide YY receptors have been evidenced on isolated rat jejunal crypt cells, but neural receptors are also likely to participate in the antisecretory effect of peptide YY in vivo. The aim of the present study was to investigate the mechanisms of the peptide YY effect on vasoactive intestinal peptide (VIP)-stimulated jejunal net water flux in the rat. Antagonist experiments using several drugs affecting neurally mediated processes were done for the purpose. A small peptide YY dose (10 pmol/kg) inhibited significantly (P < 0.005) the jejunal net water flux produced by 30 microg/kg per h of VIP. The inhibitory effect of peptide YY was suppressed, or strongly and significantly reduced, by tetrodotoxin, hexamethonium, lidocaine, idazoxan and BMY14,802 (51-(4-fluorophenyl)-4-(-4-(5-fluoro-2pyrimidinyl)-1-piperazinyl)- 1-butanol), whereas devazepide and L-NAME (L-omega-N-arginine methyl ester) had no effect. These results suggest that peptide YY inhibits VIP-stimulated jejunal net water flux in vivo through a neural mechanism implicating the participation of nicotinic synapses, alpha2-adrenoceptors and sigma receptors.
Asunto(s)
Yeyuno/metabolismo , Neuronas/metabolismo , Péptido YY/farmacología , Animales , Agua Corporal/metabolismo , Yeyuno/efectos de los fármacos , Yeyuno/inervación , Masculino , Neuronas/efectos de los fármacos , Péptido YY/antagonistas & inhibidores , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Receptores sigma/efectos de los fármacos , Receptores sigma/metabolismo , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
Thiorphan and its prodrug, acetorphan, are two inhibitors of enkephalinase (EC 3.4.24.11), a membrane-bound peptidase which plays an important role in the metabolic degradation of enkephalins. Since exogenous opioids have been reported to both stimulate and inhibit gastric secretion, the effects of thiorphan and acetorphan were studied in conscious rats equipped with chronic gastric fistulas. While i.v. thiorphan had no effect, both i.c.v. thiorphan and i.v. acetorphan potently inhibited the basal gastric acid output and the acid output stimulated by pentagastrin. Conversely, neither drug affected the histamine- or methacholine-induced stimulation of acid secretion. Neither thiorphan or acetorphan had any effect on the acid secretion stimulated by a combination of pentagastrin and acetylcholine in vagotomized rats. The results strongly suggest that both drugs inhibit gastric secretion through an effect at the level of the central nervous system, which decreases the vagal drive to the stomach. However, the effects of thiorphan and acetorphan were not prevented by naloxone. This is at variance with most of the effects of these drugs reported to date, including the inhibition of gastric secretion in cats. Furthermore, these effects were observed at doses which could inhibit other enzymes apart from enkephalinase. This suggests that the antisecretory action in rats is related to the protection of some non-opioid peptide(s) from degradation. In conclusion, both peptidase inhibitors inhibit gastric secretion of the rat through a central mechanism involving unknown, non-opioid peptide(s).
Asunto(s)
Mucosa Gástrica/efectos de los fármacos , Tiorfan/análogos & derivados , Tiorfan/farmacología , Animales , Interacciones Farmacológicas , Encefalina Metionina/análogos & derivados , Encefalina Metionina/farmacología , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Masculino , Neprilisina/antagonistas & inhibidores , Pentagastrina/farmacología , Profármacos/farmacología , Ratas , Ratas EndogámicasRESUMEN
The purpose of this work was to study whether stimulation or destruction of sensory afferents can modulate pancreatic secretion. The neurotoxin capsaicin is specific for a subpopulation of small diameter primary afferent neurons. Small doses of capsaicin were administered to anesthetized rats as intraduodenal or intragastric bolus injections to stimulate digestive sensory fibers, and pancreatic secretory response was measured. In addition, several high-dose subcutaneous capsaicin injections were administered 10 days before the experiments began, in order to inactivate sensory fibers. Basal and 2-deoxy-D-glucose (2DG)-stimulated pancreatic secretion was then measured. Intraduodenal capsaicin (96-3,050 micrograms/kg) induced a progressive (peak response 40-60 min after the injection), dose-related and long-lasting (> 180 min) increase in pancreatic output of sodium, bicarbonate, and total protein. The maximal response was obtained with 964 micrograms/kg capsaicin; it amounted to about 15% of the maximal response to exogenous cholecystokinin octapeptide (CCK8). The response was not decreased by atropine, hexamethonium, vagotomy, a mixture of adrenoceptor antagonists (prazosin + idazoxan + propranolol), or by the CCKB receptor antagonist L365,260. In contrast, the CCKA receptor antagonist L364,718 reduced by 30-40% the sodium and bicarbonate response and reduced by 90% the protein response induced by capsaicin, but not the response induced by methacholine or 2DG. However, intraluminal capsaicin did not release CCK in a preparation of isolated perfused duodeno-jejunum. Intragastric capsaicin did not significantly change pancreatic secretion. Capsaicin pretreatment had no effect on basal and 2DG-stimulated secretion, but abolished the response to intraduodenal capsaicin. In conclusion, intraduodenal capsaicin can stimulate external pancreatic secretion in anesthetized rats through capsaicin-sensitive sensory neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Capsaicina/farmacología , Neuronas Aferentes/efectos de los fármacos , Páncreas/metabolismo , Animales , Metabolismo Basal , Colecistoquinina/metabolismo , Desnervación , Desoxiglucosa/farmacología , Duodeno , Vías Eferentes/efectos de los fármacos , Técnicas In Vitro , Masculino , Perfusión , Ratas , Ratas Wistar , Estómago , Nervio Vago/efectos de los fármacosRESUMEN
Alcohol intake is a major problem in drug addicts, and it is not clear whether the effects of alcohol and opiates are additive or potentiating. Vagally stimulated pancreatic secretion in rats is potently inhibited by opiates acting centrally at mu-receptors. In the present experiments, we determined the effects of methadone on 2-deoxyglucose (2DG)-stimulated pancreatic secretion in rats treated with acute (1.9 g/kg.3 h, intravenously) or chronic (1 or 3 month drinking) ethanol. In both acute and 1 month chronic alcoholic rats, methadone administered at its 50% inhibitory dose (ID50) reduced by about 50% 2DG-stimulated pancreatic secretion of sodium, bicarbonate and protein, and ethanol had only faint, nonsignificant inhibitory effects. In 3 month chronic alcoholic rats, similar results were obtained, but methadone inhibited 2DG-stimulated pancreatic secretion by 60 to 90% in these older rats. No significant interaction was found in any condition between ethanol and methadone, suggesting that they had only additive, but not potentiating effects in this method.
Asunto(s)
Antimetabolitos/farmacología , Depresores del Sistema Nervioso Central/farmacología , Desoxiglucosa/farmacología , Etanol/farmacología , Metadona/farmacología , Narcóticos/farmacología , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Alcoholismo/fisiopatología , Análisis de Varianza , Animales , Masculino , Ratas , Ratas WistarRESUMEN
Several substances modulate the function of pancreatic acinar cells in vitro through specific receptors. All of them may also act in vivo, but the relative importance of their effect under physiological conditions is highly variable. The aim of this study was to assess the respective participation of cholinergic nerves and cholecystokinin (CCK) in the interdigestive pancreatic exocrine secretion and in the pancreatic response to intragastric or intraduodenal nutrients. Unanesthetized rats, equipped with a semichronic (5 days) pancreatic fistula, were used. They received a test-meal in the stomach (42 kJ) or the duodenum (21 kJ), and were infused intravenously with an antagonist of muscarinic (atropine, pirenzepin), nicotinic (hexamethonium), or CCK (L364718, lorglumide, Boc-Tyr(SO3)-Nle-Gly-D-Trp-Nle-Asp-NH-CH2-CH2-C6H5) receptors. Basal interdigestive pancreatic exocrine secretion decreased significantly after atropine, pirenzepine or hexamethonium. Protein output decreased more (peak inhibition 60 to 80 percent according to the drugs, p less than 0.01 to p less than 0.001) than volume or bicarbonate output (peak inhibition 25 to 65 percent according to the drugs, p less than 0.05 to p less than 0.01). CCK antagonists did not change the interdigestive pancreatic secretion. The cumulated response to the intraduodenal meal did not change after hexamethonium or pirenzepin, but increased after atropine (by approximately 50 percent, p less than 0.001 for volume and bicarbonate output, and nearly 100 percent, p less than 0.05 for protein output). The CCK antagonists entirely suppressed the protein response to the intraduodenal meal, decreased the volume response by 70 percent (p less than 0.01), and the bicarbonate response by 50 percent (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Atropina/farmacología , Colecistoquinina/metabolismo , Compuestos de Hexametonio/farmacología , Páncreas/metabolismo , Receptores Colinérgicos/efectos de los fármacos , Animales , Colecistoquinina/antagonistas & inhibidores , Masculino , Páncreas/efectos de los fármacos , Pirenzepina/farmacología , Ratas , Ratas EndogámicasRESUMEN
OBJECTIVES AND METHODS: The purpose of this study was to compare the effects of peptide YY (PYY) and neuropeptide Y (NPY) on VIP- and PGE2-stimulated intestinal net water flux at three different levels of the small intestine (duodenum, jejunum, ileum), by a technique of in situ closed loops in anaesthetised rats. RESULTS: VIP-stimulated net water flux was efficiently inhibited by both peptides at all three intestinal levels studied; PYY (ID50 about 30 pmol/kg.h) was 3 to 18 fold more potent than NPY. PGE2-stimulated net water flux was also efficiently inhibited in the jejunum and ileum; PYY (ID50 about 10 pmol/kg.h) was 30 to 90 fold more potent than NPY. A 30% inhibition of PGE2-stimulated net water flux could only be achieved in the duodenum with the largest dose of either peptide used in this study. CONCLUSIONS: PYY and NPY display potent inhibitory effects of stimulated net water flux at the three studied levels of the small intestine, except in the PGE2-stimulated duodenum. The PYY ID50s measured suggest that PYY may have a physiological action in regulating small intestinal water flux in the rat.
Asunto(s)
Duodeno/efectos de los fármacos , Íleon/efectos de los fármacos , Yeyuno/efectos de los fármacos , Neuropéptido Y/farmacología , Péptidos/farmacología , Equilibrio Hidroelectrolítico/efectos de los fármacos , Animales , Depresión Química , Dinoprostona/farmacología , Masculino , Oxitócicos/farmacología , Péptido YY , Ratas , Ratas Wistar , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
BACKGROUND AND AIMS: Leptin, the product of the ob gene, has been suggested to increase the risk of colon cancer. However, we have shown that although leptin stimulates epithelial cell proliferation it reduces the development of carcinogen induced preneoplastic lesions in the rat colon. Here, we explored the effect of leptin in vitro on proliferation of human colon cancer cells, and in vivo on the growth of HT-29 xenografts in nude mice and the development of intestinal tumours in Apc(Min/+) mice. METHODS: Proliferation of HT-29, LoVo, Caco2, and SW 480 cells was assessed in the absence or presence of leptin (20-500 ng/ml) by 3H-thymidine incorporation and cell count. Leptin (800 microg/kg/day) or its vehicle was delivered for four weeks to nude mice, inoculated with HT-29 cells on day 0, and for six weeks to Apc(Min/+) mice. RESULTS: Leptin dose dependently stimulated cell DNA synthesis and growth in all cell lines. In nude mice, leptin caused a 4.3-fold increase in plasma leptin levels compared with pair fed controls. This hyperleptinaemia, despite leptin receptor expression in tumours, did not induce significant variation in tumour volume or weight. Tumour Ki-67 index was even inhibited. In leptin treated Apc(Min/+) mice, a 2.4-fold increase in plasma leptin levels did not modify the number, size, or distribution of intestinal adenomas compared with pair fed controls. CONCLUSIONS: Leptin acts as a growth factor on colon cancer cells in vitro but does not promote tumour growth in vivo in the two models tested. These findings do not support a pivotal role for hyperleptinaemia in intestinal carcinogenesis.
Asunto(s)
Neoplasias del Colon/patología , Genes APC , Leptina/fisiología , Adenoma/genética , Adenoma/patología , Adenoma/fisiopatología , Animales , Apoptosis/fisiología , División Celular/fisiología , Línea Celular Tumoral , Colon/patología , Colon/fisiopatología , Neoplasias del Colon/genética , Neoplasias del Colon/fisiopatología , ADN de Neoplasias/biosíntesis , Humanos , Mucosa Intestinal/patología , Mucosa Intestinal/fisiopatología , Leptina/sangre , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones DesnudosRESUMEN
The effect of ST91, a clonidine derivative crossing poorly the blood-brain barrier, was compared to that of clonidine on exocrine pancreatic secretion in rats. The experiments were performed in anaesthetized rats after stimulation by a maximal dose of 2-deoxy-D-glucose, and in conscious rats under basal interdigestive conditions. In anaesthetized rats, the 2-deoxy-D-glucose-induced stimulation of pancreatic secretion was suppressed by clonidine but not by ST91, both injected subcutaneously. This effect of clonidine was not antagonized by prazosin, but was decreased by 70-100% (according to the variables measured) by yohimbine. The alpha-2 antagonists rauwolscine and corynanthine were less efficient than yohimbine, while idazoxan suppressed totally the effect of clonidine. In conscious rats, the basal interdigestive secretion was inhibited by ST91 and by clonidine. After sc injections, the potency of ST91 was about ten times smaller than that of clonidine, whereas after injections in the cerebral ventricles, ST91 was as potent as clonidine to inhibit pancreatic secretion. Most (70-90%) of the inhibition induced by sc ST91 and clonidine in conscious rats was suppressed by yohimbine or by prazosin. It is concluded that both ST91 and clonidine inhibit pancreatic secretion in rats, and that this effect has probably both central and peripheral components. The central effect involves alpha-2 receptors, while the peripheral effect may involve alpha-1 and alpha-2 receptors.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Páncreas/metabolismo , Anestesia , Animales , Clonidina/análogos & derivados , Clonidina/farmacología , Masculino , Páncreas/efectos de los fármacos , Prazosina/farmacología , Ratas , Ratas EndogámicasRESUMEN
Mechanisms of neural (vagal and cholinergic) and hormonal [cholecystokinin (CCK)] control of pancreatic exocrine secretion were studied in basal interdigestive conditions and after stimulation by an intraduodenal meal in rats equipped with a semichronic pancreatic fistula. Bile was recirculated into the duodenum, and a solution of trypsin and electrolytes was continuously infused. Pancreatic secretion was compared in control experiments, after vagotomy, and after venous infusion of cholinergic and CCK antagonists. Basal pancreatic secretion was decreased by atropine, pirenzepine, and hexamethonium and to a lesser extent by vagotomy (protein output decreased more than fluid and HCO3- outputs). The CCK antagonists L364,718 and lorglumide had no effect on basal interdigestive pancreatic secretion. Small doses of atropine (8 and 25 micrograms.kg-1.h-1) did not modify the cumulated pancreatic response to the meal, whereas larger doses (75 and 225 micrograms.kg-1.h-1) increased it by 40-85%, according to the variables. Pirenzepine and hexamethonium did not modify the pancreatic response. Vagotomy had no effect on fluid and HCO3- responses and tended to increase protein response. L364,718 and lorglumide completely inhibited the protein response and decreased the fluid and HCO3- responses by 75 and 40%, respectively. L364,718 also suppressed the increased pancreatic response induced by atropine. This work confirms the prominent role of neural cholinergic mechanisms in the control of basal interdigestive pancreatic secretion in rats. In contrast, the pancreatic protein response to an intraduodenal meal depends on CCK, whereas fluid and HCO3- responses also depend on other hormonal factors. Our results suggest that a muscarinic (probably M3) mechanism can decrease the postprandial CCK release independently of the pancreatic feedback control by trypsin.
Asunto(s)
Digestión , Duodeno/fisiología , Ingestión de Alimentos , Páncreas/metabolismo , Animales , Atropina/farmacología , Benzodiazepinonas/farmacología , Colecistoquinina/antagonistas & inhibidores , Devazepida , Digestión/efectos de los fármacos , Hexametonio , Compuestos de Hexametonio/farmacología , Cinética , Masculino , Músculo Liso/fisiología , Páncreas/efectos de los fármacos , Pirenzepina/farmacología , Proglumida/análogos & derivados , Proglumida/farmacología , Ratas , Ratas Endogámicas , Valores de Referencia , VagotomíaRESUMEN
Intestinal absorption of beta-lactamine antibiotics (e.g., cefixime and cephalexin) has been shown to proceed through the dipeptide carrier system. In a previous study, nifedipine (NFP), an L-type calcium channel blocker, enhanced the absorption of cefixime in vivo but not in vitro, and it was suggested that neural mechanisms might be involved in the effect of NFP. The aim of the present study was to assess the involvement of the nervous system on the intestinal absorption of cephalexin (CFX). To investigate this, we used a single-pass jejunal perfusion technique in rats. NFP and diltiazem enhanced approximately 2-fold the plasma levels of CFX in treated rats versus untreated controls. NFP also increased approximately 2-fold the CFX level in portal plasma and increased urinary excretion of CFX, thus indicating that CFX did effectively increase CFX intestinal absorption. Perfusing high concentrations of dipeptides in the jejunal lumen competitively reduced CFX absorption and inhibited the enhancement of CFX absorption produced by NFP. Hexamethonium and lidocaine inhibited the effect of NFP, whereas atropine, capsaicin, clonidine, and isoproterenol enhanced CFX absorption by the same order of magnitude as NFP. Thus, complex neural networks can modulate the function of the intestinal di- and tripeptide transporter. Sympathetic noradrenergic fibers, intestinal sensory neurons, and nicotinic synapses are involved in the increase of CFX absorption produced by NFP.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas Bacterianas , Cefalexina/metabolismo , Cefalosporinas/metabolismo , Absorción Intestinal , Yeyuno/fisiología , Proteínas de Transporte de Membrana/metabolismo , Antagonistas Adrenérgicos/farmacología , Animales , Cefalexina/sangre , Hexametonio/farmacología , Yeyuno/inervación , Lidocaína/farmacología , Masculino , Microvellosidades/metabolismo , Nifedipino/farmacología , Prazosina/farmacología , Ratas , Ratas Wistar , Yohimbina/farmacologíaRESUMEN
Cephalexin, a beta-lactam antibiotic, is rapidly absorbed via the di-and tripeptide intestinal transporters, as for many peptidomimetic drugs. Acute nifedipine has been shown to increase intestinal absorption of several beta-lactams: amoxicillin and cefixime in humans, and cephalexin in the rat. We showed previously that the nervous system was involved in the increasing effect of nifedipine on cephalexin intestinal absorption in anesthetized rats. The aim of the present study was 2-fold: 1) to investigate whether the effect of nifedipine is maintained in conscious rats, and 2) to determine whether the nifedipine effect will persist during chronic nifedipine administration. Acute and chronic oral administration of nifedipine significantly increased oral cephalexin area under the plasma concentration-time curve (34 and 25%, respectively) and maximum concentration in plasma (57 and 51%, respectively), while the distribution and elimination parameters of intra-arterial cephalexin were not affected by acute or chronic nifedipine administration. In conclusion, acute nifedipine effect on intestinal absorption of cephalexin is independent of anesthesia in rats. Since nifedipine could still enhance cephalexin intestinal absorption after a 7-day b.i.d. treatment, it can be envisaged to apply this effect to increase bioavailability of poorly absorbed peptidomimetic drugs in man.
Asunto(s)
Cefalexina/farmacocinética , Nifedipino/farmacología , Animales , Área Bajo la Curva , Disponibilidad Biológica , Sinergismo Farmacológico , Semivida , Absorción Intestinal , Masculino , Ratas , Ratas WistarRESUMEN
A peptide YY (PYY)-preferring receptor [PYY > neuropeptide Y (NPY)] was previously characterized in rat small intestinal crypt cells, where it mediates inhibition of fluid secretion. Here, we investigated the possible status of this receptor as a peripheral Y(2) receptor in rats. Typical Y(2) agonists (PYY(3-36), NPY(3-36), NPY(13-36), C2-NPY) and very short PYY analogs (N-alpha-Ac-PYY(22-36) and N-alpha-Ac-PYY(25-36)) acting at the intestinal PYY receptor were tested for their ability to inhibit the binding of (125)I-PYY to membranes of rat intestinal crypt cells and of CHO cells stably transfected with the rat hippocampal Y(2) receptor cDNA. Similar PYY preference was observed and all analogs exhibited comparable high affinity in both binding assays. The same held true for the specific Y(2) antagonist BIIE0246 with a K(i) value of 6.5 and 9.0 nM, respectively. BIIE0246 completely abolished the inhibition of cAMP production by PYY in crypt cells and transfected CHO cells. Moreover, the antagonist 1) considerably reversed the PYY-induced reduction of short-circuit current in rat jejunum mucosa in Ussing chamber and 2) completely abolished the antisecretory action of PYY on vasoactive intestinal peptide (VIP)-induced fluid secretion in rat jejunum in vivo. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) experiments showed that Y(2) receptor transcripts were present in intestinal crypt cells (3 x 10(2) molecules/100 ng RNA(T)) with no expression in villus cells, in complete agreement with the exclusive binding of PYY in crypt cells. Finally, a full-length Y(2) receptor was cloned by RT-PCR from rat intestinal crypt cells and also from human small intestine. We conclude that the so-called PYY-preferring receptor mediating inhibition of intestinal secretion is a peripheral Y(2) receptor.