RESUMEN
Recently, there have been advances in the development of new substances effective in managing diabetic disorders. Opioid receptors couple multiple systems to result in various biological effects, although opioids are best known for analgesia. In the present review, we used our recent data to describe the advance in plasma glucose-lowering action of herbal products, especially the mediation of ß-endorphin in glucose homeostasis of insulin-deficient diabetes. In type 1-like streptozotocin-induced diabetic rats, we identified many products purified from herbs that show a dose-dependent plasma glucose-lowering action. Increase in ß-endorphin secretion from the adrenal gland may activate peripheral opioid µ-receptors (MOR) to enhance the expression of muscle glucose transporters and/or to reduce hepatic gluconeogenesis at the gene level, thereby leading to improved glucose utilization in peripheral tissues for amelioration of severe hyperglycemia. It has also been observed that stimulation of α(1)-adrenoceptors (α(1)-ARs) in the adrenal gland by some herbal products is responsible for the increase in ß-endorphin secretion via a phospholipase C-protein kinase dependent pathway. However, an increase in ß-endorphin secretion from the adrenal gland by herbal products can function via another receptor. New insights into the mediation of endogenous ß-endorphin activation of peripheral MOR by herbal products for regulation of glucose homeostasis without the presence of insulin have been established. Therefore, an increase in ß-endorphin secretion and/or direct stimulation of peripheral MOR via an insulin-independent action might serve as the potential target for development of a therapeutic agent or promising adjuvant in intensive plasma glucose control.
RESUMEN
Abelmoschus moschatus (Malvaceae) is an aromatic and medicinal plant, distributed in many parts of Asia, including south Taiwan. The present study was undertaken to clarify whether the herb is effective in improving insulin resistance. Insulin resistance in rats was induced by a diet containing 60% fructose for 6 weeks. The degree of insulin resistance was measured by homeostasis model assessment of basal insulin resistance (HOMA-IR). Insulin sensitivity was calculated using the composite whole body insulin sensitivity index (ISIcomp) during the oral glucose tolerance test. Insulin receptor-related signaling mediators in soleus muscles of rats were evaluated by immunoprecipitation or immunoblotting. The extract of A. moschatus had a higher level of polyphenolic flavonoids. A. moschatus extract (200 mg/kg per day) displayed the characteristics of rosiglitazone (4 mg/kg per day) in reducing the higher HOMA-IR index as well as elevating ISIcomp in fructose chow-fed rats after a 2-week treatment. Treatment with moschatus extract for 2 weeks increased post-receptor insulin signaling mediated by enhancements in insulin receptor substrate-1-associated phosphatidylinositol 3-kinase step and glucose transporter subtype 4 translocation in insulin-resistant soleus muscles. A. moschatus is therefore proposed as potentially useful adjuvant therapy for patients with insulin resistance and/or the subjects wishing to increase insulin sensitivity.
Asunto(s)
Abelmoschus/química , Hiperinsulinismo/tratamiento farmacológico , Hipoglucemiantes/farmacología , Resistencia a la Insulina , Extractos Vegetales/farmacología , Animales , Flavonoides/aislamiento & purificación , Fructosa , Prueba de Tolerancia a la Glucosa , Transportador de Glucosa de Tipo 4/metabolismo , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Fenoles/aislamiento & purificación , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Ratas , Ratas Wistar , Receptor de Insulina/metabolismo , Rosiglitazona , Tiazolidinedionas/farmacologíaRESUMEN
Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in feeding and body weight regulation. However, there is little genetic evidence that overexpression or knockout of the NPY gene leads to altered body weight regulation. Previously, we developed NPY-overexpressing mice by using the Thy-1 promoter, which restricts NPY expression strictly within neurons in the central nervous system, but we failed to observe the obese phenotype in the heterozygote. Here we report that in the homozygous mice, overexpression of NPY leads to an obese phenotype, but only after appropriate dietary exposure. NPY-overexpressing mice exhibited significantly increased body weight gain with transiently increased food intake after 50% sucrose--loaded diet, and later they developed hyperglycemia and hyperinsulinemia without altered glucose excursion during 1 year of our observation period.
Asunto(s)
Arginina/análogos & derivados , Encéfalo/fisiología , Sacarosa en la Dieta/farmacología , Neuropéptido Y/fisiología , Obesidad/fisiopatología , Envejecimiento , Animales , Arginina/farmacología , Ciclohexanos/farmacología , Ingestión de Energía/efectos de los fármacos , Homocigoto , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Neuropéptido Y/genética , Obesidad/inducido químicamente , Obesidad/genética , Fenotipo , Regiones Promotoras Genéticas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Valores de Referencia , Antígenos Thy-1/genética , Xantenos/farmacologíaRESUMEN
The effect of tramadol on the plasma glucose level of streptozotocin (STZ)-induced diabetic rats was investigated. A dose-dependent lowering of plasma glucose was seen in the fasting STZ-induced diabetic rats 30 min after intravenous injection of tramadol. This effect of tramadol was abolished by pretreatment with naloxone or naloxonazine at doses sufficient to block opioid mu-receptors. However, response to tramadol was not changed in STZ-induced diabetic rats receiving p-chlorophenylalanine at a dose sufficient to deplete endogenous 5-hydroxytrptamine (5-HT). Therefore, mediation of 5-HT in this action of tramadol is ruled out. In isolated soleus muscle, tramadol enhanced the uptake of radioactive glucose in a concentration-dependent manner. The stimulatory effects of tramadol on glycogen synthesis were also seen in hepatocytes isolated from STZ-induced diabetic rats. The blockade of these actions by naloxone and naloxonazine indicated the mediation of opioid mu-receptors. The mRNA and protein levels of the subtype 4 form of glucose transporter in soleus muscle were increased after repeated treatments for 4 days with tramadol in STZ-induced diabetic rats. Moreover, similar repeated treatments with tramadol reversed the elevated mRNA and protein levels of phosphoenolpyruvate carboxykinase in the liver of STZ-induced diabetic rats. These results suggest that activation of opioid mu-receptors by tramadol can increase the utilization of glucose and/or decrease hepatic gluconeogenesis to lower plasma glucose in diabetic rats lacking insulin.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Hipoglucemiantes/farmacología , Proteínas Musculares , Naloxona/análogos & derivados , Narcóticos/farmacología , Tramadol/farmacología , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Gluconeogénesis , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4 , Glucógeno/biosíntesis , Hipoglucemiantes/administración & dosificación , Inyecciones Intravenosas , Cinética , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Proteínas de Transporte de Monosacáridos/análisis , Proteínas de Transporte de Monosacáridos/genética , Músculo Esquelético/química , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Narcóticos/administración & dosificación , Fosfoenolpiruvato Carboxiquinasa (GTP)/química , Fosfoenolpiruvato Carboxiquinasa (GTP)/genética , ARN Mensajero/análisis , Ratas , Ratas Wistar , Receptores Opioides mu/fisiología , Tramadol/administración & dosificaciónRESUMEN
Leptin, the ob gene product that can decrease caloric intake and increase energy expenditure, is functionally released by insulin from adipose tissue. Adenosine is thought to be an important regulator of the action of insulin in adipose tissue. The present study investigated the role of adenosine in the release of leptin by insulin in isolated rat white adipocytes. Release of leptin, measured by radioimmunoassay, from insulin-stimulated samples was seen after 30 min. Adenosine deaminase, at concentrations sufficient to metabolize endogenous adenosine, decreased insulin-stimulated leptin release. Also, the insulin-stimulated leptin release was completely blocked by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Mediation of endogenous adenosine in this action of insulin was further supported by the assay of adenosine released into the medium from adipocytes stimulated with insulin. In addition, activation of adenosine A1 receptors by N6-cyclopentyladenosine (CPA) induced an increase in leptin release in a concentration-dependent manner that could be blocked by antagonists, either DPCPX or 8-(p-sulfophenyl)theophylline (8-SPT). In the presence of U73312, a specific inhibitor of phospholipase C (PLC), CPA-stimulated leptin secretion from adipocytes was reduced in a concentration-dependent manner, but it was not affected by U73343, the negative control for U73312. Moreover, chelerythrine and GF 109203X diminished the CPA-stimulated leptin secretion at concentrations sufficient to inhibit protein kinase C (PKC). These results suggest that, in isolated white adipocytes, the released adenosine acts as a helper and/or a positive regulator for insulin in the release of leptin via an activation of adenosine A1 receptors that involves the PLC-PKC pathway.
Asunto(s)
Adenosina/fisiología , Adipocitos/metabolismo , Insulina/farmacología , Leptina/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Animales , Separación Celular , Inhibidores Enzimáticos/farmacología , Masculino , Proteína Quinasa C/antagonistas & inhibidores , Ratas , Ratas Wistar , Fosfolipasas de Tipo C/antagonistas & inhibidoresRESUMEN
Exposure to a cold environment may increase the activity of the sympathetic nervous system inducing an elevation of plasma norepinephrine and may result in hyperglycemia. In the present study, we found that a hypoglycemic effect was produced in streptozotocin-induced diabetic rats after cold-exposure at 4 degrees C for 1 h. In addition to the blockade of this hypoglycemic effect by guanethidine (a ganglion-blocking agent) and prazosin (an alpha1-adrenoceptor antagonist), an increase of plasma norepinephrine was also observed in streptozotocin-induced diabetic rats receiving this cold-stress. Participation of sympathetic hyperactivity can thus be considered. Furthermore, naloxone, in a dose (0.5 mg/kg, i.p.) sufficient to block opioid receptors, reversed this hypoglycemia. Also, an increase of plasma beta-endorphin-like immunoreactivity was observed in streptozotocin-induced diabetic rats receiving this cold-stress. Intravenous injection of beta-endorphin into streptozotocin-induced diabetic rats produced a lowering of plasma glucose. Administration of methoxamine at a dose sufficient to activate the alpha1-adrenoceptors produced hypoglycemia and a similar increase of plasma beta-endorphin-like immunoreactivity in streptozotocin-induced diabetic rats. However, plasma beta-endorphin-like immunoreactivity level was not modified by similar treatment with methoxamine or cold-stress in normoglycemic rats. Therefore, beta-endorphin appears to be responsible for the induction of hypoglycemic effects in streptozotocin-induced diabetic rats after cold exposure which is different to the response in normal rats.
Asunto(s)
Glucemia/análisis , Frío , Diabetes Mellitus Experimental/sangre , Estrés Fisiológico/metabolismo , Animales , Masculino , Metoxamina/farmacología , Norepinefrina/sangre , Ratas , Ratas Wistar , betaendorfina/sangreRESUMEN
Wistar rats with streptozotocin-induced diabetes (STZ-diabetic rats), which is similar to human insulin-dependent diabetic mellitus (IDDM), were employed to investigate the antihyperglycemic action of isoferulic acid. A single intravenous injection of isoferulic acid decreased the plasma glucose in a dose-dependent manner in the STZ-diabetic rats. Repeated intravenous administration of STZ-diabetic rats with isoferulic acid (5.0 mg kg(-1)) also resulted in the lowering of plasma glucose after one day. Stimulatory effects of isoferulic acid on the glucose uptake and glycogen synthesis in soleus muscles isolated from STZ-diabetic rats were also obtained indicating an increase of glucose utilization following isoferulic acid treatment which was not dependent on insulin. The mRNA level of glucose transporter subtype 4 form (GLUT4) in soleus muscle was raised by isoferulic acid after repeated treatment for 1 day in STZ-diabetic rats. Similar repeated treatment with isoferulic acid reversed the elevated mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) in liver of STZ-diabetic rats to the normal level. However, expression of GLUT4 and PEPCK genes in nondiabetic rats were not influenced by similar treatment with isoferulic acid. These results suggest that isoferulic acid can inhibit hepatic gluconeogenesis and/or increase the glucose utilization in peripheral tissue to lower plasma glucose in diabetic rats lacking insulin.
Asunto(s)
Cinamatos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Proteínas Musculares , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Radioisótopos de Carbono , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Gluconeogénesis , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4 , Glucógeno/biosíntesis , Masculino , Proteínas de Transporte de Monosacáridos/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Fosfoenolpiruvato Carboxiquinasa (GTP)/biosíntesis , Fosfoenolpiruvato Carboxiquinasa (GTP)/genética , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
The visual superiority effect (a reverse long-term modality effect) has been consistently found with Chinese logographs. For its explanation in terms of script differences, it has been believed that lexical access is more direct or quicker for Chinese logographs than for alphabetic words. It has also been believed that Chinese logographs are more unique in shape or more discriminable than alphabetic words. Finally, Chinese logographs have been considered to facilitate recall through their graphic features that classify Chinese words into categories. The results of Experiments 1-5 show that these three assumptions can be ruled out. The results of Experiments 6-10, on the other hand, support the long-term priming interpretation of the visual superiority effect, which explains (a) why the visual superiority effect can be consistently obtained for recall of Chinese words by Chinese subjects, (b) why the effect cannot be consistently obtained for recall of English words by Western subjects, (c) why the effect can be also obtained for recall of English words by Chinese subjects, (d) why the effect can be easily obtained for recall of a set of words, but not for recall of a different set of words by Chinese subjects, and (e) why the effect can be easily obtained from Chinese subjects speaking a dialect that is different from Mandarin.
Asunto(s)
Comparación Transcultural , Lenguaje , Reconocimiento Visual de Modelos , Lectura , Adulto , China , Humanos , Recuerdo Mental , Psicolingüística , Tiempo de Reacción , Aprendizaje SeriadoRESUMEN
The present study used a lexical naming task as well as a regular naming task and a lexical decision task for locating the frequency effects in lexical decision and naming. The naming of Chinese characters in the lexical naming task (pseudocharacters also presented as in the lexical decision task) involves decision processes, while they are absent in the regular naming task. Since naming a Chinese character necessarily involves lexical access, a decision component of the frequency effect in lexical decision can be isolated. This procedure will not work for alphabetic orthographies, because sublexical processes underestimate the frequency effect in the regular naming task. As a consequence, not only can a prelexical component of the frequency effect in lexical decision be estimated, but a postlexical component of the frequency effect in naming can be estimated.
Asunto(s)
Lenguaje , Recuerdo Mental , Reconocimiento Visual de Modelos , Lectura , Aprendizaje Verbal , Adolescente , Adulto , China , Aprendizaje Discriminativo , Femenino , Humanos , Masculino , Fonética , PsicolingüísticaRESUMEN
Subtypes of alpha(1)-adrenoceptor (alpha(1)-AR) in the cultured myoblast C(2)C(12) cells have been examined using molecular biological identifications. Expression of the two distinct mRNAs that encode proteins of alpha(1A)- and alpha(1B)-AR was studied using reverse transcription combined with polymerase chain reaction (RT-PCR). Results of RT-PCR demonstrated a marked expression of alpha(1A)-AR in the prostate of rats. Samples from the C(2)C(12) cells under the same amount of amplification showed the expression of alpha(1A)-AR at a level slightly lower than that from the prostate of rats. Western blotting analysis using receptor subtype-specific antibody also indicated that the alpha(1A)-AR was expressed in C(2)C(12) cells as well as in prostate of rats. However, although the expression of alpha(1B)-AR was obtained in the spleen of rats, expression of alpha(1B)-AR was undetectable in the C(2)C(12) cells either the results of RT-PCR or the Western blotting analysis. The present study suggests that alpha(1A)-AR is a major subtype of alpha(1)-AR in the C(2)C(12) cell line.
Asunto(s)
Expresión Génica , Músculo Esquelético/metabolismo , ARN Mensajero/biosíntesis , Receptores Adrenérgicos alfa 1/biosíntesis , Animales , Western Blotting , Línea Celular , Masculino , Ratones , Músculo Esquelético/citología , Especificidad de Órganos , Próstata/metabolismo , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/metabolismoRESUMEN
It is well known that the baroreflex activity decreases with aging. However, the mechanisms of this change are still not clear. Thus, we investigated one of the parameters to see whether aging alters gene expression of muscarinic receptors in the heart of Wistar rat aged between 2 months (adult) and 24 months (aged). The mRNA level determination by Northern blot analysis for muscarinic M2 cholinoceptors in aged rat was decreased as compared to that in 2-month-old rats. Quantification of receptor protein using selective antibodies indicated that the level of muscarinic M2 cholinoceptor in the heart of 24-month-old rats was lower than that in 2-month-old animals. These results indicate the decrease of muscarinic M2 cholinoceptor in heart with aging that may contribute as one of the parameters for dysfunction in baroreflex activity.
Asunto(s)
Envejecimiento/metabolismo , Expresión Génica/fisiología , Corazón/fisiología , ARN Mensajero/metabolismo , Receptores Muscarínicos/metabolismo , Envejecimiento/genética , Animales , Barorreflejo/fisiología , Masculino , Proteínas de la Membrana/metabolismo , Ratas , Ratas Wistar , Receptor Muscarínico M2 , Receptores Muscarínicos/genéticaRESUMEN
Opioid mu-receptor plays an important role in the regulation of glucose homeostasis in diabetic rats lacking insulin. Opioid mu-receptor knockout mice were employed to identify the essential role of this receptor in the present study. Western blotting analysis characterized the deletion of opioid mu-receptor in liver of knockout mice as compared to that of normal (wild-type) mice. We found that the plasma glucose concentration of diabetic mice induced by intraperitoneal injection of streptozotocin was markedly decreased after exposure to cold-stress in a cold room for 1 h. However, this plasma glucose lowering response to cold-stress was disappeared in diabetic mice lacking opioid mu-receptor. The important role of opioid mu-receptor in the plasma glucose lowering response to cold stress can thus be considered. Moreover, bilateral adrenalectomy abolished this plasma glucose lowering response to cold stress in diabetic mice with opioid mu-receptor, as compared to the shamed-operated animals. Therefore, activation of opioid mu-receptor by opioid from adrenal gland appears to be responsible for the plasma glucose lowering response to cold-stress in diabetic mice with insulin deficiency.
Asunto(s)
Glucemia/fisiología , Diabetes Mellitus Experimental/sangre , Receptores Opioides mu/deficiencia , Estrés Fisiológico/metabolismo , Glándulas Suprarrenales/metabolismo , Animales , Membrana Celular/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Hipotermia Inducida/efectos adversos , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados/sangre , Péptidos Opioides/metabolismo , Receptores Opioides mu/genética , Estrés Fisiológico/fisiopatologíaRESUMEN
Changes of adenosine A-1 receptor (A1-AR) gene expression in aging were investigated in cerebral cortex using the rat aged from 2 months (adult) to 24 months (aged). Quantification of A1-AR protein level by immunoblotting analysis showed an age-related decrease of A1-AR in cerebral cortex of Wistar rats. Compared to the preparations from 2-month-old animals, the levels of A1-AR in the 6-, 12-, and 24-month-old rats were reduced by 14.3+/-5.2, 32.5+/-4.5 and 28.2+/-5.7%, respectively. Similar decrease of mRNA level in A1-AR was also obtained using Northern blotting analysis. Two representative spots of mRNA, a 3.4-kb transcript and a 5.6-kb transcript, were observed in X-ray film from cerebral cortex of rat hybridized with rat A1-AR cDNA probe. Compared to the 2 month-old rats, levels of the 5.6-kb transcript were decreased by 17.9+/-2.5, 27.4+/-3.2 and 23.1+/-2.1% in the 6-, 12- and 24-month-old rats, respectively. These results indicated an age-related decrease of A1-AR in cerebral cortex of the rat that seems responsible for the change of response to adenosine.
Asunto(s)
Envejecimiento/genética , Envejecimiento/metabolismo , Corteza Cerebral/metabolismo , Regulación hacia Abajo/genética , Regulación de la Expresión Génica , Receptores Purinérgicos P1/biosíntesis , Receptores Purinérgicos P1/genética , Animales , Northern Blotting , Western Blotting , Química Encefálica/genética , Corteza Cerebral/fisiología , Masculino , Ratas , Ratas Wistar , Receptores Purinérgicos P1/aislamiento & purificaciónRESUMEN
In an attempt to discover the changes of superoxide dismutase (SOD) in the brain of diabetic state, we investigated the level of SOD in streptozotocin-induced diabetic rats (STZ-diabetic rats) using enzyme activity assay, Northern blotting analysis of mRNA levels and Western blotting of enzyme amount. Five discrete brain regions, cerebrocortex, hypothalamus, hippocampus, the remaining non-cortex cerebrum (NCC area) and cerebellum, were examined in STZ-diabetic rats to compare with age-matched normal rats. Higher levels of Mn-SOD including the activity, mRNA expression and immunoblot of enzyme were found in all areas of the brain from STZ-diabetic rats as compared with that in Wistar rats. Except in the cerebellum, similar changes of Cu,Zn-SOD were found in the brain of STZ-diabetic rats. These results indicate an increase of SOD both gene expression and activity in the brain of STZ-diabetic rats. This alteration of SOD may be one of the important factors for the vulnerability of the brain to oxygen free radicals or may be related to the pathophysiology of diabetes.
Asunto(s)
Encéfalo/enzimología , Diabetes Mellitus/enzimología , Superóxido Dismutasa/metabolismo , Animales , Northern Blotting , Western Blotting , Expresión Génica , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Estreptozocina , Superóxido Dismutasa/genéticaRESUMEN
We investigated the effect of loperamide, a selective agonist of opioid mu-receptor, on the plasma glucose in diabetic rats induced by an intravenous injection of streptozotocin (STZ; 60 mg/kg). Intravenous injection of loperamide induced a dose-dependent decrease of plasma glucose in fasting STZ-diabetic rats at 30 min later, but did not modify the plasma glucose level in Wistar rats. Plasma glucose lowering effect of loperamide was abolished by the pretreatment with naloxone or naloxonazine at the dose sufficient to block opioid mu-receptor. In isolated skeletal muscle, loperamide enhanced the glucose uptake into soleus muscles in a concentration-dependent manner. Blockade of this action by naloxonazine indicated the mediation of opioid mu-receptor. These results suggest that an activation of opioid mu-receptor by loperamide can increase the utilization of glucose in peripheral tissue to lower the plasma glucose in STZ-diabetic rats.
Asunto(s)
Antidiarreicos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Loperamida/farmacología , Receptores Opioides mu/metabolismo , Animales , Glucemia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Glucosa/farmacocinética , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Inyecciones Intravenosas , Masculino , Músculo Esquelético/metabolismo , Naloxona/análogos & derivados , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Ratas Wistar , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidoresRESUMEN
In an attempt to understand the antihyperglycemic action of caffeic acid, the myoblast C2C12 cells were employed to investigate the glucose uptake in the present study. Caffeic acid enhanced the uptake of radioactive glucose into C2C12 cells in a concentration-dependent manner. Similar effect of phenylephrine on the uptake of radioactive glucose was also observed in C2C12 cells. Prazosin attenuated the action of caffeic acid in a way parallel to the blockade of phenylephrine. Effect of caffeic acid on alpha1-adrenoceptors was further supported by the displacement of [3H]prazosin binding in C2C12 cells. Moreover, the glucose uptake-increasing action of phenylephrine in C2C12 cells was inhibited by the antagonists of alpha1A-adrenoceptors, both tamsulosin and WB 4101, but not by the antagonist of alpha1B-adrenoceptors, chlorethylclonidine (CEC). The presence of alpha1A-adrenoceptors in C2C12 cells can thus be considered. Similar inhibition of the action of caffeic acid was also obtained in C2C12 cells co-incubating these antagonists. An activation of alpha1A-adrenoceptors seems responsible for the action of caffeic acid in C2C12 cells. In the presence of U73312, the specific inhibitor of phospholipase C, caffeic acid-stimulated uptake of radioactive glucose into C2C12 cells was reduced in a concentration-dependent manner and it was not affected by U73343, the negative control of U73312. Moreover, chelerythrine and GF 109203X diminished the action of caffeic acid at concentrations sufficient to inhibit protein kinase C. Therefore, the obtained data suggest that an activation of alpha1A-adrenoceptors in C2C12 cells by caffeic acid may increase the glucose uptake via phospholipase C-protein kinase C pathway.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Ácidos Cafeicos/farmacología , Glucosa/metabolismo , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Humanos , Fenilefrina/farmacología , Prazosina/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Ensayo de Unión Radioligante , Fosfolipasas de Tipo C/antagonistas & inhibidores , Fosfolipasas de Tipo C/metabolismoRESUMEN
The effect of trans-cinnamaldehyde (CNMA) on the release of noradrenaline (NA) from nerve terminal was investigated using isolated ileal synaptosomes of guinea-pig. Release was determined as the amount of NA, quantified by h.p.l.c.-electrochemical detection, from samples incubated with CNMA minus that in parallel blanks treated with same volume of vehicle. CNMA stimulated the secretion of NA in a concentration-dependent manner from 5 microM to 50 microM, while the value of lactate dehydrogenase in the incubated medium was not influenced by CNMA. However, trans-cinnamic acid, cinnamoyl chloride and cinnamamide failed to produce similar effect. Specific action of CNMA can thus be considered. Guanethidine inhibited the release of NA by CNMA in a concentration- dependent manner. Saxitoxin attenuated the action of CNMA at concentrations sufficient to block sodium channels. The depolarizing effect of CNMA on the membrane potential was also illustrated by a concentration-dependent increase in the fluorescence of bisoxonol, a potential sensitive dye. The NA releasing action of CNMA was deleted by removal of calcium chloride from the bathing medium. This action of CNMA was also attenuated by Rp-cAMP at concentrations sufficient to inhibit the action of cyclic AMP. These findings suggest that CNMA can depolarize the membrane to result in a calcium-dependent and cyclic AMP-related release of NA from noradrenergic terminals.
Asunto(s)
Acroleína/análogos & derivados , Íleon/efectos de los fármacos , Terminaciones Nerviosas/efectos de los fármacos , Norepinefrina/metabolismo , Acroleína/farmacología , Antagonistas Adrenérgicos/farmacología , Animales , Calcio/fisiología , AMP Cíclico/fisiología , Femenino , Guanetidina/farmacología , Cobayas , Íleon/enzimología , Íleon/inervación , Técnicas In Vitro , L-Lactato Deshidrogenasa/metabolismo , Masculino , Potenciales de la Membrana/efectos de los fármacos , Terminaciones Nerviosas/enzimología , Terminaciones Nerviosas/metabolismo , Norepinefrina/antagonistas & inhibidoresRESUMEN
To examine the role of the adenosine A1 receptor in glucose regulation in the absence of insulin, the present study investigated the changes of plasma glucose in male streptozotocin-induced diabetic rats (STZ-diabetic rats) using dipyridamole to increase endogenous adenosine and N6-cyclopentyladenosine (CPA) to activate the adenosine A1 receptor. Intravenous injections of dipyridamole or CPA induced a dose-dependent decrease of plasma glucose in fasting STZ-diabetic rats. Plasma glucose lowering action of dipyridamole, like that of CPA, was inhibited in a dose-dependent manner by pre-treatment with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) or 8-(p-sulfophenyl)theophylline (8-SPT) at which block the adenosine A1 receptors. Action of the adenosine A1 receptors can thus be considered. In isolated skeletal muscle, CPA enhanced the glucose uptake in a concentration-dependent manner. Blockade of this action by DPCPX and 8-SPT again supported the mediation of the adenosine A1 receptor. Also, CPA produced an increase of glycogen synthesis in isolated soleus muscle. Moreover, CPA decreased plasma triglyceride and cholesterol levels significantly in STZ-diabetic rats. These results suggest that activation of adenosine A1 receptors can increase glucose utilization in peripheral tissues by increasing tissue uptake and glycogen synthesis to lower plasma glucose in rats lacking insulin.
Asunto(s)
Adenosina/análogos & derivados , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Hipoglucemiantes/administración & dosificación , Receptores Purinérgicos P1/efectos de los fármacos , Teofilina/análogos & derivados , Adenosina/administración & dosificación , Animales , Colesterol/sangre , Diabetes Mellitus Experimental/inducido químicamente , Dipiridamol/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glucosa/metabolismo , Glucosa/farmacocinética , Glucógeno/metabolismo , Insulina/sangre , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Antagonistas de Receptores Purinérgicos P1 , Ratas , Ratas Wistar , Receptores Purinérgicos P1/metabolismo , Estreptozocina , Teofilina/administración & dosificación , Triglicéridos/sangre , Xantinas/administración & dosificaciónRESUMEN
In an attempt to investigate the presence of adenosine A1 receptor in cell line, we used N6-cyclopentyladenosine (CPA), an agonist of adenosine A1 receptor, to incubate with C2C12 cells in vitro. CPA increased the uptake of radioactive glucose into C2C12 cells in a concentration-dependent manner and this action was abolished by the antagonists, both 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (1,3-dipropy1-8-cyclopentylxanthine) and 8-(p-sulfophenyl)theophylline (8-SPT), at concentrations sufficient to block adenosine A1 receptor. Northern blot analysis showed the expression of adenosine A1 receptor mRNA by C2C12 cells. Western blotting also indicated a positive correlation (r = 0.99) of antibody recognized adenosine A1 receptor with membrane protein. The presence of adenosine A1 receptor in C2C12 cells can thus be considered. In the presence of U73312 (1-[6[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H- pyrrole-2,5-dione), the specific inhibitor of phospholipase C, glucose uptake stimulated by CPA into C2C12 cells was reduced concentration-dependently while it was not modified by U73343 (1-[6[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-2,5- pyrrolidinedione), the negative control of U73312. Moreover, chelerythrine and GF 109203X (3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3- yl)-1H-pyrrole-2,5-dione) also diminished the CPA-stimulated glucose uptake at concentrations sufficient to inhibit protein kinase C. The obtained data suggest that activation of adenosine A1 receptor in C2C12 cells may increase the glucose uptake via phospholipase C-protein kinase C pathway.
Asunto(s)
Células Cultivadas/metabolismo , Músculo Esquelético/metabolismo , Receptores Purinérgicos P1/efectos de los fármacos , Receptores Purinérgicos P1/metabolismo , Transducción de Señal/fisiología , Adenosina/análogos & derivados , Adenosina/farmacología , Animales , Células Cultivadas/citología , Células Cultivadas/efectos de los fármacos , Desoxiglucosa/farmacocinética , Inmunohistoquímica , Insulina/farmacología , Ratones , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/embriología , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores Purinérgicos P1/genética , Transducción de Señal/efectos de los fármacosRESUMEN
In an attempt to elucidate the effect of isoferulic acid on alpha1-adrenoceptor (AR), the myoblast C2C12 cells of mice were employed to investigate the change of glucose uptake in the present study. Isoferulic acid enhanced the uptake of radioactive glucose into C2C12 cells in a concentration-dependent manner, which were abolished by pretreatment with prazosin. Effect of isoferulic acid on alpha1-AR was further characterized using the displacement of [3H]YM617 binding in C2C12 cells. The radioactive glucose uptake increasing action of isoferulic acid was abolished by tamsulosin or WB 4101 at concentration sufficient to block alpha1A-adrenoceptor (alpha1A-AR) but it was not modified by chlorethylclonidine (CEC) at the concentration sufficient to abolish alpha1B-AR. An activation of alpha1A-AR by isoferulic acid in C2C12 cells can thus be considered. Pharmacological inhibition of phospholipase C (PLC) by U73312 resulted in a concentration-dependent reduction of isoferulic acid-stimulated glucose uptake in C2C12 cells. This inhibition by U73112 was specific because the inactive congener, U73343, failed to modify the action of isoferulic acid. Also, chelerythrine and GF 109203X diminished the action of isoferulic acid at concentration sufficient to inhibit the activity of protein kinase C (PKC). The obtained data suggest that an activation of alpha1A-AR by isoferulic acid may increase the glucose uptake via PLC-PKC pathway in C2C12 cells.