RESUMEN
The liver plays an important role in maintaining glucose homeostasis in the body. In the prandial state, some of the glucose which is absorbed by the gastrointestinal tract is converted into glycogen and stored in the liver. In contrast, the liver produces glucose by glycogenolysis and gluconeogenesis while fasting. Thus, the liver contributes to maintaining blood glucose level within normoglycemic range. Glycogenesis and glycogenolysis are regulated by various mechanisms including hormones, the sympathetic and parasympathetic nervous systems and the hepatic glucose content. In this study, we examined a rat model in which the celiac superior mesenteric ganglion (CSMG) was resected. We attempted to elucidate how the celiac sympathetic nervous system is involved in regulating glucose homeostasis by assessing the effects of CSMG resection on glucose excursion during an oral glucose tolerance test, and by examining hepatic glycogen content and hepatic glycogen phosphorylase (GP) activity. On the oral glucose tolerance test, CSMG-resected rats demonstrated improved glucose tolerance and significantly increased GP activity compared with sham-operated rats, whereas there were no significant differences in insulin, glucagon or catecholamine levels between the 2 groups. These results suggest that the celiac sympathetic nervous system is involved in regulating the rate of glycogen consumption through GP activity. In conclusion, the examined rat model showed that the celiac sympathetic nervous system regulates hepatic glucose metabolism in conjunction with vagal nerve innervations and is a critical component in the maintenance of blood glucose homeostasis.
Asunto(s)
Glucemia/análisis , Catecolaminas/sangre , Ganglionectomía , Glucagón/sangre , Homeostasis , Insulina/sangre , Hígado/metabolismo , Animales , Regulación hacia Abajo , Ganglios Simpáticos/cirugía , Prueba de Tolerancia a la Glucosa , Glucógeno/biosíntesis , Glucógeno Fosforilasa de Forma Hepática/metabolismo , Glucogenólisis , Hígado/irrigación sanguínea , Hígado/inervación , Masculino , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Circulación Esplácnica , Aumento de PesoRESUMEN
The present study was undertaken to investigate endothelial function and epoxyeicosatrienoic acids (EETs), which is a cytochrome P-450 monooxygenase (CYP) metabolite and one of the candidates as an endothelium-derived hyperpolarizing factor (EDHF) in the renal artery isolated from short-term hypercholesterolemic rabbits, and also to characterize the effects of pioglitazone on it. Rabbits were fed normal, 0.5% cholesterol chow, or 0.5% cholesterol chow plus 300 ppm pioglitazone for 5 weeks. The tension of isolated renal artery rings was measured isometrically. Serum lipid levels were measured and morphometric analysis was performed. EET contents in the renal artery were also determined. The cholesterol chow diet for 5 weeks increased serum lipid levels, and pioglitazone had no influence on it. In the phenylephrine precontracted renal artery, the cholesterol chow did not affect acetylcholine-induced relaxation. The N(G)-nitro-l-arginine- and indomethacin-resistant endothelium-dependent relaxation induced by acetylcholine was significantly enhanced in rabbits receiving the cholesterol chow as compared to rabbits receiving the control diet, and pioglitazone normalized it. The resistant part of acetylcholine-induced relaxation was significantly inhibited when the renal artery was treated with charybdotoxin, an inhibitor of large- and intermediate-conductance Ca(2+)-activated K(+) channels, or N,N-di-ethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525a), a nonselective CYP inhibitor, and it was significantly inhibited by sulfaphenazole, a selective CYP2C9 inhibitor in rabbits receiving only the cholesterol chow. In KCl-precontracted renal artery, the cholesterol chow inhibited acetylcholine-induced relaxation and pioglitazone normalized it. The cholesterol chow increased the production of EETs and reduced nitrate/nitrite contents in the renal artery, and pioglitazone strongly suppressed them. These results suggest that the EETs may be one of the EDHFs in the rabbit renal artery and beneficial effects of pioglitazone on alterations in endothelial function induced by cholesterol feeding are due, in part, to the protective action on the nitric oxide system and/or the suppression of increased production of EETs.
Asunto(s)
Endotelio Vascular/fisiopatología , Hipercolesterolemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Arteria Renal/fisiopatología , Tiazolidinedionas/uso terapéutico , Acetilcolina/farmacología , Animales , Factores Biológicos/fisiología , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Eicosanoides/metabolismo , Inhibidores Enzimáticos/farmacología , Hipercolesterolemia/fisiopatología , Indometacina/farmacología , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Nitratos/metabolismo , Nitritos/metabolismo , Nitroarginina/farmacología , Fenilefrina/farmacología , Pioglitazona , Bloqueadores de los Canales de Potasio/farmacología , Cloruro de Potasio/farmacología , Conejos , Arteria Renal/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
The aim of this study was to investigate the changes in mRNA level of embryonic form of myosin heavy chain (SMemb), endothelin-1 (ET-1) and plasminogen activator inhibitor-1 (PAI-1), which are considered to be involved in the angiogenesis and atherosclerosis in diabetic blood vessels, in human umbilical vein endothelial cells (HUVECs) caused by high ambient glucose, and the effects of 2-aminophenoxazine-3-one (Phx-3), which was produced by the reaction of bovine hemoglobin with o-aminophenol, on them. The mRNA level of SMemb, ET-1 and PAI-1 and the level of SMemb protein were extensively upregulated in HUVECs treated with high concentration of glucose (15 mM), compared with those in the cells with normal concentration of glucose (5 mM). The migration activity of HUVECs evaluated by the cell migration assay was accelerated by 15 mM glucose. When 10 microM Phx-3, at the concentration of which the proliferation of HUVECs was not affected, was administered to HUVECs with 15 mM glucose, the mRNA level of SMemb, ET-1 and PAI-1 and the level of SMemb protein were significantly downregulated to the normal levels in the cells. However, when 10 microM Phx-3 was administered to HUVECs with 5 mM of glucose, the mRNA level of SMemb, ET-1 and PAI-1 and the level of SMemb protein were not affected. The migration activity of HUVECs, which was accelerated by high glucose, was reversed by 10 microM Phx-3. The present results suggest that Phx-3 may be a drug to prevent the high glucose-associated endothelial damage, vascular angiogenesis in diabetic patients, by inhibiting the expression of angiogenic factors, such as SMemb, ET-1 and PAI-1, in the endothelial cells.
Asunto(s)
Células Endoteliales/efectos de los fármacos , Endotelina-1/metabolismo , Glucosa/farmacología , Cadenas Pesadas de Miosina/metabolismo , Oxazinas/farmacología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Células Cultivadas , Embrión de Mamíferos , Células Endoteliales/metabolismo , Endotelina-1/antagonistas & inhibidores , Glucosa/antagonistas & inhibidores , Humanos , Cadenas Pesadas de Miosina/antagonistas & inhibidores , Oxazinas/química , Venas Umbilicales/efectos de los fármacos , Venas Umbilicales/metabolismoRESUMEN
A liquid chromatographic method with fluorescence detection coupled with a solid-phase extraction was applied to the rapid determination of epoxyeicosatrienoic acids (EETs) in the rabbit renal artery. The EETs were extracted with an acetonitrile from renal artery homogenate and concentrated by a solid-phase extraction method. The concentrated EETs were reacted directly with a 6, 7-dimethoxy-1-methyl-2 (1H)-quinoxalinone-3-propionyl-carboxylic acid (DMEQ) hydrazide and separated by a reversed-phase HPLC with eluting a combination of a step-wise and a gradient of a mixture of methanol and water. The content of EETs in the renal arteries was significantly greater in the 0.5% cholesterol fed rabbits than in control rabbits. It is suggested that hyperchlesterolemia increases the production of EETs in the rabbit renal artery.
Asunto(s)
Ácidos Araquidónicos/análisis , Arteria Renal/química , Animales , Ácidos Araquidónicos/biosíntesis , Ácidos Araquidónicos/química , Colesterol en la Dieta/administración & dosificación , Cromatografía Líquida de Alta Presión/métodos , Fluorescencia , Lípidos/sangre , Masculino , Conejos , Arteria Renal/efectos de los fármacos , Arteria Renal/metabolismoRESUMEN
Hypothyroidism was induced by the administration of 0.03% methimazole to drinking water for 1, 2 or 6 weeks to study whether there is a change in adrenoceptor- and muscarinic receptor-mediated blood pressure responses in hypothyroid rats. After 1, 2 and 6 weeks of treatment, the pressor response to norepinephrine was progressively suppressed, and after 6 weeks a significant suppression was observed as compared to control. The depressor response induced by isoprenaline, acetylcholine or sodium nitroprusside was not significantly different between control and hypothyroid rats at any time. The pressor response induced by N(G)-nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide (NO) synthase, was significantly reduced in hypothyroid rats after 1, 2 or 6 weeks of treatment, and the magnitude of the reduction was almost the same for three groups. These results indicated that hypothyroidism causes a time-dependent decrease in pressor responses mediated by alpha-adrenoceptors, but a time-independent decrease in those induced by L-NOARG, and suggest that a progressive decrease in alpha-adrenoceptor-mediated pressor responses occurs in hypothyroidism; however, the decrease in basal NO production and/or release in the peripheral vasculature already occurs in hypothyroid rats at an early stage of the disease.
Asunto(s)
Presión Sanguínea/fisiología , Hipotiroidismo/fisiopatología , Receptores Adrenérgicos/fisiología , Receptores Muscarínicos/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Hipotiroidismo/inducido químicamente , Masculino , Metimazol/toxicidad , Norepinefrina/farmacología , Ratas , Ratas WistarRESUMEN
The present study was undertaken to investigate vascular function in hypercholesterolemic rabbits and also to characterize the effects of pioglitazone on it. Rabbits were fed normal, 0.5% cholesterol chow, or 0.5% cholesterol chow plus 300 ppm pioglitazone for 5 or 10 weeks. The tension of isolated renal artery rings was measured isometrically, and morphometric analysis was performed. The cholesterol chow diet administered for 5 weeks did not affect acetylcholine-induced relaxation in the renal artery but that for 10 weeks decreased it. The N(G)-nitro-L-arginine (L-NOARG)- and indomethacin-resistant endothelium-dependent relaxation induced by acetylcholine in the renal artery was enhanced in rabbits receiving the cholesterol chow for 5 or 10 weeks, as compared to rabbits receiving the control diet, and the percentage of plaque area formation was increased in the renal artery by the cholesterol chow for 10 weeks. Pioglitazone normalized them without lowering serum lipid levels. The resistant parts of acetylcholine-induced relaxation was significantly inhibited when the renal artery was treated with charybdotoxin, an inhibitor of large and intermediate conductance Ca(2+)-activated K(+) channels, or N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525a), a cytochrome P-450 monooxygenase inhibitor. Results indicate that hypercholesterolemia enhances endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in the rabbit renal artery and pioglitazon normalizes it without lowering serum lipid levels, and suggest that the maintenance of endothelial function by pioglitazon is related to the mechanisms for its anti-atheromatous activity.