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Male C57BL/6J mice were used to determine the possible therapeutic effects of our previously described tart cherry extract in a chronic obesity mouse model on metabolic parameters, glucose tolerance, inflammatory mediators, and antioxidant capacity. The control group received standard mouse chow, and the high fat control group was switched to a high fat diet and tap water supplemented with 5% sucrose. The high fat + anthocyanin group received the high fat and sucrose diet, but received the anthocyanin-rich tart cherry extract dissolved in their drinking water. After six weeks, an oral glucose tolerance test was performed, and the water-soluble antioxidant capacity (ACW), superoxide dismutase (SOD) activity, and the plasma levels of insulin, C-peptide, leptin, IL-6, MCP-1, adiponectin and resistin were measured. The high fat diet increased body weight, reduced glucose tolerance, and caused an elevation in leptin, IL-6, MCP-1, and resistin levels. Furthermore, antioxidant capacity was decreased with a significant elevation of SOD activity. Anthocyanin treatment failed to reverse the effects of the high fat diet on body weight and glucose tolerance, but significantly reduced the leptin and IL-6 levels. The tart cherry extract also made a significant enhancement in antioxidant capacity and SOD activity. Our results show that chronic anthocyanin intake has a potential to enhance redox status and alleviate inflammation associated with obesity.
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Antocianinas/química , Dieta Alta en Grasa/efectos adversos , Inflamación/metabolismo , Obesidad/inducido químicamente , Extractos Vegetales/farmacología , Prunus avium/química , Adipoquinas , Adiponectina , Animales , Antioxidantes , Diabetes Mellitus Tipo 2/inducido químicamente , Prueba de Tolerancia a la Glucosa , Humanos , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/química , Resistina , Superóxido DismutasaRESUMEN
A natural fat-soluble thiamine derivative, namely N-[(4-amino-2-methylpyrimidin-5-yl)methyl]-N-[(2E)-5-hydroxy-3-(prop-2-en-1-yldisulfanyl)pent-2-en-2-yl]formamide (allithiamine) has been identified only in garlic (Allium sativum) until now. Hungarian red sweet pepper (Capsicum annuum) was found as a new source of allithiamine. Extraction procedure and analytical method were developed for the isolation of allithiamine and a chemical synthesis of the compound was also developed. First solid-liquid extraction was performed with 96 % ethanol to isolate allithiamine from pepper seeds. Thereafter, solid phase extraction was applied from ethanolic extract using C18 cartridge to concentrate and purify samples for further analysis. The structure of the synthesized and the isolated compounds was verified by reverse phase HPLC, HPLC-MS, MALD-TOF MS and NMR. Furthermore, effect of allithiamine was investigated on streptozotocin-induced diabetic mice with neuropathy. The results show that neuropathic pain sensation is improved by allithiamine treatment similarly to benfothiamine.
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OBJECTIVE: Exploring the pathophysiological changes in transient receptor potential vanilloid 1 (TRPV1) receptor of the trigeminovascular system in high-fat, high-sucrose (HFHS) diet-induced obesity of experimental animals. BACKGROUND: Clinical and experimental observations suggest a link between obesity and migraine. Accumulating evidence indicates that metabolic and immunological alterations associated with obesity may potentially modulate trigeminovascular functions. A possible target for obesity-induced pathophysiological changes is the TRPV1/capsaicin receptor which is implicated in the pathomechanism of headaches in a complex way. METHODS: Male Sprague-Dawley rats were fed a regular (n = 25) or HFHS diet (n = 26) for 20 weeks. At the end of the dietary period, body weight of the animals was normally distributed in both groups and it was significantly higher in animals on HFHS diet. Therefore, experimental groups were regarded as control and HFHS diet-induced obese groups. Capsaicin-induced changes in meningeal blood flow and release of calcitonin gene-related peptide (CGRP) from dural trigeminal afferents were measured in control and obese rats. The distribution of TRPV1- and CGRP-immunoreactive meningeal sensory nerves was also compared in whole mount preparations of the dura mater. Metabolic parameters of the animals were assessed by examining glucose and insulin homeostasis as well as plasma cytokine concentrations. RESULTS: HFHS diet was accompanied by reduced food consumption and greater fluid and energy intakes in addition to increased body weight of the animals. HFHS diet increased fasting blood glucose and insulin concentrations as well as levels of circulating proinflammatory cytokines interleukin-1ß and interleukin-6. In obese animals, dural application of the archetypal TRPV1 agonist capsaicin resulted in significantly augmented vasodilatory and vasoconstrictor responses as compared to controls. Diet-induced obesity was also associated with enhanced basal and capsaicin-induced CGRP release from meningeal afferents ex vivo. Except for minor morphological changes, the distribution of dural TRPV1- and CGRP-immunoreactive afferents was similar in control and obese animals. CONCLUSIONS: Our results suggest that obesity induced by long-term HFHS diet results in sensitization of the trigeminovascular system. Changes in TRPV1-mediated vascular reactions and CGRP release are pathophysiological alterations that may be of relevance to the enhanced headache susceptibility of obese individuals.
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Dieta/efectos adversos , Duramadre/metabolismo , Obesidad/etiología , Obesidad/patología , Canales Catiónicos TRPV/metabolismo , Análisis de Varianza , Animales , Glucemia/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/metabolismo , Capsaicina/farmacología , Circulación Cerebrovascular/efectos de los fármacos , Modelos Animales de Enfermedad , Ingestión de Alimentos/fisiología , Ayuno/sangre , Insulina/sangre , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Meninges/irrigación sanguínea , Obesidad/sangre , Ratas , Ratas Sprague-Dawley , Estadísticas no ParamétricasRESUMEN
Background Clinical studies suggest a link between obesity and the primary headache disorder migraine. In our study we aimed to reveal the effect of obesity on meningeal nociceptor function in rats receiving a high-fat, high-sucrose diet. Methods Transient receptor potential ankyrin 1 (TRPA1) receptor activation-induced changes in meningeal blood flow, release of calcitonin gene-related peptide (CGRP) from trigeminal afferents and TRPA1 protein expression in the trigeminal ganglia were measured in control and obese rats. Metabolic parameters of the animals were assessed by measuring glucose and insulin homeostasis as well as plasma cytokine concentrations. Results The present experiments revealed an enhanced basal and TRPA1 receptor agonist-induced CGRP release from meningeal afferents of obese insulin-resistant rats and an attenuated CGRP release to potassium chloride. Obesity was also associated with an augmented vasodilatation in meningeal arteries after dural application of the TRPA1 agonist acrolein, a reduction in TRPA1 protein expression in the trigeminal ganglia and elevations in circulating proinflammatory cytokines IL-1ß and IL-6 in addition to increased fasting blood glucose and insulin concentrations. Conclusions Our results suggest trigeminal sensitisation as a mechanism for enhanced headache susceptibility in obese individuals after chemical exposure of trigeminal nociceptors.
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Péptido Relacionado con Gen de Calcitonina/metabolismo , Dieta Alta en Grasa/efectos adversos , Sacarosa en la Dieta/efectos adversos , Obesidad/metabolismo , Canal Catiónico TRPA1/fisiología , Ganglio del Trigémino/metabolismo , Cefalalgias Vasculares/metabolismo , Animales , Glucemia/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Obesidad/complicaciones , Ratas , Ratas Sprague-Dawley , Cefalalgias Vasculares/etiologíaRESUMEN
Meal-induced insulin sensitization (MIS), an endogenous adaptive mechanism is activated post-prandially. Reduced MIS leads to diabetes, but its activation improves insulin sensitivity. MIS is preserved to single olanzapine administration, therefore we aimed to investigate the chronic effect of olanzapine on fasted-state insulin sensitivity and on MIS in female Sprague-Dawley rats. Daily food and water intake, stool and urine production and body weight were determined. The MIS was characterized by a rapid insulin sensitivity test. Fasting hepatic and peripheral insulin sensitivity were determined by a hyperinsulinaemic euglycaemic glucose clamping supplemented with radiotracer technique. Fasted and post-prandial blood samples were obtained for plasma insulin, leptin, ghrelin, amylin, GLP-1, GIP, PYY and PP determination. Adiposity was characterized by weighing intra-abdominal and inguinal fat pads. Olanzapine caused hepatic insulin resistance and a reduced metabolic clearance rate of insulin, but the MIS retained its function. Body weight and adiposity were enhanced, but olanzapine failed to increase food intake. Fasting insulin and leptin were elevated and the post-prandial reduction in ghrelin level was inhibited by olanzapine.The MIS remained functionally intact after long-term olanzapine treatment. Altered insulin, leptin and ghrelin levels indicate olanzapine-induced metabolic derangements. Pharmacological activation of MIS could potentially be exploited to treat or prevent olanzapine-induced insulin resistance.
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Benzodiazepinas/administración & dosificación , Hormonas Gastrointestinales/sangre , Resistencia a la Insulina/fisiología , Insulina/biosíntesis , Animales , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Ghrelina/sangre , Leptina/sangre , Obesidad/sangre , Olanzapina , Ratas , Ratas Sprague-DawleyRESUMEN
The major role of liver glycogen is to supply glucose to the circulation maintaining the normal blood glucose level. In muscle and liver the accumulation and breakdown of glycogen are regulated by the reciprocal activities of glycogen phosphorylase and glycogen synthase. Glycogen phosphorylase catalyses the key step of glycogen degradation and its activity can be inhibited by glucose and its analogues. Obviously, any readily accessible inhibitor of glycogen phosphorylase can be used as a potential therapy of non-insulin-dependent or type 2 diabetes. Hepatic glycogen phosphorylase has been identified as a new target for drugs that control blood glucose concentration. In our experiments glucopyranosylidene-spirothiohydantoin (TH) was tested on the insulin sensitivity and blood glucose level of control and streptozotocin-treated rats. The streptozotocin-treated rats failed to gain weight and exhibited stable hyperglycemia (4.7 ± 0.5 mmol/L glucose in control vs. 7.8 ± 0.5 mmol/L) and low plasma insulin levels (9.6 ± 1.9 µIU/mL in control vs. 3.2 ± 2.2 µIU/mL). When insulin supplementation with slow-release implants (2 IU/day) was started 8 weeks after streptozotocin injection, blood glucose concentration remained suppressed, plasma insulin level dramatically increased and the insulin sensitivity restored. TH administration significantly reduced the high blood glucose concentration and restored the insulin sensitivity of STZtreated rats.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Glucógeno Fosforilasa/antagonistas & inhibidores , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Insulina/sangre , Monosacáridos/uso terapéutico , Compuestos de Espiro/uso terapéutico , Animales , Glucemia/análisis , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/enzimología , Glucógeno/metabolismo , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Insulina/uso terapéutico , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Monosacáridos/administración & dosificación , Ratas Wistar , Compuestos de Espiro/administración & dosificación , EstreptozocinaRESUMEN
Olanzapine, an atypical antipsychotic, can acutely induce fasting insulin resistance, but we do not know whether it is able to modulate the meal-induced insulin sensitization (MIS). Two main experimental groups (control and olanzapine-treated) were created with two subgroups (fasted and re-fed) within each. After oral vehicle/olanzapine administration, the first meal size and duration and the total amount of consumed food was recorded in conscious rats. Then, under anaesthesia, the carotid artery and jugular vein was prepared and cannulated to obtain samples for blood glucose and hormone determination as well as for insulin/glucose infusion, respectively. Basal insulin sensitivity and MIS was determined by homeostasis model assessment (HOMA) calculation and by rapid insulin sensitivity test, respectively. In fasted animals, olanzapine increased blood glucose and plasma insulin and reduced basal insulin sensitivity, but it failed to modify other hormone levels. Postprandial leptin and glucose-dependent insulinotropic polypeptide (GIP) levels increased, and ghrelin level decreased significantly (p < 0.05) both in vehicle- and olanzapine-treated groups, but plasma insulin increased only in vehicle-treated animals. Furthermore, decrement in ghrelin level was attenuated in olanzapine-treated animals compared to controls. There was no significant change in the first meal size and duration or in the total amount of food consumed. Olanzapine had no effect on the MIS. We demonstrated that olanzapine can induce insulin resistance without weight gain in healthy rats. Furthermore, the MIS was preserved after acute olanzapine treatment. The blunted postprandial ghrelin and insulin response could contribute to the effect of olanzapine on feeding behaviour. Pharmacological induction of MIS may improve the olanzapine-induced insulin resistance.
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Benzodiazepinas/farmacología , Peso Corporal/efectos de los fármacos , Ingestión de Energía/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Resistencia a la Insulina , Animales , Glucemia/metabolismo , Ayuno , Femenino , Ghrelina/sangre , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Leptina/sangre , Olanzapina , Periodo Posprandial , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Insulin resistance has been recognized as the most significant predictor of further development of type 2 diabetes mellitus (T2DM). Here we investigated the effect of a heat shock protein (HSP) co-inducer, BGP-15, on insulin sensitivity in different insulin-resistant animal models and compared its effect with insulin secretagogues and insulin sensitizers. METHODS: Insulin sensitivity was assessed by the hyperinsulinemic euglycemic glucose clamp technique in normal and cholesterol-fed rabbits and in healthy Wistar and Goto-Kakizaki (GK) rats in dose-ranging studies. We also examined the effect of BGP-15 on streptozotocin-induced changes in the vasorelaxation of the aorta in Sprague-Dawley rats. RESULTS: BGP-15 doses of 10 and 30 mg/kg increased insulin sensitivity by 50% and 70%, respectively, in cholesterol-fed but not in normal rabbits. After 5 days of treatment with BGP-15, the glucose infusion rate was increased in a dose-dependent manner in genetically insulin-resistant GK rats. The most effective dose was 20 mg/kg, which showed a 71% increase in insulin sensitivity compared to control group. Administration of BGP-15 protected against streptozotocin-induced changes in vasorelaxation, which was similar to the effect of rosiglitazone. CONCLUSION: Our results indicate that the insulin-sensitizing effect of BGP-15 is comparable to conventional insulin sensitizers. This might be of clinical utility in the treatment of T2DM.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Oximas/uso terapéutico , Piperidinas/uso terapéutico , Animales , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/metabolismo , Masculino , Conejos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Vasodilatación/efectos de los fármacosRESUMEN
Clozapine increases meal size and meal duration, effects similar to the pharmacological blockade or congenital deficiency of CCK-1 receptor. We aimed to investigate the role of CCK-1 receptor in clozapine-induced weight gain and insulin sensitivity in CCK-1 receptor deficient, male Otsuka Long Evans Tokushima Fatty rats (OLETF). Long Evans Tokushima Otsuka (LETO) rats served as healthy control. Animals were orally treated with either clozapine (10mg/kg) or its vehicle over 25 days. Daily metabolic parameters were measured by metabolic cages. The insulin sensitivity was determined by hyperinsulinaemic euglycaemic glucose clamping (HEGC). Adiposity was determined by measuring the perirenal, intraabdominal and epididymal white adipose tissue fat pads. Hypothalamic mRNA expression of CCK-1 and CCK-2 receptor was measured by real-time PCR, plasma insulin by radioimmunoassay. Clozapine failed to increase weight gain or daily food intake, but it increased adiposity, 1st meal size and duration and decreased insulin sensitivity both in OLETF or LETO rats. The glucose infusion rate during the steady state of the HEGC was unaltered, but the metabolic clearance rate of insulin was reduced by the clozapine treatment. Hypothalamic mRNA of CCK-1 and CCK-2 receptor was elevated in LETO rats, but the mRNA of CCK-2 receptor was reduced by clozapine in OLETF rats. Our results suggest that the CCK-1 receptor has no direct role in the clozapine-induced adiposity and insulin resistance. We also demonstrated that atypical antipsychotic treatment can induce insulin resistance in the absence of manifest obesity in male rats.
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Clozapina/efectos adversos , Receptores de Colecistoquinina/deficiencia , Animales , Composición Corporal/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Resistencia a la Insulina , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas OLETF , Receptores de Colecistoquinina/genética , Factores de Tiempo , Aumento de Peso/efectos de los fármacosRESUMEN
INTRODUCTION: Computational molecular database screening helps to decrease the time and resources needed for drug development. Reintroduction of generic drugs by second medical use patents also contributes to cheaper and faster drug development processes. We screened, in silico, the Food and Drug Administration-approved generic drug database by means of the One-dimensional Drug Profile Matching (oDPM) method in order to find potential peroxisome proliferator-activated receptor gamma (PPARγ) agonists. The PPARγ action of the selected generics was also investigated by in vitro and in vivo experiments. MATERIALS AND METHODS: The in silico oDPM method was used to determine the binding potency of 1,255 generics to 149 proteins collected. In vitro PPARγ activation was determined by measuring fatty acid-binding protein 4/adipocyte protein gene expression in a Mono Mac 6 cell line. The in vivo insulin sensitizing effect of the selected compound (nitazoxanide; 50-200 mg/kg/day over 8 days; n = 8) was established in type 2 diabetic rats by hyperinsulinemic euglycemic glucose clamping. RESULTS: After examining the closest neighbors of each of the reference set's members and counting their most abundant neighbors, ten generic drugs were selected with oDPM. Among them, four enhanced fatty acid-binding protein/adipocyte protein gene expression in the Mono Mac 6 cell line, but only bromfenac and nitazoxanide showed dose-dependent actions. Induction by nitazoxanide was higher than by bromfenac. Nitazoxanide lowered fasting blood glucose levels and improved insulin sensitivity in type 2 diabetic rats. CONCLUSION: We demonstrated that the oDPM method can predict previously unknown therapeutic effects of generic drugs. Nitazoxanide can be the prototype chemical structure of the new generation of insulin sensitizers.
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Simulación por Computador , Medicamentos Genéricos/farmacología , PPAR gamma/agonistas , Tiazoles/farmacología , Animales , Benzofenonas/administración & dosificación , Benzofenonas/farmacología , Glucemia/efectos de los fármacos , Bromobencenos/administración & dosificación , Bromobencenos/farmacología , Línea Celular Tumoral , Bases de Datos Farmacéuticas , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Medicamentos Genéricos/administración & dosificación , Técnica de Clampeo de la Glucosa , Humanos , Insulina/metabolismo , Ligandos , Masculino , Nitrocompuestos , PPAR gamma/metabolismo , Ratas , Ratas Wistar , Tiazoles/administración & dosificación , Factores de TiempoRESUMEN
Patients with perturbed metabolic control are more prone to develop cardiac rhythm disturbances. The main purpose of the present preclinical study was to investigate the possible role of euglycemic hyperinsulinemia in development of cardiac arrhythmias. Euglycemic hyperinsulinemia was induced in conscious rabbits equipped with a right ventricular pacemaker electrode catheter by hyperinsulinemic euglycemic glucose clamp (HEGC) applying two different rates of insulin infusion (5 and 10 mIU/kg/min) and variable rate of glucose infusion to maintain euglycemia (5.5 ± 0.5 mmol/l). The effect of hyperinsulinemia on cardiac electrophysiological parameters was continuously monitored by means of 12-lead surface ECG recording. Arrhythmia incidence was determined by means of programmed electrical stimulation (PES). The possible role of adrenergic activation was investigated by determination of plasma catecholamine levels and intravenous administration of a beta adrenergic blocking agent, metoprolol. All of the measurements were performed during the steady-state period of HEGC and subsequent to metoprolol administration. Both 5 and 10 mIU/kg/min insulin infusion prolonged significantly QTend, QTc, and Tpeak-Tend intervals. The incidence of ventricular arrhythmias generated by PES was increased significantly by euglycemic hyperinsulinemia and exhibited linear relationship to plasma levels of insulin. No alteration on plasma catecholamine levels could be observed; however, metoprolol treatment restored the prolonged QTend, QTc, and Tpeak-Tend intervals and significantly reduced the hyperinsulinemia-induced increase of arrhythmia incidence. Euglycemic hyperinsulinemia can exert proarrhythmic effect presumably due to the enhancement of transmural dispersion of repolarization. Metoprolol treatment may be of benefit in hyperinsulinemia associated with increased incidence of cardiac arrhythmias.
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Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Hiperinsulinismo/complicaciones , Hiperinsulinismo/fisiopatología , Enfermedad Aguda , Animales , Arritmias Cardíacas/sangre , Hiperinsulinismo/sangre , Masculino , Conejos , Distribución AleatoriaRESUMEN
Increased risk of anticancer chemotherapy in seriously obese patients is known. Obesity may be among factors that predict treatment-related toxicity during chemotherapy. We investigated whether functional changes in granulopoiesis may also contribute to increased myelotoxicity in addition to the known alterations of pharmacokinetic parameters in obesity. Hemopoiesis - as measured by cellularity, frequency of granulocyte-macrophage progenitors (CFU-GM) and total CFU-GM content of the femoral bone marrow - did not differ in obese, insulin resistant Zucker rats compared with Wistar rats. Nevertheless increased sensitivity of their CFU-GM progenitor cells to cytotoxic drugs was found by culturing them in vitro in the presence of carboplatin, doxorubicin and 5-fluorouracil. All drugs were more toxic on CFU-GM progenitor cells of insulin resistant Zucker rats than on CFU-GM cells of the control strain. This might be based on metabolic disorders, at least in part, because we could demonstrate a similar increase in toxicity of the studied anticancer drugs to the CFU-GM progenitors originated from the non-obese but insulin resistant Goto-Kakizaki rats in the same dose ranges. After in vivo administration of rosiglitazone, an insulin sensitizer, the anticancer drug sensitivity of CFU-GM progenitors of Goto-Kakizaki rats was decreased concurrently with improvement of insulin resistance. Although the increased treatment-related myelotoxicity and mortality are well-known among obese patients with malignant diseases, only the altered half lives, volumes of distribution and clearances of cytotoxic drugs are thought to be the underlying reasons. According to our knowledge the results presented here, are the first observations about an impaired granulopoiesis in obese animals.
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Antineoplásicos/farmacología , Citotoxinas/farmacología , Células Progenitoras de Granulocitos y Macrófagos/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Resistencia a la Insulina , Obesidad/patología , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/efectos de los fármacos , Carboplatino/farmacología , Recuento de Células , Doxorrubicina/farmacología , Células Progenitoras de Granulocitos y Macrófagos/citología , Masculino , Ratas , Ratas Wistar , Ratas ZuckerRESUMEN
BACKGROUND AND PURPOSE: High-fat diet and consequent metabolic syndrome (MS) can lead to elevated risk for cardiac arrhythmias. This preclinical study was to investigate if cicletanine (CIC) could produce cardioprotective effects in conscious rabbits exhibiting the main symptoms of MS. METHODS: NZW rabbits that had undergone an 8-week-long cholesterol-enriched diet (1.5%) were instrumented with a pacemaker electrode and randomly assigned into 3 groups according to the oral treatment of either CIC (50 mg·kg) or sotalol (25 mg·kg) and their placebo b.i.d. over 5 days. Study groups were subjected to either "arrhythmia challenge" by programmed electrical stimulation in the "Arrhythmogenesis" study (N = 54) or global myocardial ischemia by rapid pacing in the "Ventricular Overdrive Pacing-induced Myocardial Ischemia" study (N = 18). The antiarrhythmic effect was evaluated by the establishment of the incidence of programmed electrical stimulation-induced arrhythmias. Proarrhythmia indicators (eg, QTc, Tpeak-Tend) were also measured to assess the cardiac safety profile of CIC. To evaluate the background of antiarrhythmic effect, cardiac cyclic nucleotide (cyclic 3',5'-guanosine monophosphate [cGMP], cyclic 3',5'-adenosine monophosphate [cAMP]) and nitric oxide content were determined. The antiischemic effect was characterized by change of intracavital ST segment. RESULTS: Cicletanine treatment significantly decreased the incidence of ventricular arrhythmias, increased cardiac cGMP and nitric oxide content and reduced cardiac cAMP level. Cicletanine did not modify significantly QTc and Tpeak-Tend interval. The ST-segment change in response to rapid pacing was reduced significantly by CIC. (P < 0.05). CONCLUSIONS: Cicletanine exerts beneficial cardiac effects in rabbits with symptoms of MS, which may be of influence with regard to the clinical application of the drug.
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Antiarrítmicos/farmacología , Arritmias Cardíacas/prevención & control , Síndrome Metabólico/tratamiento farmacológico , Piridinas/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Arritmias Cardíacas/sangre , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Presión Sanguínea/efectos de los fármacos , Estimulación Cardíaca Artificial , Colesterol en la Dieta , Estado de Conciencia , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Electrocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Lípidos/sangre , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/etiología , Síndrome Metabólico/fisiopatología , Miocardio/metabolismo , Óxido Nítrico/metabolismo , Conejos , Sotalol/farmacología , Factores de TiempoRESUMEN
We investigated whether progressive sensory neuropathy was accompanied by changes in whole-body insulin sensitivity (WBIS) in rats made diabetic by streptozotocin (STZ). The effects of early and late insulin supplementation were also studied. The STZ-treated rats failed to gain weight and exhibited stable hyperglycemia and low plasma insulin levels with a decrease in nerve conduction velocity (NCV) measured in A and C fibers of the saphenous nerve. A decreased sensory neuropeptide (SNP) release such as that of substance P, somatostatin, and calcitonin gene-related peptide determined from organ fluid of tracheal preparations subjected to electrical field stimulation also occurred in diabetic animals. These features were accompanied by a decrease in WBIS measured by hyperinsulinemic-euglycemic glucose clamping and a decrease in insulin-stimulated glucose uptake in cardiac and gastrocnemius muscle. When insulin supplementation with slow-release implants (2 IU/d) was started 4 weeks after STZ injection, blood glucose level normalized. Both insulin sensitivity and sensory nerve function reflected in either NCV or SNP release completely recovered by the 12th post-STZ week. When the insulin implants were applied from the eighth post-STZ week, both WBIS and glucose uptake remained significantly decreased, with a seriously impaired NCV and SNP release with strong hyperglycemia. Late insulin supplementation, however, even by using double implantation from the 10th post-STZ week, was unable to restore blood glucose, WBIS, NCV, and SNP release by the 12th week. Insulin resistance occurs in parallel with sensory neuropathy in STZ-diabetic rats. Both can be improved by early but not late insulin supplementation.
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Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Resistencia a la Insulina/fisiología , Insulina/farmacología , Conducción Nerviosa/efectos de los fármacos , Células Receptoras Sensoriales/fisiología , Animales , Glucemia/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/sangre , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/tratamiento farmacológico , Técnica de Clampeo de la Glucosa , Insulina/uso terapéutico , Masculino , Ratas , Ratas Wistar , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/metabolismo , Somatostatina/sangre , Sustancia P/sangreRESUMEN
PURPOSE: Hemodynamic nitrate tolerance has been shown to result in an insulin-resistant state. We studied whether nitrate tolerance induced by a 7-day continuous exposure to transdermal nitroglycerin influenced the meal-induced insulin sensitization phenomenon in rabbits. METHODS: Changes in insulin sensitivity in response to feeding in conscious rabbits were determined by rapid insulin sensitivity test, in both nitrate-tolerant and nitrate-intolerant animals. In a separate series of experiments with anesthetized rabbits with or without nitrate tolerance, the hyperinsulinemic euglycemic glucose clamping methods was used to study the effect of intraportal infusion of cholecystokinin (CCK) on whole-body insulin sensitivity. RESULTS: Rabbits with normal feeding exhibited a 46 ± 6% increase in insulin sensitivity as compared with their matching fasting controls. A 7-day period of treatment with patches releasing 0.07 mg of nitroglycerin per hour yielded nitrate tolerance and a state of insulin resistance and no increase in insulin sensitivity in response to food. Intraportal infusion of CCK8 (0.3-3.0 µg/kg over 20 minutes) resulted in a dose-dependent increase in insulin sensitivity in normal but not in nitrate-tolerant, fasted anesthetized animals. CONCLUSIONS: Nitrate tolerance blocks both the meal-induced insulin sensitization phenomenon and the insulin-sensitizing effect of intraportal CCK.
Asunto(s)
Tolerancia a Medicamentos/fisiología , Resistencia a la Insulina/fisiología , Nitroglicerina/farmacología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/metabolismo , Ingestión de Alimentos/fisiología , Ayuno/fisiología , Técnica de Clampeo de la Glucosa , Frecuencia Cardíaca/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Nitroglicerina/administración & dosificación , Conejos , Sincalida/farmacologíaRESUMEN
Artificial femoral arterio-venous (AV) shunts are widely used in rodent models for studying shunt maturation and to optimize various surgical techniques. However, little is known about complex circulatory, microcirculatory, and hemorheological effects of end-to-side saphenous AV shunts. We aimed to study these parameters in mature AV shunts. Studying these questions in CD rats, end-to-side anastomoses were made between the left saphenous artery and vein. On the right-side the nonoperated saphenous vessels served as own control. Furthermore healthy control animals were also investigated. On the 8th to 12th postoperative week microcirculatory and blood flow measurements were performed and blood samples were taken both from the shunt's arterial and venous limbs and from the nonoperated side vessels. Hematological parameters, erythrocyte aggregation, and deformability were determined. The entire shunt and the control vessels were removed for histological examinations. The skin microcirculation on shunt side slightly increased on thigh and decreased on paws versus the nonoperated side. Blood flow measurements made directly on the vessels showed that arterial to venous blood flow rate ratio was 1.59 ± 0.29 on nonoperated side and 1.2 ± 0.13 on the shunt side, and 1.49 ± 0.05 in control animals. Erythrocyte aggregation and deformability worsened on the shunt side. Histologically increased number of smooth muscle elements and connective tissue were found in venous limb of the shunts. The artificial AV shunt between the saphenous artery and vein seems to be a suitable model for further functional-morphological and hemorheological examinations of hemodialysis in various states and diseases.
Asunto(s)
Derivación Arteriovenosa Quirúrgica , Animales , Animales no Consanguíneos , Agregación Eritrocitaria , Deformación Eritrocítica , Hemorreología , Miembro Posterior/irrigación sanguínea , Microcirculación , Microcirugia , Ratas , Flujo Sanguíneo Regional , Vena Safena , Piel/irrigación sanguíneaRESUMEN
The objective of the study was to investigate the role of cholecystokinin (CCK) on the food-induced insulin sensitization phenomenon in healthy Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats. Whole body insulin sensitivity determined by hyperinsulinaemic euglycaemic glucose clamping and the rapid insulin sensitivity test served as endpoints. Determinations were done in both fasted and re-fed animals. The involvement of CCK in post-prandial insulin sensitization was assessed by using proglumide, a CCK receptor blocker, by assessment of hypothalamic CCK-1/CCK-2 receptor expression by rt-PCR technique and by plasma insulin immunoreactivity determinations by means of radioimmunoassay as pharmacological, genetic and analytical approaches, respectively. The body weight of the OLETF rats and the amount of food consumed much exceeded those seen with LETO rats. The post-prandial increase in insulin sensitivity was marked in LETO, but not in OLETF rats. Intravenous proglumide attenuated post-prandial insulin sensitivity in LETO rats, with no effect in OLETF rats. Nevertheless, baseline insulin sensitivity was much lower in OLETF than in LETO rats. Treatment with rosiglitazone increased baseline insulin sensitivity of OLETF rats and evoked an increase in CCK-1 receptor gene expression in LETO rats. The results provide evidence for the involvement of CCK receptors in adjustment of both fasting and post-prandial insulin sensitivity. The data obtained with OLETF rats strongly suggest the predominant role of CCK-1 receptors.
Asunto(s)
Colecistoquinina/metabolismo , Resistencia a la Insulina , Insulina/sangre , Receptor de Colecistoquinina A/metabolismo , Animales , Regulación de la Expresión Génica , Técnica de Clampeo de la Glucosa , Hipoglucemiantes/farmacología , Masculino , Obesidad/metabolismo , Reacción en Cadena de la Polimerasa , Periodo Posprandial , Ratas , Ratas Endogámicas OLETF , Ratas Long-Evans , Receptor de Colecistoquinina B/metabolismo , Rosiglitazona , Tiazolidinedionas/farmacologíaRESUMEN
Several reports confirmed the phenomenon of postprandial increase in whole-body insulin sensitivity. Although the initial step of this process is unknown, the pivotal role of postprandial hyperinsulinemia has strongly been suggested. The aim of the present study was to determine whether hyperinsulinemia per se induces insulin sensitization in healthy male Wistar rats. Rapid insulin sensitivity test (RIST) were performed in fasted, anesthetized rats before and during stable hyperinsulinemia achieved by hyperinsulinemic euglycemic glucose clamping (HEGC) with insulin infused either through the jugular vein (systemic HEGC) or into the portal circulation (portal HEGC) at a rate of 3 mU/(kg min). Insulin sensitivity expressed by the rapid insulin sensitivity (RIST) index (in milligrams per kilogram) was characterized by the total amount of glucose needed to maintain prestudy blood glucose level succeeding an intravenous bolus infusion of 50 mU/kg insulin over 5 minutes. In fasted animals, the RIST index was 37.4 +/- 3.1 mg/kg. When hyperinsulinemia mimicking the postprandial state was achieved by systemic HEGC, the RIST index (39.7 +/- 10.6 mg/kg) showed no significant changes as compared with the pre-HEGC values. Hyperinsulinemia achieved by portal insulin infusion also failed to modify the RIST index (35.7 +/- 4.3 mg/kg). The results demonstrate that acute hyperinsulinemia, no matter how induced, does not yield any sensitization to the hypoglycemic effect of insulin.
Asunto(s)
Glucemia/metabolismo , Ingestión de Alimentos , Hiperinsulinismo/sangre , Insulina/farmacología , Animales , Glucemia/efectos de los fármacos , Ayuno , Técnica de Clampeo de la Glucosa , Infusiones Intravenosas , Insulina/administración & dosificación , Venas Yugulares , Masculino , Ratas , Ratas WistarRESUMEN
We studied the role of cholecystokinin in meal-induced insulin sensitization in rats. Experiments were done with fed or fasted male Wistar rats. Whole-body insulin sensitivity was determined by the rapid insulin sensitivity test in either group. The fed animals were more sensitive to the hypoglycemic effect of insulin than those in the fasted group. Single intravenous doses of proglumide, a cholecystokinin-1 receptor antagonist, decreased insulin sensitivity in fed animals in a dose-dependent manner, whereas it was without effect in the fasted state. We conclude that prandial insulin sensitization strongly depends on pathways regulated by cholecystokinin.
Asunto(s)
Colecistoquinina/fisiología , Insulina/farmacología , Proglumida/farmacología , Animales , Alimentos , Masculino , Ratas , Ratas Wistar , Receptores de Colecistoquinina/antagonistas & inhibidoresRESUMEN
Exposure of the anterior hepatic plexus to 2% perineurial capsaicin solution over three days caused transient insulin resistance confirmed by hyperinsulinaemic euglycaemic glucose clamping. Three additional perineurial capsaicin treatments divided by 3-month intervals yielded diabetes characterized by an increase in fasting blood glucose and glycated haemoglobin levels. Both insulin sensitivity and glycated haemoglobin level re-normalized over an additional 6-month period. We conclude that chronic partial hepatic sensory denervation produces diabetes in rabbits.