RESUMEN
All aerobic organisms are susceptible to damage by reactive oxygen species (ROS). ROS-induced damage has been associated with aging and diseases such as metabolic syndrome and cancer. However, not all organisms develop these diseases, nor do they age at the same rate; this is partially due to resistance to oxidative stress, a quantitative trait attributable to the interaction of factors including genetics and environmental. Drosophila melanogaster represents an ideal system to study how genetic variation can affect resistance to oxidative stress. In this work, oxidative stress (total and mitochondrial ROS), antioxidant response, and Cap 'n' collar isoform C and Spineless gene expression, one pesticide resistant (Oregon R(R)-flare) and wild-type (Canton-S) strains of D. melanogaster, were analyzed to test resistance to basal oxidative stress. ROS, catalase, and superoxide dismutase were determined by flow cytometry, and Cap 'n' collar isoform C and Spineless expression by qRT-PCR. The intensity of oxidative stress due to the pro-oxidant zearalenone in both was evaluated by flow cytometry. Data confirm expected differences in oxidative stress between strains that differ in Cyp450s levels. The Oregon (R)R-flare showed greater ROS, total and mitochondrial, compared to Canton-S. Regarding oxidative stress genes expression Cap 'n' collar isoform C and Spineless (Ss), Oregon R(R)-flare strain showed higher expression. In terms of response to zearalenone mycotoxin, Canton-S showed higher ROS concentration. Our data show variation in the resistance to oxidative stress among these strains of D. melanogaster.
RESUMEN
Bilateral ovariectomy is the best characterized and the most reported animal model of human menopause. Ovariectomized rodents develop insulin resistance (IR) and visceral obesity, the main risk factors in the pathophysiology of metabolic syndrome (MS). These alterations are a consequence of hypoestrogenic status, which produces an augment of visceral fat, high testosterone levels (hyperandrogenism), as well as inflammation, oxidative stress, and metabolic complications, such as dyslipidemia, hepatic steatosis, and endothelial dysfunction, among others. Clinical trials have reported that menopause per se increases the severity and incidence of MS, and causes the highest mortality due to cardiovascular disease in women. Despite all the evidence, there are no reports that clarify the influence of estrogenic deficiency as a cause of MS. In this review, we provide evidence that ovariectomized rodents can be used as a menopausal metabolic syndrome model for evaluating and discovering new, safe, and effective therapeutic approaches in the treatment of cardiometabolic complications associated to MS during menopause.
Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Grasa Intraabdominal/patología , Síndrome Metabólico/metabolismo , Animales , Enfermedades Cardiovasculares/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Resistencia a la Insulina , Grasa Intraabdominal/metabolismo , Menopausia , Síndrome Metabólico/patología , Ovariectomía/métodos , Ovario/fisiología , RoedoresRESUMEN
INTRODUCCIÓN: Existe una disminución de la Filtración Glomerular (FG) en adultos mayores y la práctica del ejercicio puede causar cambios en la función renal. OBJETIVO: Evaluar el efecto de diferentes intensidades de ejercicio agudo sobre la filtración glomerular en adultos mayores. MÉTODO: 20 adultos mayores aparentemente sanos de 69,8 ± 4 años realizaron 3 pruebas de ejercicio físico: máxima y 2 sub-máximas (80% y 60%). Se colectaron muestras de sangre venosa para estimar la filtración glomerular por creatinina, antes y después del ejercicio. RESULTADOS: Se observó una disminución significativa post-ejercicio en la filtración glomerular, estimada a partir de creatinina sérica en las pruebas máxima y sub-máxima a 80% (p < 0,05). CONCLUSIÓN: El ejercicio físico agudo máximo y sub-máximo al 80% de intensidad en adultos mayores aparentemente sanos, provoca una disminución de la filtración glomerular
INTRODUCTION: There is a decrease in Glomerular Filtration Rate (GFR) in older adults and the exercise practice may lead to changes in renal function. Purpose: To evaluate the effect of different intensities of acute exercise on elderly population GFR. METHODS: 20 apparently healthy older adults (69,8 ± 4 years) performed 3 exercise tests a week apart: one maximal and 2 submaximal (80% and 60%). Blood samples were collected to determine serum creatinine and to estimate GFR, before and after each exercise test. RESULTS: A significant post-exercise decline in GFR, estimated from serum creatinine values, was observed in the maximal and submaximal 80% tests (p <0,05). CONCLUSION: Maximum and sub-maximum acute physical exercise at 80% intensity causes a decrease in glomerular filtration in apparently healthy older adults
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Tasa de Filtración Glomerular/fisiología , Esfuerzo Físico/fisiología , Deportes/fisiología , Estudios Longitudinales , Estudios Prospectivos , Índice de Masa Corporal , Análisis de VarianzaRESUMEN
Non-Alcoholic Fatty Liver Disease (NAFLD) is the cause of chronic liver disease. Even though NAFLD is strongly associated with obesity and metabolic syndrome, there is a proportion of patients who develop this condition in the absence of obesity and the underlying mechanisms are poorly understood. We investigated early events in the pathogenesis of non-obese NAFLD, analyzing the impact of the chronic intake of a moderate fat-enriched diet on hepatic lipid accumulation and their relationship with inflammation. Rabbits fed with a moderate Fatty-Acid- Enriched Diet 3% palmitic acid (FAED), were evaluated for body weight, biochemical parameters, and liver function. Liver samples were analyzed by histology and RT-qPCR to measure lipid accumulation, the expression of inflammation-related genes IL-1ß, IL-6, IL-10, IL-13, IL-18, COX-2, TNF-α, and TLR-4. Chronic consumption by 6-months of FAED did not generate metabolic changes, but it induced fatty liver. We also observed the development of low-grade inflammation characterized by the up regulation of TNF-α, IL-13 and IL-18. The consumption by 12-months of FAED caused the overexpression of IL-6, IL-10, IL-13, COX-2, and TLR-4. We show that hepatic steatosis is an early consequence of fat-enriched diets, and that it is accompanied by an immune response that exerts protective effects that prevent the development of metabolic disorders, such as overweight/obesity and metabolic syndrome. However, the excessive intake of fatty acids renders these mechanisms less efficient for delaying the start of metabolic alterations. Rabbits fed with FAED can be used as a model of NAFLD in non-obese and obese groups, especially at early stages of the disease.
Asunto(s)
Dieta Alta en Grasa , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Animales , Peso Corporal , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Inflamación/patología , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Gotas Lipídicas/metabolismo , Hígado/metabolismo , Masculino , Obesidad/patología , Conejos , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Regulación hacia ArribaRESUMEN
The in vivo effect of continuous angiotensin II (Ang II) infusion on arterial blood pressure, vascular hypertrophy and α1 -adrenoceptors (α1 -ARs) expression was explored. Alzet(®) minipumps filled with Ang II (200 ng kg(-1) min(-1) ) were subcutaneously implanted in male Wistar rats (3 months-old). Groups of rats were also treated with losartan, an AT1 R antagonist, or with BMY 7378, a selective α1D -AR antagonist. Blood pressure was measured by tail-cuff; after 2 or 4 weeks of treatment, vessels were isolated for functional and structural analyses. Angiotensin II increased systolic blood pressure. Phenylephrine-induced contraction in aorta was greater (40% higher) in Ang II-treated rats than in the controls, and similar effect occurred with KCl 80 mm. Responses in tail arteries were not significantly different among the different groups. Angiotensin II decreased α1D -ARs without modifying the other α1 -ARs and induced an increase in media thickness (hypertrophy) in aorta, while no structural change occurred in tail artery. Losartan prevented and reversed hypertension and hypertrophy, while BMY 7378 prevented and reversed the aorta's hypertrophic response, without preventing or reversing hypertension. Findings indicate that Ang II-induced aortic hypertrophic response involves Ang II-AT1 Rs and α1D -ARs. Angiotensin II-induced α1D -AR-mediated vascular remodeling occurs independently of hypertension. Findings identify a α1D -AR-mediated process whereby Ang II influences aortic hypertrophy independently of blood pressure elevation.
Asunto(s)
Angiotensina II/toxicidad , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Músculo Liso Vascular/fisiología , Receptores Adrenérgicos alfa 1/fisiología , Bloqueadores del Receptor Tipo 2 de Angiotensina II/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Relación Dosis-Respuesta a Droga , Hipertrofia/inducido químicamente , Hipertrofia/metabolismo , Masculino , Músculo Liso Vascular/efectos de los fármacos , Técnicas de Cultivo de Órganos , Ratas , Ratas WistarRESUMEN
The antihyperglycaemic properties of the aqueous extract from the leaves and stems of Coriandrum sativum L. were evaluated in normoglycaemic rats, and on α-glucosidase activity from Saccharomyces cerevisiae, in order to validate its use in folk medicine. In in vivo experiments rats were administered with the aqueous extract of the plant at 100, 300 and 500 mg/kg, to observe the effect on oral sucrose tolerance test. The aqueous extract exhibited significant antihyperglycaemic activity at the three tested doses. In vitro experiments with α-glucosidase exhibited a competitive-type inhibition. These results confirm the antidiabetic properties of the extract of C. sativum L., probably by the inhibition of α-glucosidase in the gastrointestinal tract.
Asunto(s)
Coriandrum/química , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemia/prevención & control , alfa-Glucosidasas/efectos de los fármacos , Administración Oral , Animales , Glucemia/análisis , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Humanos , Masculino , Extractos Vegetales/farmacología , Hojas de la Planta/química , Tallos de la Planta/química , Ratas , Rutina/farmacología , Saccharomyces cerevisiae/efectos de los fármacosRESUMEN
Annona genus contains plants used in folk medicine for the treatment of diabetes. In the present study, an aqueous extract prepared from Annona macroprophyllata (Annonaceae, also known as A. diversifolia) leaves was evaluated on both the activity of yeast α -glucosidase (an in vitro assay) and sucrose tolerance in Wistar rats. The results have shown that the aqueous extract from A. macroprophyllata inhibits the yeast α -glucosidase with an IC50 = 1.18 mg/mL, in a competitive manner with a K(i) = 0.97 mg/mL, a similar value to that of acarbose (K(i) = 0.79 mg/mL). The inhibitory activity of A. macroprophyllata was reinforced by its antihyperglycemic effect, at doses of 100, 300, and 500 mg/kg in rats. Chromatographic analysis identified the flavonoids rutin and isoquercitrin in the most polar fractions of A. macroprophyllata crude extract, suggesting that these flavonoids are part of the active constituents in the plant. Our results support the use of A. macroprophyllata in Mexican folk medicine to control postprandial glycemia in people with diabetes mellitus, involving active constituents of flavonoid nature.
Asunto(s)
Annona/química , Inhibidores Enzimáticos , Flavonoides , Inhibidores de Glicósido Hidrolasas , Extractos Vegetales , Animales , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/enzimología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Flavonoides/química , Flavonoides/farmacología , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/enzimología , Masculino , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Saccharomyces cerevisiae/enzimología , Proteínas de Saccharomyces cerevisiae/antagonistas & inhibidoresRESUMEN
We investigated captopril effects, an ACE inhibitor, on hypertension development, on Ang II and Ang-(1-7) plasma concentrations, on Ang II-induced contraction in isolated kidneys, and on kidney AT1R from spontaneously hypertensive (SHR) rats. Five weeks-old SHR and Wistar Kyoto (WKY) rats were treated with captopril at 30 mg/kg/day, in drinking water for 2 or 14 weeks. Systolic blood pressure (SBP) was measured, and isolated kidneys were tested for perfusion pressure and AT1R expression; while Ang II and Ang-(1-7) concentrations were determined in plasma. Captopril did not modify SBP in WKY rats and avoided its increase as SHR aged. Plasma Ang-II concentration was â¼4-5 folds higher in SHR rats, and captopril reduced it (P<0.05); while captopril increased Ang-(1-7) by â¼2 fold in all rat groups. Captopril increased Ang II-induced pressor response in kidneys of WKY and SHR rats, phenomenon not observed in kidneys stimulated with phenylephrine, a α1-adrenoceptor agonist. Captopril did not modify AT1R in kidney cortex and medulla among rat strains and ages. Data indicate that captopril increased Ang II-induced kidney perfusion pressure but not AT1R density in kidney of WKY and SHR rats, due to blockade of angiotensin II synthesis; however, ACE inhibitors may have other actions like activating signaling processes that could contribute to their diverse effects.
Asunto(s)
Angiotensina II/sangre , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Captopril/uso terapéutico , Hipertensión/prevención & control , Riñón/efectos de los fármacos , Prehipertensión/tratamiento farmacológico , Resistencia Vascular/efectos de los fármacos , Envejecimiento , Angiotensina I/sangre , Angiotensina II/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Animales , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Captopril/efectos adversos , Hipertensión/etiología , Riñón/irrigación sanguínea , Riñón/metabolismo , Riñón/fisiopatología , Corteza Renal/efectos de los fármacos , Corteza Renal/metabolismo , Médula Renal/efectos de los fármacos , Médula Renal/metabolismo , Masculino , Fragmentos de Péptidos/sangre , Prehipertensión/sangre , Prehipertensión/metabolismo , Prehipertensión/fisiopatología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptor de Angiotensina Tipo 1/metabolismo , Organismos Libres de Patógenos EspecíficosRESUMEN
1 The pressor action of the α(1A)-adrenoceptor (α(1A)-AR) agonist A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulfonamide) and the α(1)-ARs agonist phenylephrine and their blockade by selective α(1)-ARs antagonists in the isolated mesenteric vascular bed of wild-type (WT) mice and α(1D)-AR knockout (KO α(1D)-AR) mice were evaluated. 2 The apparent potency of A61603 to increase the perfusion pressure in the mesenteric vascular bed of WT and KO α(1D)-AR mice is 86 and 138 times the affinity of phenylephrine, respectively. 3 A61603 also enhanced the perfusion pressure by ≈1.7 fold in the mesenteric vascular bed of WT mice compared with KO α(1D)-AR mice. 4 Because of its high affinity, low concentrations of the α(1A)-AR selective antagonist RS100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy) phenyl]-1-piperazinyl] propyl]-2,4-(1H)-pyrimidinedione) shifted the agonist concentration-response curves to the right in the mesenteric vascular bed of WT and KO α(1D)-AR mice. 5 The α(1D)-AR selective antagonist BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5] decane-7,9-dione) did not modify the A61603 or the phenylephrine-induced pressor effect. 6 The α(1B/D)-ARs alkylating antagonist chloroethylclonidine (CEC) shifted the agonist concentration-response curves to the right and decreased the maximum phenylephrine-induced vascular contraction in KO α(1D)-AR mice when compared to WT mice; however, CEC only slightly modified the contraction induced by A61603. 7 The results indicate that the isolated mesenteric vascular bed of WT and KO α(1D)-AR mice expresses α(1A)-AR, that the pressor action of α(1A)-AR is up-regulated for α(1D)-AR in WT mice and suggest an important role of α(1B)-AR in the vascular pressure evoked by phenylephrine in KO α(1D)-AR mice.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Receptores Adrenérgicos alfa 1/fisiología , Circulación Esplácnica/fisiología , Vasoconstricción/fisiología , Animales , Clonidina/análogos & derivados , Clonidina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Imidazoles/antagonistas & inhibidores , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Ratones , Ratones Noqueados , Fenilefrina/antagonistas & inhibidores , Fenilefrina/farmacología , Piperazinas/farmacología , Receptores Adrenérgicos alfa 1/genética , Circulación Esplácnica/efectos de los fármacos , Tetrahidronaftalenos/antagonistas & inhibidores , Tetrahidronaftalenos/farmacología , Timina/farmacología , Vasoconstricción/efectos de los fármacosRESUMEN
1 The effect of angiotensin II (Ang II) on α(1A)-, α(1B)-, and a(1D)-adrenoceptors (α(1)-AR) expression was analyzed in aorta smooth muscle cells obtained from wild-type (WT) and knock out of α(1D)-AR (α(1D)-AR KO) mice. 2 The relative abundance of mRNA for the three α(1)-ARs was determined in WT and α(1D)-AR KO aortic smooth muscle cells. There were no significant differences between WT and α(1D)-AR KO cells. 3 As early as 1 h Ang II increased α(1B)-AR mRNA in WT cells ≈ 2 fold compared with control; in contrast, in α(1D)-AR KO cells the α(1B)-AR transcript was ≈ 50% of control. 4 Western blot assays showed that Ang II incremented protein content for α(1A)-AR, 86% and 107% in WT and α(1D)-AR KO cells, respectively. 5 Protein for α(1B)- and α(1D)-ARs did not change significantly with Ang II in both WT and a(1D)-AR KO cells. 6 The effect of Ang II on α(1B)-AR mRNA seems to be influenced by the absence of α(1D)-AR in aortic smooth muscle cells, which might be important to understand the interactions among α(1)-ARs.
Asunto(s)
Angiotensina II/fisiología , Aorta/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Receptores Adrenérgicos alfa 1/biosíntesis , Receptores Adrenérgicos alfa 1/fisiología , Angiotensina II/farmacología , Animales , Aorta/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos del Músculo Liso/efectos de los fármacos , Cultivo Primario de Células , Receptores Adrenérgicos alfa 1/genéticaRESUMEN
1 The molecular mechanism underlying stress-induced hyperglycemia has not been comprehensively clarified. Recently, we demonstrated in ischaemia-reperfusion (I-R) stress-subjected liver that inosine and adenosine are mainly responsible for the hyperglycemia observed. 2 We aimed to advance in the knowledge of the role of inosine plus adenosine as mediators of hepatic-induced hyperglycemia detected after I-R in lower limbs. 3 Acute ischaemia was conducted in anesthetized rats by occluding downstream abdominal aorta and cava vein; then, reperfusion was allowed. Blood samples from hepatic or abdominal cava veins were taken throughout the experiments to measure glucose, inosine and adenosine. Antagonists to adenosine (AdoR) and adrenergic receptors (AdrR) were administered during ischaemia to analyze their effect on hepatic glucose release. 4 Ischaemia up to 60 min produced minor increase of glucose and nucleosides blood values, but 5 min of ischaemia followed by 2- (or 10-) min reperfusion increased glucose 23%, and those of inosine or adenosine by 100%. After 60 min of ischaemia and 10 min of reperfusion, glycemia rose 2-fold and blood inosine and adenosine, 3.3- and 2.7-fold, respectively. A linear positive correlation, r(2), as high as 0.839 between glucose and either nucleoside blood values was calculated. The hyperglycemia response to I-R decreased by 0, 25, 33, 45 and 100% after selective inhibition of A(2B) AdoR, A(2A) AdoR, a(1B) AdrR, A(1) AdoR, and A(3) AdoR, respectively. 5 Inosine-adenosine couple through activation of hepatic A(3) AdoR is the main signal for releasing glucose from liver glycogen and for promoting hyperglycemia following experimental injury of I-R from lower limbs.
Asunto(s)
Adenosina/fisiología , Hiperglucemia/etiología , Inosina/fisiología , Receptor de Adenosina A3/fisiología , Daño por Reperfusión/metabolismo , Adenosina/sangre , Antagonistas del Receptor de Adenosina A3 , Adenosina Trifosfato/metabolismo , Animales , Glucemia/análisis , Extremidades/irrigación sanguínea , Glucosa/metabolismo , Inosina/sangre , Hígado/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
1 The aim of the current study was to characterize the alpha(1)-adrenergic receptors (alpha(1)-ARs) present in the isolated tunica media of aorta, in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats during the course of ageing and hypertension (rats of 1, 3, 6 and 12 months of age). In all vessels, endothelium was removed. 2 In isolated aortic rings, phenylephrine increased contraction in a concentration- and age-dependent manner and was impaired in old SHR compared with WKY rats. 3 The alpha(1)-AR selective antagonist prazosin showed high affinity (pA(2)) in vessels from both rat strains. 4 The potency of the alpha(1A)-AR selective antagonists, RS 100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy) phenyl]-1-piperazinyl] propyl]-2,4-(1H)-pyrimidinedione) and 5-methylurapidil in antagonizing aortic phenylephrine-responses was low. 5 The alpha(1D)-AR selective antagonist, BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1 piperazynil] ethyl]-8-azaspiro [4.5] decane-7,9-dione) potently blocked phenylephrine-induced responses in aorta from both strains and at all ages. 6 Adventitia removal decreased E(max) in older rats and modified the relative affinity (pD(2)), but did not affect the affinity of the selective antagonists. 7 The results suggest that aorta tunica alpha(1D)-AR is the main subtype involved in phenylephrine-induced contraction of rat aorta, while alpha(1A)-AR plays only a minor role. 8 Ageing and hypertension did not modify alpha(1)-ARs in the blood vessel and the tunica adventitia does not seem to participate in contraction, even though alpha(1)-ARs are expressed.
Asunto(s)
Envejecimiento/fisiología , Endotelio Vascular/fisiología , Hipertensión/fisiopatología , Receptores Adrenérgicos alfa 1/fisiología , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/farmacología , Animales , Fibroblastos/fisiología , Hipertensión/metabolismo , Masculino , Contracción Muscular/fisiología , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/fisiología , Piperazinas/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Timina/farmacología , Túnica Media/fisiología , Aumento de Peso/fisiologíaRESUMEN
1 The hypothesis that alpha(1D)-adrenoceptors may mediate the pro-hypertensive actions of angiotensin II (Ang II) was tested in isolated aorta (alpha(1D)-adrenoceptor bearing tissue) of the aryl hydrocarbon receptor null mouse (AhR(-/-)), which shows increased levels of Ang II, cardiac hypertrophy and hypertension. 2 The effect of captopril (an angiotensin converting enzyme inhibitor) on both blood pressure and aortic alpha(1D)-adrenoceptor expression and function in mice were determined. 3 Basal blood pressure was higher in AhR(-/-) mice, while captopril therapy decreased it to wild-type (WT) values. 4 Aortas of adult WT and AhR(-/-) mice were stimulated by phenylephrine or noradrenaline to induce contraction; the maximal effect was higher in AhR(-/-) mice, without a significant change in pEC(50). 5 PA(2) values for the selective alpha(1D)-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazynil]ethyl]-8-azaspiro [4.5]decane-7,9-dione) were 9.19 and 8.94 for WT and AhR(-/-), respectively; while Schild slopes were not different from 1. 6 PCR experiments showed c. 77% increase in AhR(-/-)alpha(1D)-adrenoceptors cDNA compared with WT mice; while western blot analysis demonstrated c. 88% increase in alpha(1D)-adrenoceptor protein in AhR(-/-) mice. 7 Captopril therapy decreased alpha(1D)-adrenoceptor-induced contraction and protein in AhR(-/-) mice to WT levels. 8 These data support the hypothesis that under conditions where Ang II is elevated, vascular alpha(1D)-adrenoceptors are increased, and further suggest that both Ang II and vascular alpha(1D)-adrenoceptors could be related in the onset of hypertension.
Asunto(s)
Angiotensina II/metabolismo , Aorta Torácica/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Hidrocarburo de Aril/genética , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/farmacología , Angiotensina II/antagonistas & inhibidores , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Presión Sanguínea/efectos de los fármacos , Western Blotting , Captopril/farmacología , Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Norepinefrina/farmacología , Fenilefrina/farmacología , Piperazinas/farmacología , Receptores Adrenérgicos alfa 1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vasoconstricción/efectos de los fármacosRESUMEN
We studied whether mitochondrial functions and Ca2+ metabolism were altered in Wistar Kyoto normotensive (WKY) and spontaneous hypertensive rats (SHR). Ca2+ uptake was decreased in SHR compared to WKY rats. Accumulation of Ca2+ was more efficient in WKY than in SHR rats. mDeltaPsi was lower in SHR compared to WKY rats. Basal complex IV activity was higher in SHR than WKY rats, whereas basal L-citrulline production, an indicator of nitric oxide synthesis, was decreased in SHR and dependent on Ca2+ concentration (p<0.05). Impact of Ca2+ was counteracted by EGTA. These data show an age-dependent decreased mitochondrial functions in brain mitochondria during hypertension.
Asunto(s)
Envejecimiento/metabolismo , Calcio/metabolismo , Calcio/farmacología , Hipertensión/metabolismo , Mitocondrias/metabolismo , Animales , Encéfalo/ultraestructura , Citrulina/análisis , Citrulina/biosíntesis , Ácido Egtácico/farmacología , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Mitocondrias/genética , Óxido Nítrico Sintasa/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especificidad de la Especie , Espectrometría de Fluorescencia , Factores de TiempoRESUMEN
AIM: The present investigation was designed to determine the in vivo antidiabetic effect of naringenin (NG) in normoglycaemic and diabetic rat models through blood glucose (GLU) measurements following acute and subchronic time periods. Possible modes of action of NG were investigated and its acute toxicity determined. METHODS: Normoglycaemic and non-insulin-dependent diabetes mellitus (NIDDM) rat models were treated for acute and subchronic (5 days) time periods with 50 mg/kg/day of NG. Blood biochemical profiles were determined after 5 days of the treatment in normoglycaemic and NIDDM rats using commercial kits for GLU, triglycerides (TG), total cholesterol (CHOL) and high-density lipoprotein (HDL). In order to elucidate its antidiabetic mode of action, NG was administered intragastrically and an oral glucose tolerance test performed using GLU and sucrose (2 g/kg) as substrates. The inhibitory effect of a single concentration of NG (10 microM) on 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity in vitro was determined. Finally, the preclinical safety and tolerability of NG was determined by toxicological evaluation in mice and rats using Organization for Economic Cooperation and Development (OECD) protocols. RESULTS: Intragastrically administered NG (50 mg/kg) induced a significant decrease in plasma GLU in normoglycaemic and NIDDM rat models (p < 0.05) following acute and subchronic time periods. After 5 days of administration, NG produced significant diminished blood GLU and TG levels in streptozotocin-nicotinamide-induced diabetic rats. The administration of NG to normal rats significantly increased the levels of TG, CHOL and HDL (p < 0.05). NG (5 and 50 mg/kg) induced a total suppression in the increase of plasma GLU levels after administration of substrates (p < 0.01), but NG did not produce inhibition of alpha-glucosidase activity in vitro. However, NG (10 microM) was shown to inhibit 11beta-HSD1 activity by 39.49% in a cellular enzyme assay. Finally, NG showed a Medium Lethal Dose LD(50) > 5000 mg/kg and ranking at level five based on OECD protocols. CONCLUSION: Our findings suggest that NG may exert its antidiabetic effect by extra-pancreatic action and by suppressing carbohydrate absorption from intestine, thereby reducing the postprandial increase in blood GLU levels.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Flavanonas/uso terapéutico , Hipoglucemiantes/uso terapéutico , Animales , Glucemia/análisis , Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Flavanonas/toxicidad , Prueba de Tolerancia a la Glucosa , Gliburida/uso terapéutico , Hipoglucemiantes/toxicidad , Dosificación Letal Mediana , Masculino , Ratones , Distribución Aleatoria , Ratas , Ratas Wistar , Triglicéridos/sangreRESUMEN
1 Alpha1-Adrenoceptor (alpha1-AR) subtypes were characterized in isolated omental arteries obtained after abdominal surgery in patients with end-stage renal disease (ESRD) or with Diabetes Mellitus type 2 plus ESRD (ESRD-DM). 2 Omental arteries from patients with ESRD and ESRD-DM elicited a significant increase in sensitivity to phenylephrine with a pD(2) (-log EC50) of 6.7 and 6.6, respectively, vs. the control (5.8, P < 0.001). 3 Stimulation with phenylephrine was conducted in the presence or absence of selective alpha1-AR competitive antagonists: 5-methylurapidil (alpha1A-), AH11110A (1-[biphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2-ol; alpha1B-) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4.5] decane-7,9-dione; alpha(1D)-). The relative abundance of mRNA for all three alpha(1)-ARs was determined. 4 The maximal contractile responses to phenylephrine were: E(max) 1.59 +/- 0.17, 1.48 +/- 0.08 and 1.55 +/- 0.14 g for the ESRD, ESRD-DM and control groups, respectively. 5 Functionally, there was an increment in the affinity for the alpha(1A)-AR antagonist (pA2: control 7.45, ESRD 8.36, ESRD-DM 8.0; P < 0.01), and a reduction in the alpha1B-AR antagonist affinity (8.3 for controls, 7.6 for ESRD and 7.3 for ESRD-DM; P < 0.01) associated with renal disease. The affinities for the alpha1D-AR antagonist were similar among the studied groups (8.5 for the controls, 8.7 for the ESRD and 8.1 for the ESRD-DM groups). 6 Renal disease increased mRNA expression of alpha(1B)-ARs and reduced both alpha1A- and alpha(1D)-ARs subtypes in ESRD and ESRD-DM patients. 7 The results suggest that human omental arteries exposed to chronic uraemia show vascular hypersensitivity to phenylephrine, because of functional alpha1-AR changes.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Fallo Renal Crónico/metabolismo , Epiplón/irrigación sanguínea , Receptores Adrenérgicos alfa 1/metabolismo , Vasoconstricción , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Adulto , Arterias/metabolismo , Arterias/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Iminas/farmacología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Fenilefrina/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , ARN Mensajero/metabolismo , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Receptores Adrenérgicos alfa 1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacologíaRESUMEN
1 The pressor action of the alpha1A-adrenoceptor agonist, A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulfonamide) or the alpha1-adrenoceptor agonist phenylephrine, and their blockade by selective alpha1-adrenoceptor antagonists in the mouse isolated mesenteric vascular bed were evaluated. 2 A61603 showed a approximately 235-fold higher potency in elevating perfusion pressure in mesenteric bed compared to phenylephrine. 3 The alpha1A-adrenoceptor selective antagonist RS 100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy) phenyl]-1-piperazinyl] propyl]-2,4-(1H)-pyrimidinedione), displaced with high affinity agonist concentration-response curves to the right in a concentration-dependent manner. 4 The alpha1D-adrenoceptor selective antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5] decane-7,9-dione), did not displace A61603 nor did it block the phenylephrine-induced pressor response. 5 The alpha1B/D-adrenoceptor alkylating antagonist chloroethylclonidine (CEC), caused a rightward shift of the phenylephrine concentration-response curve and reduced its maximum response; however, CEC only slightly modified A61603 evoked contraction. 6 The results indicate that the isolated mouse mesenteric vascular bed expresses alpha1A-adrenoceptors and suggest a very discrete role for 1B-adrenoceptors.
Asunto(s)
Presión Sanguínea/fisiología , Arterias Mesentéricas/fisiología , Receptores Adrenérgicos alfa 1/fisiología , Vasoconstricción/efectos de los fármacos , Agonistas de Receptores Adrenérgicos alfa 1 , Antagonistas de Receptores Adrenérgicos alfa 1 , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Clonidina/análogos & derivados , Clonidina/farmacología , Relación Dosis-Respuesta a Droga , Imidazoles/farmacología , Técnicas In Vitro , Masculino , Arterias Mesentéricas/efectos de los fármacos , Ratones , Ratones Endogámicos , Fenilefrina/farmacología , Piperazinas/farmacología , Tetrahidronaftalenos/farmacología , Timina/farmacologíaRESUMEN
1. Non-steroidal anti-inflammatory drugs (NSAIDs) [acetylsalicylic acid (ASS), naproxen, nimesulide and piroxicam] decreased adrenaline- or dibutyryl cAMP-stimulated glycerol release in isolated adipocytes. We aimed to determine the mechanism of this NSAIDs action. 2. Non-steroidal anti-inflammatory drugs decreased cAMP-dependent protein kinase A (PKA) activity in rat adipocyte lysates and in a commercial bovine heart PKA holoenzyme. If added before cAMP, NSAIDs impaired PKA activation by the cyclic nucleotide; however, if PKA was first activated by cAMP, NSAIDs were ineffective. NSAIDs were also ineffective against PKA catalytic subunits. 3. Consequently, NSAIDs lowered hormone-sensitive lipase translocation from cytosol to lipid storage droplets in adipocytes lysates, the critical event to promote lipolysis. 4. These results indicate that inhibition of PKA activation explains NSAIDs-induced decrease in adrenaline-stimulated lipolysis. We suggest that reproduction of such inhibition in nociceptive cells might enhance the understanding of the mechanism underlying the analgesic effects of NSAIDs.
Asunto(s)
Adipocitos/efectos de los fármacos , Antiinflamatorios no Esteroideos/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Adipocitos/enzimología , Animales , Aspirina/farmacología , Bovinos , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Masculino , Miocardio/enzimología , Naproxeno/farmacología , Piroxicam/farmacología , Prostaglandina-Endoperóxido Sintasas , Ratas , Ratas Wistar , Esterol Esterasa/metabolismo , Sulfonamidas/farmacologíaRESUMEN
Tournefortia hartwegiana is a Mexican medicinal plant that is used for the treatment of diabetes, diarrhea and kidney pain. In a previous investigation, the methanolic extract of Tournefortia hartwegiana (METh) showed significant hypoglycemic and anti-diabetic properties on normoglycemic and alloxanized rats. In this context, the purpose of the present study was to establish one of the possible modes of action of METh to induce anti-diabetic activity. METh (310mg/kg) effect on alpha-glucosidase activity was investigated. METh intragastric administration was conducted to determine oral glucose tolerance test (OGTT), using different substrates: glucose, sucrose and maltose. The increase in plasma glucose level was significantly suppressed (P<0.05) by the extract after substrates administration. On the other hand, METh inhibited alpha-glucosidase activity in vitro, in a concentration-dependent manner (IC(50) of 3.16mg/mL). These results suggest that METh might exert its anti-diabetic effect by suppressing carbohydrate absorption from intestine, and thereby reducing the post-prandial increase of blood glucose. On the other hand, the bio-guided fractionation of this extract led to the isolation of: beta-sitosterol (1), stigmasterol (2), lupeol (3), ursolic acid (4), oleanolic acid (5), saccharose (6) and myo-inositol (7), using various chromatographic techniques.