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1.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;45(5): 392-400, May 2012. ilus
Artigo em Inglês | LILACS | ID: lil-622764

RESUMO

Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.


Assuntos
Humanos , Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Obesidade/fisiopatologia , Hipertensão/etiologia , Resistência à Insulina/fisiologia , Obesidade/complicações , Fatores de Risco , Sistema Renina-Angiotensina/fisiologia , Sistema Nervoso Simpático/fisiopatologia
2.
Braz J Med Biol Res ; 45(5): 392-400, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22488221

RESUMO

Obesity is strongly associated with high blood pressure, dyslipidemia, and type 2 diabetes. These conditions synergistically increase the risk of cardiovascular events. A number of central and peripheral abnormalities can explain the development or maintenance of high blood pressure in obesity. Of great interest is endothelial dysfunction, considered to be a primary risk factor in the development of hypertension. Additional mechanisms also related to endothelial dysfunction have been proposed to mediate the development of hypertension in obese individuals. These include: increase in both peripheral vasoconstriction and renal tubular sodium reabsorption, increased sympathetic activity and overactivation of both the renin-angiotensin system and the endocannabinoid system and insulin resistance. The discovery of new mechanisms regulating metabolic and vascular function and a better understanding of how vascular function can be influenced by these systems would facilitate the development of new therapies for treatment of obesity-associated hypertension.


Assuntos
Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Obesidade/fisiopatologia , Humanos , Hipertensão/etiologia , Resistência à Insulina/fisiologia , Obesidade/complicações , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco , Sistema Nervoso Simpático/fisiopatologia
3.
Life Sci ; 91(13-14): 600-6, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22521290

RESUMO

AIMS: Cytokines interfere with signaling pathways and mediators of vascular contraction. Endothelin-1 (ET-1) plays a major role on vascular dysfunction in conditions characterized by increased circulating levels of adipokines. In the present study we tested the hypothesis that the adipokine chemerin increases vascular contractile responses via activation of ET-1/ET-1 receptors-mediated pathways. MAIN METHODS: Male, 10-12 week-old Wistar rats were used. Endothelium-intact and endothelium-denuded aortic rings were incubated with chemerin (0.5 ng/mL or 5 ng/mL, for 1 or 24h), and isometric contraction was recorded. Protein expression was determined by Western blotting. KEY FINDINGS: Constrictor responses to phenylephrine (PE) and ET-1 were increased in vessels treated for 1h with chemerin. Chemerin incubation for 24h decreased PE contractile response whereas it increased the sensitivity to ET-1. Endothelium removal significantly potentiated chemerin effects on vascular contractile responses to PE and ET-1. Incubation with either an ERK1/2 inhibitor (PD98059) or ETA antagonist (BQ123) abolished chemerin effects on PE- and ET-1-induced vasoconstriction. Phosphorylation of MEK1/2 and ERK1/2 was significantly increased in vessels treated with chemerin for 1 and 24h. Phosphorylation of these proteins was further increased in vessels incubated with ET-1 plus chemerin. ET-1 increased MEK1/2, ERK1/2 and MKP1 protein expression to values observed in vessels treated with chemerin. SIGNIFICANCE: Chemerin increases contractile responses to PE and ET-1 via ERK1/2 activation. Our study contributes to a better understanding of the mechanisms by which the adipose tissue affects vascular function and, consequently, the vascular alterations present in obesity and related diseases.


Assuntos
Adipocinas/administração & dosagem , Aorta Torácica/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Adipocinas/metabolismo , Animais , Aorta Torácica/metabolismo , Western Blotting , Quimiocinas , Relação Dose-Resposta a Droga , Endotelina-1/administração & dosagem , Endotelina-1/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Flavonoides/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Masculino , Peptídeos Cíclicos/farmacologia , Fenilefrina/farmacologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de Tempo
4.
Life Sci ; 90(17-18): 689-94, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22498877

RESUMO

AIMS: Inflammation may have an important role in the beginning and in the progress of cardiovascular diseases. Testosterone exerts important effects on vascular function, which is altered in arterial hypertension. Thus, the aim of this study was to evaluate the influence of endogenous testosterone on leukocyte behavior in post-capillary venules of the mesenteric bed of spontaneously hypertensive rats (SHR). MAIN METHODS: 18 week-old intact SHR, castrated SHR and normotensive rats (intact Wistar) were used. Blood pressure was measured by tail plethysmography and serum testosterone levels by ELISA. Leukocyte rolling, adhesion and migration were evaluated in vivo in situ by intravital microscopy. KEY FINDINGS: Castration significantly reduced blood pressure and reversed the increased leukocyte rolling and adhesion observed in SHRs. Leukocyte counts and other hemodynamic parameters did not differ among groups. SHRs displayed increased protein expression of P-selectin and ICAM-1 in mesenteric venules when compared to intact Wistar. Castration of SHRs restored the protein expression of the cell adhesion molecules. SIGNIFICANCE: The findings of the present study demonstrate the critical role of endogenous testosterone mediating the effects of hypertension increasing leukocyte-endothelial cell interaction. Increased expression of cell adhesion molecules contribute to the effects of endogenous testosterone promoting increased leukocyte rolling and adhesion in SHRs.


Assuntos
Comunicação Celular , Células Endoteliais/citologia , Hipertensão/imunologia , Leucócitos/citologia , Ratos Endogâmicos SHR/imunologia , Testosterona/imunologia , Animais , Adesão Celular , Células Endoteliais/imunologia , Hemodinâmica , Hipertensão/genética , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/imunologia , Migração e Rolagem de Leucócitos , Leucócitos/imunologia , Masculino , Orquiectomia , Selectina-P/genética , Selectina-P/imunologia , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos SHR/genética , Ratos Wistar , Vênulas/citologia
5.
Life Sci ; 90(5-6): 228-35, 2012 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-22154980

RESUMO

AIMS: Metformin is an insulin sensitizing agent with beneficial effects in diabetic patients on glycemic levels and in the cardiovascular system. We examined whether the metabolic changes and the vascular dysfunction in monosodium glutamate-induced obese non-diabetic (MSG) rats might be improved by metformin. MAIN METHODS: 16 week-old MSG rats were treated with metformin for 15 days and compared with age-matched untreated MSG and non-obese non-diabetic rats (control). Blood pressure, insulin sensitivity, vascular reactivity and prostanoid release in the perfused mesenteric arteriolar bed as well as nitric oxide production and reactive oxygen species generation in isolated mesenteric arteries were analyzed. KEY FINDINGS: 18-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia, insulin resistance and hyperinsulinemia. Metformin treatment improved these alterations. The norepinephrine-induced response, increased in the mesenteric arteriolar bed from MSG rats, was corrected by metformin. Indomethacin corrected the enhanced contractile response in MSG rats but did not affect metformin effects. The sensitivity to acetylcholine, reduced in MSG rats, was also corrected by metformin. Indomethacin corrected the reduced sensitivity to acetylcholine in MSG rats but did not affect metformin effects. The sensitivity to sodium nitroprusside was increased in preparations from metformin-treated rats. Metformin treatment restored both the reduced PGI2/TXA2 ratio and the increased reactive oxygen species generation in preparations from MSG rats. SIGNIFICANCE: Metformin improved the vascular function in MSG rats through reduction in reactive oxygen species generation, modulation of membrane hyperpolarization, correction of the unbalanced prostanoids release and increase in the sensitivity of the smooth muscle to nitric oxide.


Assuntos
Hipoglicemiantes/administração & dosagem , Artérias Mesentéricas/metabolismo , Metformina/administração & dosagem , Óxido Nítrico Sintase/metabolismo , Obesidade/tratamento farmacológico , Acetilcolina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Dislipidemias/tratamento farmacológico , Epoprostenol/metabolismo , Hiperinsulinismo/tratamento farmacológico , Indometacina/farmacologia , Insulina/sangue , Resistência à Insulina , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/análise , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Obesidade/induzido quimicamente , Obesidade/fisiopatologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Glutamato de Sódio/administração & dosagem , Tromboxano A2/metabolismo
6.
Histol Histopathol ; 26(8): 1049-56, 2011 08.
Artigo em Inglês | MEDLINE | ID: mdl-21692037

RESUMO

Placentation starts with the formation of a spheroidal trophoblastic shell surrounding the embryo, thus facilitating both implantation into the uterine stroma and contact with maternal blood. Although it is known that diabetes increases the placental size and weight, the mechanisms responsible for this alteration are still poorly understood. In mammals, cellular proliferation occurs in parallel to placental development and it is possible that diabetes induces abnormal uncontrolled cell proliferation in the placenta similar to that seen in other organs (e.g. retina). To test this hypothesis, the objective of this work was to determine cell proliferation in different regions of the placenta during its development in a diabetic rat model. Accordingly, diabetes was induced on day 2 of pregnancy in Wistar rats by a single injection of alloxan (40 mg/kg i.v.). Placentas were collected on days 14, 17, and 20 postcoitum. Immunoperoxidase was used to identify Ki67 nuclear antigen in placental sections. The number of proliferating cells was determined in the total placental area as well as in the labyrinth, spongiotrophoblast and giant trophoblast cell regions. During the course of pregnancy, the number of Ki67 positive cells decreased in both control and diabetic rat placentas. However, starting from day 17 of pregnancy, the number of Ki67 positive cells in the labyrinth and spongiotrophoblast regions was higher in diabetic rat placentas as compared to control. The present results demonstrate that placentas from the diabetic rat model have a significantly higher number of proliferating cells in specific regions of the placenta and at defined developmental stages. It is possible that this increased cell proliferation promotes thickness of the placental barrier consequently affecting the normal maternal-fetal exchanges.


Assuntos
Diabetes Mellitus Experimental/patologia , Placenta/patologia , Placentação/fisiologia , Gravidez em Diabéticas/patologia , Animais , Biomarcadores/metabolismo , Proliferação de Células , Diabetes Mellitus Experimental/metabolismo , Feminino , Técnicas Imunoenzimáticas , Antígeno Ki-67/metabolismo , Troca Materno-Fetal/fisiologia , Tamanho do Órgão/fisiologia , Placenta/metabolismo , Gravidez , Gravidez em Diabéticas/metabolismo , Ratos , Ratos Wistar
7.
Nutr Metab Cardiovasc Dis ; 21(10): 808-16, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20554176

RESUMO

BACKGROUND AND AIM: given that obesity is an independent risk factor for the development of cardiovascular diseases we decided to investigate the mechanisms involved in microvascular dysfunction using a monosodium glutamate (MSG)-induced model of obesity, which allows us to work on both normotensive and normoglycemic conditions. METHODS AND RESULTS: Male offspring of Wistar rats received MSG from the second to the sixth day after birth. Sixteen-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia and insulin resistance, with no alteration in glycemia and blood pressure. The effect of norepinephrine (NE), which was increased in MSG rats, was potentiated by L-nitro arginine methyl ester (L-NAME) or tetraethylammonium (TEA) and was reversed by indomethacin and NS-398. Sensitivity to acetylcholine (ACh), which was reduced in MSG rats, was further impaired by L-NAME or TEA, and was corrected by indomethacin, NS-398 and tetrahydrobiopterin (BH4). MSG rats displayed increased endothelium-independent relaxation to sodium nitroprusside. A reduced prostacyclin/tromboxane ratio was found in the mesenteric beds of MSG rats. Mesenteric arterioles of MSG rats also displayed reduced nitric oxide (NO) production along with increased reactive oxygen species (ROS) generation; these were corrected by BH4 and either L-NAME or superoxide dismutase, respectively. The protein expression of eNOS and cyclooxygenase (COX)-2 was increased in mesenteric arterioles from MSG rats. CONCLUSION: Obesity/insulin resistance has a detrimental impact on vascular function. Reduced NO bioavailability and increased ROS generation from uncoupled eNOS and imbalanced release of COX products from COX-2 play a critical role in the development of these vascular alterations.


Assuntos
Animais Recém-Nascidos , Microvasos/fisiopatologia , Óxido Nítrico/fisiologia , Obesidade/induzido quimicamente , Prostaglandinas/fisiologia , Glutamato de Sódio/administração & dosagem , Animais , Arteríolas/enzimologia , Arteríolas/metabolismo , Ciclo-Oxigenase 2/análise , Masculino , Mesentério/irrigação sanguínea , Óxido Nítrico Sintase Tipo III/análise , Obesidade/fisiopatologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
8.
Inflamm Res ; 57(9): 438-43, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18777112

RESUMO

OBJECTIVE AND DESIGN: Knowing that hyperglycemia is a hallmark of vascular dysfunction in diabetes and that neonatal streptozotocin-induced diabetic rats (n-STZ) present reduced inflammatory response, we decided to evaluate the effect of chlorpropamide-lowered blood glucose levels on carrageenan-induced rat paw edema and pleural exudate in n-STZ. MATERIALS: Diabetes was induced by STZ injection (160 mg/kg, ip) in neonates (2-day-old) Wistar rats. TREATMENT: n-STZ diabetic rats were treated with chlorpropamide (200mg/kg, 15d, by gavage) 8 weeks after STZ injection. METHODS: Carrageenan-induced paw edema and pleural exudate volumes were assessed concomitantly with peripheral and exudate leukocyte count. We also evaluated the expression of inducible nitric oxide synthase (iNOS) in lungs of all experimental groups. RESULTS: Chlorpropamide treatment improved glucose tolerance, beta-cell function (assessed by HOMA-beta), corrected paw edema, and pleural exudate volume in n-STZ. Neither leukocyte count nor iNOS expression were affected by diabetes or by chlorpropamide treatment. CONCLUSION: Chlorpropamide treatment by restoring beta-cell function, reducing blood sugar levels, and improving glucose tolerance might be contributing to the correction of the reduced inflammatory response tested as paw edema and pleural exudate in n-STZ diabetic rats.


Assuntos
Clorpropamida/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Edema/etiologia , Hipoglicemiantes/uso terapêutico , Pleurisia/etiologia , Animais , Glicemia/análise , Carragenina , Diabetes Mellitus Experimental/fisiopatologia , Edema/fisiopatologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Masculino , Óxido Nítrico Sintase Tipo II/genética , Pleurisia/fisiopatologia , RNA Mensageiro/análise , Ratos , Ratos Wistar , Estreptozocina
9.
J Anat ; 212(1): 31-41, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18067546

RESUMO

During embryo implantation, invasive trophoblast cells mediate embryo invasion into the decidualized stroma, forming a rich network of lacunae that connect the embryonic tissues to the maternal blood vessels. Placentation is probably guided by the composition and organization of the endometrial extracellular matrix. Certain pathological conditions that occur during pregnancy, including diabetes, have been linked to abnormal placental morphology and consequent fetal morbidity. We used immunoperoxidase techniques to identify members of the collagen, proteoglycan and glycoprotein families in the various compartments of the rat placenta and to determine whether experimentally induced diabetes affects placental morphology and alters the distribution of these molecules during pregnancy. Single injections of alloxan (40 mg kg(-1) i.v.) were used to induce diabetes on day 2 of pregnancy in Wistar rats. Placentas were collected on days 14, 17, and 20. Type I and III collagen, as well as the proteoglycans decorin and biglycan, were found to be distributed throughout the placentas of control and diabetic rats. In both groups, laminin expression decreased at the end of pregnancy. In contrast, fibronectin was detected in the labyrinth region of diabetic rats at all gestational stages studied, whereas it was detected only at term pregnancy in the placentas of control rats. These results show for the first time that some extracellular matrix molecules are modulated during placental development. However, as diabetic rats presented increased fibronectin deposition exclusively in the labyrinth region, we speculate that diabetes alters the microenvironment at the maternal-fetal interface, leading to developmental abnormalities in the offspring.


Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Gestacional/patologia , Proteínas da Matriz Extracelular/análise , Placentação , Animais , Biglicano , Colágeno Tipo I/análise , Colágeno Tipo III/análise , Decorina , Endométrio/química , Feminino , Fibronectinas/análise , Técnicas Imunoenzimáticas , Laminina/análise , Placenta/química , Gravidez , Proteoglicanas/análise , Ratos , Ratos Wistar
10.
J Pharm Pharmacol ; 59(8): 1117-23, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17725854

RESUMO

Hyperglycaemia is a primary cause of vascular complications in diabetes. A hallmark of these vascular complications is endothelial cell dysfunction, which is partly due to reduced production of nitric oxide. The aim of this study was to verify the influence of improved glycaemic control with chlorpropamide on microvascular reactivity, endothelial nitric oxide synthase (e-NOS) expression, and NOS activity in neonatal streptozotocin-induced diabetic rats (n-STZ). Diabetes was induced by STZ injection into neonates Wistar rats. n-STZ diabetic rats were treated with chlorpropamide (200 mg kg(-1), 15 days, by gavage). The changes in mesenteric arteriolar and venular diameters were determined in anaesthetized control and n-STZ diabetic rats, before and after topical application of acetylcholine, bradykinin and sodium nitroprusside (SNP). We also assessed e-NOS expression (using polymerase chain reaction after reverse transcription of mRNAs into cDNAs) and NOS activity (conversion of L-arginine to citrulline) in the mesenteric vascular bed of chlorpropamide-treated n-STZ, vehicle-treated n-STZ, and control rats. In n-STZ, chlorpropamide treatment reduced high glycaemic levels, improved glucose tolerance and homoeostatic model assessment (HOMA-beta), and restored NOS activity. Impaired vasodilator responses of arterioles and venules to acetylcholine, bradykinin and SNP were partially corrected by chlorpropamide treatment in n-STZ. We concluded that improved metabolic control and restored NOS activity might be collaborating with improved microvascular reactivity found in chlorpropamide-treated n-STZ.


Assuntos
Glicemia/efeitos dos fármacos , Clorpropamida/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Óxido Nítrico Sintase/efeitos dos fármacos , Acetilcolina/farmacologia , Animais , Bradicinina/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Regulação da Expressão Gênica , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroprussiato/farmacologia , RNA Mensageiro , Ratos , Ratos Wistar , Estreptozocina
11.
Inflamm Res ; 55(1): 16-22, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16328103

RESUMO

OBJECTIVE: The effects of insulin on intercellular adhesion molecule (ICAM)-1-mediated leukocyte adhesion and migration were investigated. METHODS: Diabetic rats (alloxan, 42 mg/kg, i. v., 42 days), matching controls, and insulin (NPH, 2 IU/day for 12 days) treated diabetic rats were used. The internal spermatic fascia of the animals was used for direct vital microscopy of the microcirculation, and for quantitation of ICAM-1 expression by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Experiments were performed 2 h after the local injection of recombinant rat tumor necrosis factor-alpha (5 ng). RESULTS: Relative to controls (C), diabetic (D) rats exhibited a reduced number of adhered (D: 2.2 +/- 0.4 and C: 14.1 +/- 0.6 cells/100 microm venule length, P < 0.001) and migrated leukocytes (D: 1.1 +/- 0.3 and C: 6.3 +/- 0.6 cells/1,000 microm (2), P < 0.001) accompanied by low expression of ICAM-1 in postcapillary venules (D: 18 +/- 4 and C: 51 +/- 7 arbitrary units, P < 0.001). There were no differences in ICAM-1 mRNA levels (D: 1.01 +/- 0.05 and C: 1.18 +/- 0.09 ICAM-1/GAPDH ratio, P > 0.05). Treatment of diabetic rats with insulin restored the number of adhered (10.9 +/- 1.2 cells/100 microm venule length), and migrated leukocytes (4.0 +/- 0.3 cells/1,000 microm (2)) as well as ICAM-1 expression (45 +/- 3 arbitrary units). Levels of mRNA for ICAM-1 remained unchanged after treatment (1.15 +/- 0.04 ICAM-1/GAPDH ratio). CONCLUSION: Insulin modulates TNF-alpha-induced ICAM-1 expression on microvascular endothelium controlling, therefore, leukocyte adhesion and migration.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Insulina/metabolismo , Molécula 1 de Adesão Intercelular/biossíntese , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Adesão Celular , Diabetes Mellitus Experimental/terapia , Endotélio Vascular/metabolismo , Imuno-Histoquímica , Leucócitos/citologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo
12.
Peptides ; 26(8): 1454-62, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16042985

RESUMO

We investigated whether gender differences in renal damage in DOCA-salt hypertension are associated with effects of ovarian hormones and/or endothelin-1 (ET-1). Renal injuries and renal pre-pro-ET-1 mRNA expression were enhanced in male and female ovariectomized (OVX) DOCA rats versus female DOCA rats. Treatment with estrogen plus progesterone or progesterone, but not estrogen alone, attenuated renal damage and pre-pro-ET-1 mRNA expression in OVX DOCA rats. The ETA antagonist BMS182874 greatly ameliorated renal damage in male and OVX DOCA rats. In conclusion, the ovarian hormones have a protective role on the renal structural alterations in female DOCA rats by modulating effects of ET-1, via ETA receptors.


Assuntos
Endotelina-1/farmacologia , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Caracteres Sexuais , Animais , Compostos de Dansil/farmacologia , Desoxicorticosterona/antagonistas & inibidores , Desoxicorticosterona/química , Modelos Animais de Doenças , Endotelina-1/genética , Estrogênios/farmacologia , Feminino , Hidralazina/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Rim/química , Rim/fisiopatologia , Nefropatias/induzido quimicamente , Nefropatias/fisiopatologia , Masculino , Ovariectomia/métodos , Progesterona/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Receptor de Endotelina A/efeitos dos fármacos , Cloreto de Sódio
13.
Inflamm Res ; 54(4): 173-9, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15883740

RESUMO

OBJECTIVES: To investigate the effect of insulin on microvascular responses to inflammatory mediators in a model of type 2 diabetes mellitus. MATERIALS: We used the neonatal streptozotocin (n-STZ)-induced diabetes model. Diabetes was induced in male newborn (2-day-old) Wistar rats through STZ administration. Experiments were performed 10-12 weeks later. METHODS: Rats were divided into control (sham-injected) and study (n-STZ) groups. Using a closed-circuit video camera coupled to a microscope, changes in mesenteric arteriolar and venular diameters induced by topical application of the inflammatory mediators histamine, bradykinin and platelet-activating factor were assessed in chloral hydrate-anesthetized rats. TREATMENT: The n-STZ rats received NPH insulin s.c. for either 4 h or 12 days. RESULTS: Impaired arteriole and venule responses to the inflammatory mediators tested were observed in n-STZ rats. Both acute and chronic insulin treatment corrected the alterations. CONCLUSION: We conclude that insulin is beneficial, restoring microvascular reactivity to inflammatory mediators in type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Mediadores da Inflamação/farmacologia , Insulina/farmacologia , Microcirculação/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Glicemia/metabolismo , Pressão Sanguínea , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Insulina/sangue , Masculino , Fator de Ativação de Plaquetas/farmacologia , Ratos , Ratos Wistar , Estreptozocina/farmacologia
14.
Pol J Pharmacol ; 56(5): 617-9, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15591652

RESUMO

The inflammatory response is decreased in diabetic animals. After adrenals removal this impaired response in type 2 diabetic rats evaluated by pleurisy and vascular permeability tests was restored. Our studies demonstrate that endogenous corticosteroids play a partial role in the impaired inflammatory response in type 2 streptozotocin diabetic rats.


Assuntos
Corticosteroides/fisiologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Mediadores da Inflamação/fisiologia , Animais , Masculino , Ratos , Ratos Wistar
15.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;36(9): 1143-1158, Sept. 2003. ilus
Artigo em Inglês | LILACS | ID: lil-342861

RESUMO

The cardiovascular protective actions of estrogen are partially mediated by a direct effect on the vessel wall. Estrogen is active both on vascular smooth muscle and endothelial cells where functionally competent estrogen receptors have been identified. Estrogen administration promotes vasodilation in humans and in experimental animals, in part by stimulating prostacyclin and nitric oxide synthesis, as well as by decreasing the production of vasoconstrictor agents such as cyclooxygenase-derived products, reactive oxygen species, angiotensin II, and endothelin-1. In vitro, estrogen exerts a direct inhibitory effect on smooth muscle by activating potassium efflux and by inhibiting calcium influx. In addition, estrogen inhibits vascular smooth muscle cell proliferation. In vivo, 17ß-estradiol prevents neointimal thickening after balloon injury and also ameliorates the lesions occurring in atherosclerotic conditions. As is the case for other steroids, the effect of estrogen on the vessel wall has a rapid non-genomic component involving membrane phenomena, such as alteration of membrane ionic permeability and activation of membrane-bound enzymes, as well as the classical genomic effect involving estrogen receptor activation and gene expression


Assuntos
Humanos , Sistema Cardiovascular , Endotélio Vascular , Estrogênios , Músculo Liso Vascular , Sistema Cardiovascular , Endotélio Vascular , Músculo Liso Vascular
16.
Braz J Med Biol Res ; 36(9): 1143-58, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12937779

RESUMO

The cardiovascular protective actions of estrogen are partially mediated by a direct effect on the vessel wall. Estrogen is active both on vascular smooth muscle and endothelial cells where functionally competent estrogen receptors have been identified. Estrogen administration promotes vasodilation in humans and in experimental animals, in part by stimulating prostacyclin and nitric oxide synthesis, as well as by decreasing the production of vasoconstrictor agents such as cyclooxygenase-derived products, reactive oxygen species, angiotensin II, and endothelin-1. In vitro, estrogen exerts a direct inhibitory effect on smooth muscle by activating potassium efflux and by inhibiting calcium influx. In addition, estrogen inhibits vascular smooth muscle cell proliferation. In vivo, 17beta-estradiol prevents neointimal thickening after balloon injury and also ameliorates the lesions occurring in atherosclerotic conditions. As is the case for other steroids, the effect of estrogen on the vessel wall has a rapid non-genomic component involving membrane phenomena, such as alteration of membrane ionic permeability and activation of membrane-bound enzymes, as well as the classical genomic effect involving estrogen receptor activation and gene expression.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Estrogênios/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Sistema Cardiovascular/citologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Humanos , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiologia
17.
Inflamm Res ; 52(5): 191-8, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12813623

RESUMO

OBJECTIVE: To study the influence of sex on the responses of microvessels to vasoactive agents in experimental diabetes. MATERIALS: Diabetes was induced by alloxan (40 mg/kg, iv) in male and female Wistar rats (8-10-week-old). METHODS: Using an image splitter television microscope, mesenteric arteriolar and venular diameter changes induced by topically applied vasoactive agents (histamine, bradykinin, platelet activating factor-PAF, acetylcholine, sodium nitroprusside, noradrenaline and angiotensin II) were examined. RESULTS: Whereas the vasoconstrictor response to noradrenaline was equivalent in normal and diabetic animals, either female or male rats, an increased vasoconstrictor response to angiotensin II was observed in male but not in female diabetic rats in comparison with respective controls. Similarly to that observed in males, the dilator response of microvessels to topically applied bradykinin, histamine and PAF was impaired in female diabetic rats. Whereas reversal of the impaired responses to these agents was obtained by acute treatment of diabetic animals with insulin the altered responses to angiotensin II observed in male diabetic rats were not corrected. Differently from that observed in males, impaired response of microvessels to acetylcholine but not to sodium nitroprusside was observed in female diestrous diabetic rats; acute insulin treatment corrected it. CONCLUSIONS: We conclude that not all the alterations of the microvascular reactivity and the correction by insulin are gender dependent in diabetes.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Bradicinina/farmacologia , Ciclo Estral/efeitos dos fármacos , Feminino , Histamina/farmacologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Microcirculação/anatomia & histologia , Microcirculação/efeitos dos fármacos , Microcirculação/fisiopatologia , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Fator de Ativação de Plaquetas/farmacologia , Ratos , Ratos Wistar , Caracteres Sexuais , Útero/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
18.
Braz J Med Biol Res ; 35(9): 1061-8, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12219177

RESUMO

We determined if the increased vascular responsiveness to endothelin-1 (ET-1) observed in male, but not in female, DOCA-salt rats is associated with differential vascular mRNA expression of ET-1 and/or ET A/ET B receptors or with functional differences in Ca2+ handling mechanisms by vascular myocytes. Uninephrectomized male and female Wistar rats received DOCA and drinking water containing NaCl/KCl. Control rats received vehicle and tap water. Blood pressure and contractile responses of endothelium-denuded aortic rings to agents which induce Ca2+ influx and/or its release from internal stores were measured using standard procedures. Expression of mRNA for ET-1 and ET A/ET B receptors was evaluated by RT-PCR after isolation of total cell RNA from both aorta and mesenteric arteries. Systolic blood pressure was higher in male than in female DOCA rats. Contractions induced by Bay K8644 (which activates Ca2+ influx through voltage-operated L-type channels), and by caffeine, serotonin or ET-1 in Ca2+-free buffer (which reflect Ca2+ release from internal stores) were significantly increased in aortas from male and female DOCA-salt compared to control aortas. DOCA-salt treatment of male, but not female, rats statistically increased vascular mRNA expression of ET-1 and ET B receptors, but decreased the expression of ET A receptors. Molecular up-regulation of vascular ET B receptors, rather than differential changes in smooth muscle Ca2+ handling mechanisms, seems to account for the increased vascular reactivity to ET-1/ET B receptor agonists and higher blood pressure levels observed in male DOCA-salt rats.


Assuntos
Cálcio/metabolismo , Endotelina-1/genética , Hipertensão/metabolismo , Receptores de Endotelina/metabolismo , Caracteres Sexuais , Vasoconstrição , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil) , Animais , Cafeína/farmacologia , Agonistas dos Canais de Cálcio/farmacologia , Desoxicorticosterona , Feminino , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptor de Endotelina A , Receptor de Endotelina B , Receptores de Endotelina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;35(9): 1061-1068, Sept. 2002. ilus, graf
Artigo em Inglês | LILACS | ID: lil-325901

RESUMO

We determined if the increased vascular responsiveness to endothelin-1 (ET-1) observed in male, but not in female, DOCA-salt rats is associated with differential vascular mRNA expression of ET-1 and/or ET A/ET B receptors or with functional differences in Ca2+ handling mechanisms by vascular myocytes. Uninephrectomized male and female Wistar rats received DOCA and drinking water containing NaCl/KCl. Control rats received vehicle and tap water. Blood pressure and contractile responses of endothelium-denuded aortic rings to agents which induce Ca2+ influx and/or its release from internal stores were measured using standard procedures. Expression of mRNA for ET-1 and ET A/ET B receptors was evaluated by RT-PCR after isolation of total cell RNA from both aorta and mesenteric arteries. Systolic blood pressure was higher in male than in female DOCA rats. Contractions induced by Bay K8644 (which activates Ca2+ influx through voltage-operated L-type channels), and by caffeine, serotonin or ET-1 in Ca2+-free buffer (which reflect Ca2+ release from internal stores) were significantly increased in aortas from male and female DOCA-salt compared to control aortas. DOCA-salt treatment of male, but not female, rats statistically increased vascular mRNA expression of ET-1 and ET B receptors, but decreased the expression of ET A receptors. Molecular up-regulation of vascular ET B receptors, rather than differential changes in smooth muscle Ca2+ handling mechanisms, seems to account for the increased vascular reactivity to ET-1/ET B receptor agonists and higher blood pressure levels observed in male DOCA-salt rats


Assuntos
Animais , Masculino , Feminino , Ratos , Desoxicorticosterona , Endotelina-1 , Hipertensão , Receptores de Endotelina , Cloreto de Sódio , Vasoconstrição , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , RNA Mensageiro , Caracteres Sexuais
20.
Inflamm Res ; 50(9): 460-5, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11603851

RESUMO

OBJECTIVES AND DESIGN: To verify whether the inflammatory responses in animals with type 2 diabetes are altered to an extent similar to that in type 1 diabetes. MATERIALS: Male newborn (2 days old) Wistar rats were made diabetic by streptozotocin (160 mg/kg, i.p.) and used 8-10 weeks later (10 rats/group). METHODS: The inflammatory responses were evaluated using paw edema (induced by local injection of carrageenan or dextran), pleurisy (by pleural injection of carrageenan), increases in vascular permeability (induced by intradermal injection of histamine, serotonin and bradykinin) and leukocyte counts in peripheral blood and pleural exudate. RESULTS: Diabetic animals showed reduced inflammatory responses to carrageenan but not to dextran. The increase in vascular permeability induced by serotonin and bradykinin was reduced whereas that to histamine was not altered in diabetic compared to control rats. Although the pleural exudate was reduced, leukocyte counts were similar in diabetic and control rats. Insulin (2 IU, 4 h before), though effective in reducing blood sugar levels, did not restore the altered responses in diabetic rats. In contrast to that in rats with type 1 diabetes, in rats with type 2 diabetes, removal of the adrenal glands restored the reduced inflammatory responses. CONCLUSIONS: Insulin resistance in type 2 diabetic rats led to reduced inflammatory responses, which were partially corrected by adrenalectomy.


Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Inflamação/patologia , Adrenalectomia , Animais , Animais Recém-Nascidos , Permeabilidade Capilar/efeitos dos fármacos , Carragenina , Edema/induzido quimicamente , Edema/prevenção & controle , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Resistência à Insulina/fisiologia , Contagem de Leucócitos , Masculino , Pleurisia/induzido quimicamente , Pleurisia/prevenção & controle , Ratos , Ratos Wistar
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