RESUMEN
There is evidence that diets rich in salt or simple sugars as fructose are associated with abnormalities in blood pressure regulation. However, the mechanisms underlying pathogenesis of salt- and fructose-induced kidney damage and/or consequent hypertension yet remain largely unexplored. Here, we tested the role of oxidative state as an essential factor along with high salt and fructose treatment in causing hypertension. Fischer male rats were supplemented with a high-fructose diet (20% in water) for 20 weeks and maintained on high-salt diet (8%) associate in the last 10 weeks. Fructose-fed rats exhibited a salt-dependent hypertension accompanied by decrease in renal superoxide dismutase activity, which is the first footprint of antioxidant inactivation by reactive oxygen species (ROS). Metabolic changes and the hypertensive effect of the combined fructose-salt diet (20 weeks) were markedly reversed by a superoxide scavenger, Tempol (10 mg/kg, gavage); moreover, Tempol (50 mM) potentially reduced ROS production and abolished nuclear factor-kappa B (NF-κB) activation in human embryonic kidney HEK293 cells incubated with L-fructose (30 mM) and NaCl (500 mosmol/kg added). Taken together, our data suggested a possible role of oxygen radicals and ROS-induced activation of NF-κB in the fructose- and salt-induced hypertension associated with the progression of the renal disease.
Asunto(s)
Fructosa/efectos adversos , Hipertensión/metabolismo , Hipertensión/patología , FN-kappa B/metabolismo , Estrés Oxidativo , Cloruro de Sodio/efectos adversos , Antioxidantes/metabolismo , Presión Sanguínea , Peso Corporal , Óxidos N-Cíclicos/farmacología , Dieta , Conducta de Ingestión de Líquido , Conducta Alimentaria , Regulación de la Expresión Génica/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Células HEK293 , Humanos , Hipertensión/sangre , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/enzimología , Riñón/patología , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Marcadores de Spin , Superóxido Dismutasa/metabolismoRESUMEN
Overweight and obesity are conditions associated with an overall range of clinical health consequences, and they could be involved with the development of neuropsychiatric diseases, such as generalized anxiety disorder (GAD) and panic disorder (PD). A crucial brain nuclei involved on the physiological functions and behavioral responses, especially fear, anxiety and panic, is the dorsomedial hypothalamus (DMH). However, the mechanisms underlying the process whereby the DMH is involved in behavioral changes in obese rats still remains unclear. The current study further investigates the relation between obesity and generalized anxiety, by investigating the GABAA sensitivity to pharmacological manipulation within the DMH in obese rats during anxiety conditions. Male Wistar rats were divided in two experimental groups: the first was fed a control diet (CD; 11% w/w) and second was fed a high fat diet (HFD; 45% w/w). Animals were randomly treated with muscimol, a GABAA agonist and bicuculline methiodide (BMI), a GABAA antagonist. Inhibitory avoidance and escape behaviors were investigated using the Elevated T-Maze (ETM) apparatus. Our results revealed that the obesity facilitated inhibitory avoidance acquisition, suggesting a positive relation between obesity and the development of an anxiety-like state. The injection of muscimol (an anxiolytic drug), within the DMH, increased the inhibitory avoidance latency in obese animals (featuring an anxiogenic state). Besides, muscimol prolonged the escape latency and controlling the possible panic-like behavior in these animals. Injection of BMI into the DMH was ineffective to produce an anxiety-like effect in obese animals opposing the results observed in lean animals. These findings support the hypotheses that obese animals are susceptible to develop anxiety-like behaviors, probably through changes in the GABAergic neurotransmission within the DMH.
Asunto(s)
Ansiedad/etiología , Ansiedad/patología , Dieta Alta en Grasa/efectos adversos , Núcleo Hipotalámico Dorsomedial/metabolismo , Obesidad/etiología , Ácido gamma-Aminobutírico/metabolismo , Animales , Ansiedad/tratamiento farmacológico , Bicuculina/análogos & derivados , Bicuculina/farmacología , Reacción de Fuga/efectos de los fármacos , Agonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Muscimol/farmacología , Muscimol/uso terapéutico , Obesidad/complicaciones , Obesidad/psicología , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacosRESUMEN
A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine-a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 ± 16 bpm vs. IVA: 260 ± 14 bpm, p = 0.0005) and intrinsic HR (VEH: 369 ± 9 bpm vs. IVA: 326 ± 11 bpm, p = 0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 ± 4.6 vs. IVA: 29.8 ± 6.4; p > 0.05); HF (nu) (VEH: 75.1 ± 3.7 vs. IVA: 69.2 ± 5.8; p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal index; VEH: 0.91± 0.02 vs. IVA: 0.88 ± 0.03, p = 0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 ± 12 bpm vs. IVA: 207 ± 11 bpm, p < 0.0001), without affecting RSNA (VEH: 117 ± 16 vs. IVA: 120 ± 9 spikes/s, p = 0.9100) and mean arterial pressure (VEH: 70 ± 4 vs. IVA: 77 ± 6 mmHg, p = 0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart.
RESUMEN
The malnutrition in early life is associated with metabolic changes and cardiovascular impairment in adulthood. Deficient protein intake-mediated hypertension has been observed in clinical and experimental studies. In rats, protein malnutrition also increases the blood pressure and enhances heart rate and sympathetic activity. In this review, we discuss the effects of post-weaning protein malnutrition on the resting mean arterial pressure and heart rate and their variabilities, cardiovascular reflexes sensitivity, cardiac autonomic balance, sympathetic and renin-angiotensin activities and neural plasticity during adult life. These insights reveal an interesting prospect on the autonomic modulation underlying the cardiovascular imbalance and provide relevant information on preventing cardiovascular diseases.
RESUMEN
BACKGROUND: The mechanisms responsible for the cardiac dysfunction associated with dietary protein restriction (PR) are poorly understood. Thus, this study was designed to evaluate the effects of PR on calcium kinetics, basal and ß-adrenergic contractility in murine ventricular cardiomyocytes. METHODS: After breastfeeding male Fisher rats were distributed into a control group (CG, n = 20) and a protein-restricted group (PRG, n = 20), receiving isocaloric diets for 35 days containing 15% and 6% protein, respectively. Biometric and hemodynamic variables were measured. After euthanasia left ventricles (LV) were collected for histopathological evaluation, SERCA2a expression, cardiomyocytes contractility and Ca(2+)sparks analysis. RESULTS: PRG animals showed reduced general growth, increased heart rate and arterial pressure. These animals presented extracellular matrix expansion and disorganization, cardiomyocytes hypotrophy, reduced amplitudes of shortening and maximum velocity of contraction and relaxation at baseline and after ß-adrenergic stimulation. Reduced SERCA2a expression as well as higher frequency and lower amplitude of Ca(2+)sparks were observed in PRG cardiomyocytes. CONCLUSION: The observations reveal that protein restriction induces marked myocardial morphofunctional damage. The pathological changes of cardiomyocyte mechanics suggest the potential involvement of the ß-adrenergic system, which is possibly associated with changes in SERCA2a expression and disturbances in Ca(2+) intracellular kinetics.
Asunto(s)
Calcio/metabolismo , Proteínas en la Dieta/administración & dosificación , Regulación hacia Abajo , Miocitos Cardíacos/fisiología , Receptores Adrenérgicos beta/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Animales , Masculino , Miocitos Cardíacos/metabolismo , Ratas , Ratas Endogámicas F344RESUMEN
Protein restriction (PR) is associated with cardiovascular diseases. The purpose of this study was to investigate the effects on single ventricular cardiomyocyte contractile function of a short-term PR after weaning. Male Fischer rats that were 28 days old were randomly divided into a control group (CG, n = 16) and a protein-restricted group (PRG, n = 16). After weaning, CG and PRG animals received isocaloric diets containing 15 and 6% protein, respectively, for 35 days. Biometric parameters were then measured, and the hearts were removed for the analysis of contractile function and calcium transient in isolated cardiomyocytes of the left ventricule (LV), and the quantification of calcium and collagen fibers in LV myocardium. PRG animals had lower body weight (BW) and LV weight (LVW), an increased LVW to BW ratio and a higher proportion of collagen fibers than CG animals. PRG animals exhibited reduced tissue levels of calcium, reduced the length, width and volume of cardiomyocytes and their sarcomere length compared to CG animals. Cardiomyocytes from PRG animals had a lower amplitude of shortening, a slower time to the peak of shortening and a longer time to half-relaxation than those from the CG. Cardiomyocytes from PRG animals also presented a lower peak of calcium transient and a longer calcium transient decay time than CG animals. Taken together, the results indicate that short-term PR after weaning induces a marked structural remodeling of the myocardium parenchyma and stroma that coexists with contractile dysfunctions in single LV cardiomyocytes of rats, which is probably associated with pathological changes of the intracellular calcium kinetics, rather than inadequate available amounts of this mineral in cardiac tissue.
Asunto(s)
Calcio/metabolismo , Enfermedades Cardiovasculares/etiología , Dieta con Restricción de Proteínas/efectos adversos , Contracción Miocárdica/fisiología , Miocitos Cardíacos/fisiología , Desnutrición Proteico-Calórica/etiología , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Modelos Animales de Enfermedad , Ventrículos Cardíacos/citología , Masculino , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Desnutrición Proteico-Calórica/metabolismo , Desnutrición Proteico-Calórica/fisiopatología , Distribución Aleatoria , Ratas , Ratas Endogámicas F344 , DesteteRESUMEN
Previous studies have shown that postweaning protein restriction induces changes in the sympathetic nervous system in rats, leading to alterations in cardiovascular parameters. In addition, the renin-angiotensin system is also affected in these animals. Here, we hypothesized that adjustments in the interaction between the RAS and SNS underlie the cardiovascular adaptations observed in rats fed a low-protein diet. Thus, we evaluated the alterations in the mean arterial pressure (MAP) and heart rate of Fisher rats fed a protein-deficient diet before and after systemic administration of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II (Ang II) type 1 (AT(1)) receptor antagonist losartan alone or in combination with the α(1)-adrenergic receptor antagonist prazosin. Administration of enalapril or losartan decreased the MAP only of rats under protein restriction. Prazosin injection after the infusion of losartan caused a further decrease in the MAP of malnourished rats. In contrast, only the administration of prazosin elicited a reduction in the MAP of control animals. When the sequence of administration of the antagonists was inverted, infusion of prazosin in animals fed the standard or the low-protein diet induced a reduction in the MAP that was further decreased by the subsequent injection of losartan. Importantly, in both protocols the responses of malnourished animals to losartan were markedly greater when compared with the control group. Moreover, these animals presented lower levels of circulating Ang II and a reduced responsiveness to Ang II. In contrast, the expression of AT(1) receptors in the aorta of malnourished animals was increased. Thus, our data suggest that the renin-angiotensin system is an important factor supporting blood pressure in rats fed a low-protein diet and that the sympathetic nervous system activity in these animals is under strong influence of Ang II acting via AT(1) receptors.
Asunto(s)
Angiotensina II/metabolismo , Presión Arterial/efectos de los fármacos , Receptor de Angiotensina Tipo 1/metabolismo , Antagonistas de Receptores de Angiotensina/farmacología , Animales , Dieta con Restricción de Proteínas , Enalapril/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Losartán/farmacología , Masculino , Prazosina/farmacología , Ratas , Ratas Endogámicas F344 , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/fisiologíaRESUMEN
Pre- and postnatal protein deficiency may lead to decreased foetal intra-uterine development and postnatal growth, which is common in developing countries. The present study aimed to investigate the consequences of a low-protein intake during gestation and postnatally on adult female rats' offspring. Female rats were given either a control or a protein-deficient diet throughout the gestation and lactation periods. A subset of females was killed at day 20 of pregnancy for foetal and placental measurements. Another subset of females farrowed and the number, length, and weight of the offspring were measured. After weaning, the offspring received the same diet as their dams until 70 days of age. They were sacrificed, and some organs were weighed and collected for histomorphometrical analyses. Placental weight and size and foetal weight were lower in protein-deficient dams. The weight and length of pups at birth were also lower in the deficient group. The organs to body weight ratio were higher in the deficient animals at 70 days of age. The protein-deficient female offspring had a smaller ovarian area, greater numbers of primordial follicles and developing follicles per square millimetres of ovarian cortex, and no corpora lutea. The liver showed smaller nuclear diameter of the hepatocytes and height of the hepatocytes cords. The kidneys showed smaller cortical area with reduced glomerular number and diameter. These results provide the first evidence of the histomorphological changes of the association between gestational and postnatal protein deficiency in female rats' offspring.
Asunto(s)
Riñón/crecimiento & desarrollo , Hígado/crecimiento & desarrollo , Deficiencia de Proteína/fisiopatología , Proteínas/administración & dosificación , Animales , Cuerpo Lúteo/crecimiento & desarrollo , Dieta con Restricción de Proteínas , Femenino , Desarrollo Fetal , Tamaño de los Órganos , Folículo Ovárico/crecimiento & desarrollo , Placentación , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
1. In the present study, we evaluated the autonomic balance of the heart in protein/energy-undernourished rats. 2. Rats were divided into two groups according to the diet they received after weaning: (i) the control group (n=16), given a 15% protein diet, and (ii) the malnourished group (n=14), fed a 6% protein diet. Cardiovascular recordings were made and, through selective autonomic blockade, the tonic autonomic balance, cardiac autonomic index and the power spectrum of heart rate (HR) variability were determined. 3. Muscarinic receptor blockade with methylatropine (5.0 mg/kg, i.v.) increased HR in the control group (371 ± 6 vs 427 ± 15 b.p.m. before and after drug administration, respectively), but not the malnourished group (438 ± 24 vs 472 ± 38 b.p.m. before and after drug administration, respectively). Inhibition of ß(1)-adrenoceptors with metoprolol (2.0 mg/kg, i.v.) reduced HR in malnourished rats (428 ± 24 vs 355 ± 16 b.p.m. before and after drug administration, respectively), but had no effect on the HR of the control group (363 ± 8 vs 362 ± 7 b.p.m. before and after drug administration, respectively). Double autonomic blockade by inhibiting both muscarinic cholinoceptors and ß(1)-adrenoceptors reduced HR in the malnourished group (428 ± 24 vs 342 ± 14 b.p.m.) but had no effect on HR in the control group (371 ± 6 vs 382 ± 6 b.p.m.). 4. Sympathetic tone was augmented in malnourished compared with control rats (131 ± 17 vs 41 ± 11 b.p.m., respectively), whereas parasympathetic tone was reduced in malnourished compared with control rats (-4 ± 4 vs 22 ± 9 b.p.m., respectively). 5. The ratio of oscillations in HR induced by sympathetic and parasympathetic activity was higher in malnourished compared with control rats (0.43 ± 0.03 vs 0.34 ± 0.02, respectively). 6. The results of the present study indicate that protein malnutrition after weaning increases sympathetic activity and reduces vagal activity to the heart in rats. These data provide a new perspective on the pathophysiology of metabolic and cardiovascular diseases associated with protein malnutrition, especially with regard to autonomic modulation.
Asunto(s)
Sistema Nervioso Autónomo/fisiología , Enfermedades Cardiovasculares/fisiopatología , Desnutrición Proteico-Calórica/fisiopatología , Animales , Derivados de Atropina/administración & dosificación , Derivados de Atropina/farmacología , Sistema Nervioso Autónomo/efectos de los fármacos , Dieta con Restricción de Proteínas , Electrocardiografía , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Metoprolol/administración & dosificación , Metoprolol/farmacología , Parasimpatolíticos/administración & dosificación , Parasimpatolíticos/farmacología , Ratas , Ratas Endogámicas F344 , Simpaticolíticos/administración & dosificación , Simpaticolíticos/farmacología , DesteteRESUMEN
Earlier studies from the authors' laboratory showed that malnourishment induces alterations in the cardiovascular homeostasis increasing the basal mean arterial pressure and heart rate. In this study, the authors evaluated whether the sympathetic and parasympathetic efferent activities contribute to changes in the cardiovascular homeostasis through altered modulation of the arterial baroreflex of malnourished rats. After weaning, male Fischer rats were given 15% (Normal Protein--NP) or 6% (Low Protein--LP) protein diet for 35 d. The baroreflex gain and latency were evaluated before and after selective autonomic blockades in control and malnourished rats. It was observed that malnourishment affected the baroreflex gain in response to activation and deactivation of the arterial baroreflex. Moreover, malnourished rats showed increased baroreflex latency as compared to that of control rats. Regarding the autonomic efferent activity directed to the heart, the data showed increased sympathetic and decreased parasympathetic efferent activities in malnourished rats, and such alterations could be related to the observed changes in the arterial baroreflex gain as well as in the basal mean arterial pressure and heart rate.
Asunto(s)
Derivados de Atropina/farmacología , Barorreflejo/efectos de los fármacos , Metoprolol/farmacología , Proteínas/metabolismo , Animales , Arterias/patología , Peso Corporal/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Regulación de la Expresión Génica , Masculino , Presión , Ratas , Ratas Endogámicas F344RESUMEN
Epidemiologic and experimental data suggest that excess iron may contribute to the development of cardiovascular diseases (CVD). Because increased LDL cholesterol, decreased HDL cholesterol and alteration of systolic blood pressure (SBP) have all been implicated as risk factors for atherosclerosis and related CVD, the present study was designed to determine whether excess iron alters serum lipids and SBP in control and hypercholesterolemic rats. Female Fischer rats were divided into four groups. The control group (C) was fed the control diet, the CI group was fed the control diet and given iron dextran injections, the hypercholesterolemic group (H) was fed a 1 g/100 g cholesterol diet, and the HI group was fed the cholesterol diet and given iron dextran injections. The rats were fed the diets for 8 wk and iron dextran injections were given during wk 6 at doses of 10 mg/d for 5 d. Excess iron reduced (P < 0.01) plasma total cholesterol in rats fed the cholesterol diet (5.31 +/- 0.83 and 3.17 +/- 0.31 mmol/L for H and HI, respectively). Excess iron also resulted in a redistribution of cholesterol among the various lipoprotein fractions, with an increase (P < 0.01) in HDL cholesterol (0.56 +/- 0.12 and 0.85 +/- 0.16 mmol/L for H and HI, respectively) and a decrease (P < 0.01) in LDL cholesterol (4.49 +/- 0.77 and 2.09 +/- 0.26 mmol/L for H and HI, respectively). This redistribution also occurred in the rats fed the control diet. The treatments did not affect SBP or heart rate. The high cholesterol diet affected iron homeostasis; group H had lower transferrin saturation than group C (P < 0.01); group HI had a lower serum iron concentration than group CI but did not differ from group H (P < 0.05). Therefore, we conclude that if iron has any effect on CVD, it is not through its influence on serum lipids and blood pressure.