RESUMEN
BACKGROUND: Hypertension has seriously affected a large part of the adult and elderly population. The complications caused by hypertension are important risk factors for cardiovascular disease accidents. Capsaicin, a pungent component of chili pepper has been revealed to improve hypertension. However, its potential mechanism in improving hypertension remains to be explored. PURPOSE: In the present study, we aimed to investigate whether capsaicin could attenuate the SIRT1/NF-κB/MAPKs pathway in the paraventricular nucleus of hypothalamus (PVN). METHODS: We used spontaneous hypertensive rats (SHRs) as animal model rats. Micro osmotic pump was used to give capsaicin through PVN for 28 days, starting from age12-week-old. RESULTS: The results showed that capsaicin significantly reduced blood pressure from the 16th day of infusion onward. At the end of the experimental period, we measured cardiac hypertrophy index and the heart rate (HR), and the results showed that the cardiac hypertrophy and heart rate of rats was significantly improved upon capsaicin chronic infusion. Norepinephrine (NE) and epinephrine (EPI) in plasma of SHRs treated with capsaicin were also decreased. Additionally, capsaicin increased the protein expression and number of positive cells of SIRT1 and the 67-kDa isoform of glutamate decarboxylase (GAD67), decreased the production of reactive oxygen species (ROS), number of positive cells of NOX2, those of Angiotensin Converting Enzyme (ACE) and p-IKKß, tyrosine hydroxylase (TH), the gene expression levels of NOX4 and pro-inflammatory cytokines. Capsaicin also decreased the relative protein expressions of protein in MAPKs pathway. CONCLUSION: Current data indicated that capsaicin within the PVN improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the PVN of SHRs, supporting its potential as candidate drug for preventing and improving hypertension.
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Hipertensión , FN-kappa B , Anciano , Humanos , Ratas , Animales , FN-kappa B/metabolismo , Núcleo Hipotalámico Paraventricular , Capsaicina/farmacología , Sirtuina 1/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/metabolismo , Ratas Endogámicas SHRRESUMEN
SCOPE: Gut dysbiosis and dysregulation of the gut-brain-axis contributes to the pathogenesis of hypertension. Vitamin C (VC) is a common dietary supplement that shows the ability to lower the elevated blood pressure in hypertensive animals. Thus, the hypothesis that the gut microbiota is involved in the anti-hypertensive effect of VC is proposed. METHODS AND RESULTS: The changes of the gut microbiota and pathology in a spontaneously hypertensive rat (SHR) model after daily oral intake of VC in dosage of 200 or 1000 mg kg-1 are examined. After 4 weeks, the elevated blood pressure of SHRs in both VC-treated groups is attenuated. Sequencing of the gut microbiota shows improvement in its diversity and abundance. Bioinformatic analysis suggests restored metabolism and biosynthesis-related functions of the gut, which are confirmed by the improvement of gut pathology and integrity. Analysis of the hypothalamus paraventricular nucleus (PVN), the central pivot of blood pressure regulation, also shows reduced inflammatory responses and oxidative stress. CONCLUSIONS: The reduced blood pressure, enriched gut microbiota, improved gut pathology and integrity, and reduced inflammatory responses and oxidative stress in the PVN together suggest that the anti-hypertensive effects of VC involve reshaping of gut microbiota composition and function.
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Antihipertensivos/farmacología , Ácido Ascórbico/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Administración Oral , Animales , Antihipertensivos/administración & dosificación , Ácido Ascórbico/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Hipertensión/microbiología , Intestinos/efectos de los fármacos , Intestinos/patología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/patología , Ratas Endogámicas SHR , Ratas WistarRESUMEN
AIMS: Exercise and food supplement of vitamin C (VC) are beneficial to human health, especially for those who suffer from hypertension. Here we tend to explore if gut microflora is involved in the anti-hypertensive effects of exercise and VC-supplement therapies. MATERIALS AND METHODS: With the spontaneously hypertensive rat (SHR) model, the small intestine pathology and the fecal microbiota was analyzed along with the pro- and anti-inflammatory cytokines (PICs and AICs) and reactive oxygen species (ROS) in the hypothalamus paraventricular nucleus (PVN) and intestine. KEY FINDINGS: We found that both exercise and VC intake, individually or combined, were able to alleviate the blood pressure in the SHRs comparing to the normotensive control Wistar-kyoto (WKY) rats. The expression level of PICs in the PVN and intestine of the SHRs was down-regulated while the AICs were up-regulated after treatments, together with down-regulation of ROS in the PVN. At meantime, the gut pathology was dramatically improved in the SHRs with exercise training or VC intake. Analysis of the gut microflora revealed significant changes in their composition. Several important micro-organisms that were deficient in the SHRs were found up-regulated by the treatments, including Turicibacter and Romboutsia which are involved in the short-chain fatty acid production. SIGNIFICANCE: Exercise training and VC intake individually can modify the gut microflora composition and improve the inflammatory state in both PVN and intestine, which contribute to their anti-hypertensive function. Combination of the two treatments enhanced their effects and worth to be considered as a non-medical aid for the hypertensive patients.
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Antioxidantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Suplementos Dietéticos , Microbioma Gastrointestinal/efectos de los fármacos , Hipertensión/prevención & control , Condicionamiento Físico Animal , Animales , Presión Sanguínea , Terapia Combinada , Citocinas/metabolismo , Hipertensión/etiología , Hipertensión/patología , Estrés Oxidativo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Berberine (BBR), a Chinese traditional herbal medicine, has many pharmacologic benefits such as anti-inflammation and anti-oxidation. It is widely used in clinical treatment of cardiovascular diseases such as hypertension. However, the mechanism of how BBR attenuates hypertension through affecting central neural system is not clear. PURPOSE: This study was designed to determine whether chronic infusion of BBR into the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway. METHODS: Two-kidney, one-clip (2K1C) renovascular hypertensive rats were randomly assigned and treated with bilateral PVN infusion of BBR (2µg/h) or vehicle (artificial cerebrospinal fluid) via osmotic minipumps for 28 days. RESULTS: 2K1C rats showed higher mean arterial pressure (MAP) and PVN Fra-like activity, plasma levels of norepinephrine (NE), PVN levels of NOX2, NOX4, Erk1/2 and iNOS, and lower PVN levels of copper/zinc superoxide dismutase (Cu/Zn-SOD). Chronic infusion of BBR reduced MAP, PVN Fra-like activity and plasma levels of NE, reduced NOX2, NOX4, Erk1/2, iNOS and induced Cu/Zn-SOD in the PVN. CONCLUSIONS: These results suggest that BBR attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway in 2K1C renovascular hypertensive rats.
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Berberina/farmacología , Hipertensión/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Animales , Presión Arterial , Masculino , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 4/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Norepinefrina/sangre , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa-1/metabolismoRESUMEN
High salt intake leads to an increase in some proinflammatory cytokines and neurotransmitters involved in the pathogenesis of hypertension. The purpose of this work was to know if oral administration of anti-oxidant and free-radical scavenger CoQ10 may attenuate high salt-induced hypertension via regulating neurotransmitters and cytokines in the hypothalamic paraventricular nucleus (PVN). Adult male Sprague-Dawley (SD) rats were fed with a normal salt diet (NS, 0.3% NaCl) or a high salt diet (HS, 8% NaCl) for 15 weeks to induce hypertension. These rats received CoQ10 (10 mg/kg/day) dissolved in olive oil was given by gavage (10 mg/kg/day) for 15 weeks. HS resulted in higher mean arterial pressure (MAP) and the sympathetic nerve activity (RSNA). These HS rats had higher PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), interleukin (IL)-1ß, NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), IL-10, copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. CoQ10 supplementation reduced NE, TH, IL-1ß, NOX2 and NOX4 in the PVN, and induced IL-10, Cu/Zn-SOD and GAD67 in the PVN. These findings suggest that CoQ10 supplementation restores neurotransmitters and cytokines in the PVN, thereby attenuating high salt-induced hypertension.
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Antioxidantes/administración & dosificación , Depuradores de Radicales Libres/administración & dosificación , Hipertensión/tratamiento farmacológico , Núcleo Hipotalámico Paraventricular/metabolismo , Ubiquinona/análogos & derivados , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Hipertensión/patología , Interleucina-1beta/metabolismo , NADPH Oxidasa 2/metabolismo , Neurotransmisores/metabolismo , Norepinefrina/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Ratas , Sales (Química)/toxicidad , Superóxido Dismutasa-1/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Ubiquinona/administración & dosificaciónRESUMEN
AIMS: High salt-induced oxidative stress plays an important role in the development of hypertension. Alpha lipoic acid (ALA) is extensively recognized as having a powerful superoxide inhibitory property. In this study, we determined whether ALA supplementation attenuates oxidative stress in hypothalamic paraventricular nucleus (PVN), decreases the sympathetic activity and arterial pressure in high salt-induced hypertension by cross-talking with renin-angiotensin system (RAS) and pro-inflammatory cytokines (PICs). METHODS: Male Wistar rats were administered a normal-salt diet (NS, 0.3% NaCl) or a high-salt diet (HS, 8.0% NaCl) for 8 weeks. These rats received ALA (60mg/kg) dissolved in vehicle (0.9% saline) or an equal voleme of vehicle, by gastric perfusion for 9 weeks. RESULTS: High salt intake resulted in higher renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP). These rats also had higher levels of superoxide, gp91(phox), gp47(phox) (subunits of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), angiotensin II type1 receptor (AT1-R), interleukin-1beta (IL-1ß), interleukin-6 (IL-6), and lower levels of interleukin-10 (IL-10) and copper/zinc superoxide dismutase (Cu/Zn-SOD) than control animals. Treatment with ALA significantly attenuated the levels of superoxide, gp91(phox), gp47(phox), ACE, AT1-R, IL-1ß and IL-6, increased the levels of IL-10 and Cu/Zn-SOD, and decreased MAP and RSNA compared with high-salt induced hypertensive rats. The mRNA expression of gp47(phox) and gp91(phox) are in accordance with their protein expression. CONCLUSION: These findings suggest that supplementation of ALA obviously decreases the sympathetic activity and arterial pressure in high salt-induced hypertension by improving the superoxide inhibitory property, suppressing the activation of RAS and restoring the balance between pro- and anti-inflammatory cytokines in the PVN.
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Antioxidantes/farmacología , Hipertensión/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cloruro de Sodio Dietético/toxicidad , Sistema Nervioso Simpático/efectos de los fármacos , Ácido Tióctico/farmacología , Animales , Antioxidantes/metabolismo , Presión Arterial/efectos de los fármacos , Hipertensión/inducido químicamente , Riñón/efectos de los fármacos , Riñón/inervación , Masculino , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Salusin ß is a multifunctional bioactive peptide and is considered as a promising candidate biomarker for predicting atherosclerotic cardiovascular diseases. The present study was designed to investigate the roles and mechanisms of salusin ß in the paraventricular nucleus (PVN) in attenuating hypertension and hypothalamic inflammation and whether central salusin ß blockade has protective effects in essential hypertension. Normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were used in this study. The rats were chronic PVN infusion either specific salusin ß blocker, antisalusin ß IgG (SIgG), or control IgG (CIgG) for 2 weeks. Hypertensive rats had significantly increased salusin ß expression compared with normotensive rats. Central blockade of salusin ß attenuated hypertension, reduced circulating norepinephrine (NE) levels, and improved cardiac hypertrophy and function in hypertensive rats. Salusin ß blockade significantly reduced proinflammatory cytokines (PICs), nuclear factor-kappa B (NF-κB) activity, reactive oxygen species (ROS) levels, and altered renin-angiotensin system (RAS) components in the PVN of hypertensive rats. These findings suggest that the beneficial effects of salusin ß blockade in essential hypertension are possibly due to down-regulate of inflammatory molecules and ROS in the PVN.
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Hipertensión/etiología , Hipertensión/metabolismo , Hipotálamo/metabolismo , Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Presión Sanguínea/efectos de los fármacos , Cardiomegalia/diagnóstico , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/etiología , Citocinas/metabolismo , Hipertensión Esencial , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/fisiopatología , Hipotálamo/efectos de los fármacos , Hipotálamo/patología , Inmunoglobulina G/farmacología , Inflamación/tratamiento farmacológico , Mediadores de Inflamación/metabolismo , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasa 2 , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Ratas , Ratas Endogámicas SHR , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the progression of heart failure (HF). We investigated whether cyclooxygenase-2 (COX-2) inhibition in the PVN attenuates the activities of sympathetic nervous system (SNS) and renin-angiotensin system (RAS) in rats with adriamycin-induced heart failure. METHODOLOGY/PRINCIPAL FINDING: Heart failure was induced by intraperitoneal injection of adriamycin over a period of 2 weeks (cumulative dose of 15 mg/kg). On day 19, rats received intragastric administration daily with either COX-2 inhibitor celecoxib (CLB) or normal saline. Treatment with CLB reduced mortality and attenuated both myocardial atrophy and pulmonary congestion in HF rats. Compared with the HF rats, ventricle to body weight (VW/BW) and lung to body weight (LW/BW) ratios, heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular peak systolic pressure (LVPSP) and maximum rate of change in left ventricular pressure (LV±dp/dtmax) were improved in HF+CLB rats. Angiotensin II (ANG II), norepinephrine (NE), COX-2 and glutamate (Glu) in the PVN were increased in HF rats. HF rats had higher levels of ANG II and NE in plasma, higher level of ANG II in myocardium, and lower levels of ANP in plasma and myocardium. Treatment with CLB attenuated these HF-induced changes. HF rats had more COX-2-positive neurons and more corticotropin releasing hormone (CRH) positive neurons in the PVN than did control rats. Treatment with CLB decreased COX-2-positive neurons and CRH positive neurons in the PVN of HF rats. CONCLUSIONS: These results suggest that PVN COX-2 may be an intermediary step for PVN neuronal activation and excitatory neurotransmitter release, which further contributes to sympathoexcitation and RAS activation in adriamycin-induced heart failure. Treatment with COX-2 inhibitor attenuates sympathoexcitation and RAS activation in adriamycin-induced heart failure.
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Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Insuficiencia Cardíaca/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Angiotensina II/sangre , Angiotensina II/metabolismo , Animales , Factor Natriurético Atrial/sangre , Factor Natriurético Atrial/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Doxorrubicina/efectos adversos , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/patología , Miocardio/metabolismo , Neurotransmisores/metabolismo , Norepinefrina/sangre , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , RatasRESUMEN
1. Several groups have reported that melatonin produces a significant decrease in blood pressure in mammals and that pinealectomy in rats causes hypertension. The purpose of the present study was to investigate the effects of melatonin and bicuculline methiodide on the blood pressure of rats, both in the developing and fully developed stage of stress-induced hypertension (SIH). 2. Rats with SIH were generated by mild electric foot shocks for 15 days, after which tail arterial systolic pressure and plasma angiotensin (Ang) II levels were measured. The effects of melatonin injections (i.p. or i.c.v.) on mean arterial pressure (MAP) in rats with SIH were also determined. 3. Pretreatment with 1 mg/kg, i.p., melatonin significantly diminished the elevated tail arterial systolic pressure and plasma AngII levels caused by 15 days stress. The suppressive effects of melatonin were blocked by i.p. injection of 1 mg/kg bicuculline methiodide, an antagonist of the GABA(A) receptor. 4. Intraperitoneal (0.2, 0.5 and 1 mg/kg) or i.c.v. (0.15 and 1.5 microg/3 microL) injection of melatonin produced a dose-dependent lowering of MAP in rats with SIH. The antihypertensive response induced by melatonin was blocked by injection of both 1 mg/kg, i.p., and 1.5 x 10(6) microg/3 microL, i.c.v., bicuculline methiodide. 5. In conclusion, melatonin not only prevents increases in blood pressure during the developing stage of SIH, but can also reduce the blood pressure of rats that have already developed SIH. The antihypertensive effect of melatonin may be mediated by GABA(A) receptors through inhibition of plasma AngII levels.
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Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Melatonina/farmacología , Receptores de GABA-A/fisiología , Estrés Psicológico/complicaciones , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Bicuculina/administración & dosificación , Bicuculina/análogos & derivados , Ventrículos Cerebrales/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/fisiopatología , Inyecciones Intraperitoneales , Inyecciones Intraventriculares , Masculino , Melatonina/administración & dosificación , Melatonina/uso terapéutico , Distribución Aleatoria , Ratas , Ratas Wistar , Receptores de GABA-A/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/fisiopatologíaRESUMEN
OBJECTIVE: To investigate the changes of xanthine oxidase (XOD), myeloperoxidase (MPO) and mitochondrial succinate dehydrogenase (SDH) in the testis and the protective effect of ganoderma lucidum spores on the testicular tissue of rats with non-insu- lin-dependent diabetes mellitus (NIDDM). METHODS: Fifty male Wistar rats were divided randomly into a model, a ganoderma and a normal control group, the first two groups injected with 2% STZ (25 mg/kg) through the peritoneum, and the last one with half-and-half sodium citrate/citrate buffer solution. Two weeks after normal diet, glucose tolerance tests were performed and the rats with abnormal glucose tolerance in the model and ganoderma groups received high-fat and high-carbohydrate food, the latter given ganoderma lycium spores (250 mg/kg x d) in addition, both for 10 weeks and all rats fed alone. Glucose tolerance tests were repeated 1 day before the end of the experiment and the testes of the rats were harvested for the determination of XOD, MPO and SDH. RESULTS: SDH was significantly lower (P < 0.05) while XOD and MPO significantly higher in the model group than in the ganoderma and control groups (P < 0.05). The model rats exhibited abnormal convoluted seminiferous tubules, indistinct parietal layers, decreased or abolished gonepoiesis, luminal peripheral fibrous tissue (interstitial substance) accrementition, basal lamina thickening, and vessel wall fibrous tissue accrementition and sclerosis. CONCLUSION: Ganoderma lucidum spores can protect the testis of diabetic rats by reducing free radical-induced damage to the testicular tissue and enhancing the activity of SDH.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Reishi , Testículo/metabolismo , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Masculino , Peroxidasa/metabolismo , Ratas , Ratas Wistar , Esporas Fúngicas , Succinato Deshidrogenasa/metabolismo , Xantina Oxidasa/metabolismoRESUMEN
The expression of proinflammatory cytokines increases in the hypothalamus of rats with heart failure (HF). The pathophysiological significance of this observation is unknown. We hypothesized that hypothalamic proinflammatory cytokines upregulate the activity of central neural systems that contribute to increased sympathetic nerve activity in HF, specifically, the brain renin-angiotensin system (RAS) and the hypothalamic-pituitary-adrenal (HPA) axis. Rats with HF induced by coronary ligation and sham-operated controls (SHAM) were treated for 4 wk with a continuous intracerebroventricular infusion of the cytokine synthesis inhibitor pentoxifylline (PTX, 10 microg/h) or artificial cerebrospinal fluid (VEH). In VEH-treated HF rats, compared with VEH-treated SHAM rats, the hypothalamic expression of proinflammatory cytokines was increased, along with key components of the brain RAS (renin, angiotensin-converting enzyme, angiotensin type 1 receptor) and corticotropin-releasing hormone, the central indicator of HPA axis activation, in the paraventricular nucleus (PVN) of the hypothalamus. The expression of other inflammatory/excitatory mediators (superoxide, prostaglandin E(2)) was also increased, along with evidence of chronic neuronal excitation in PVN. VEH-treated HF rats had higher plasma levels of norepinephrine, ANG II, interleukin (IL)-1beta, and adrenocorticotropic hormone, increased left ventricular end-diastolic pressure, and increased wet lung-to-body weight ratio. With the exception of plasma IL-1beta, an indicator of peripheral proinflammatory cytokine activity, all measures of neurohumoral excitation were significantly lower in HF rats treated with intracerebroventricular PTX. These findings suggest that the increase in brain proinflammatory cytokines observed in rats with ischemia-induced HF is functionally significant, contributing to neurohumoral excitation by activating brain RAS and the HPA axis.
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Antiinflamatorios/farmacología , Citocinas/metabolismo , Insuficiencia Cardíaca/metabolismo , Hipotálamo/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Isquemia Miocárdica/complicaciones , Pentoxifilina/farmacología , Potenciales de Acción , Hormona Adrenocorticotrópica/metabolismo , Angiotensina II/metabolismo , Animales , Antiinflamatorios/administración & dosificación , Ciclooxigenasa 2/metabolismo , Citocinas/sangre , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Hipotálamo/metabolismo , Hipotálamo/fisiopatología , Infusiones Parenterales , Interleucina-1beta/metabolismo , Masculino , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/fisiopatología , Norepinefrina/metabolismo , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/metabolismo , Pentoxifilina/administración & dosificación , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Sistema Renina-Angiotensina/efectos de los fármacos , Superóxidos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , UltrasonografíaRESUMEN
Aldosterone acts upon mineralocorticoid receptors in the brain to increase blood pressure and sympathetic nerve activity, but the mechanisms are still poorly understood. We hypothesized that aldosterone increases sympathetic nerve activity by upregulating the renin-angiotensin system (RAS) and oxidative stress in the brain, as it does in peripheral tissues. In Sprague-Dawley rats, aldosterone (Aldo) or vehicle (Veh) was infused for 1 wk via an intracerebroventricular (ICV) cannula, while RU-28318 (selective mineralocorticoid receptor antagonist), Tempol (superoxide dismutase mimetic), losartan [angiotensin II type 1 receptor (AT(1)R) antagonist], or Veh was infused simultaneously via a second ICV cannula. After 1 wk of ICV Aldo, plasma norepinephrine was increased and mean arterial pressure was slightly elevated, but heart rate was unchanged. These effects were ameliorated by ICV infusion of RU-28318, Tempol or losartan. Aldo increased expression of AT(1)R and angiotensin-converting enzyme (ACE) mRNA in hypothalamic tissue. RU-28318 minimized and Tempol prevented the increase in AT(1)R mRNA; RU-28318 prevented the increase in ACE mRNA. Losartan had no effect on AT(1)R or ACE mRNA. Immunohistochemistry revealed Aldo-induced increases in dihydroethidium staining (indicating oxidative stress) and Fra-like activity (indicating neuronal excitation) in neurons of the hypothalamic paraventricular nucleus (PVN). RU-28318 prevented the increases in superoxide and Fra-like activity in PVN; Tempol and losartan minimized these effects. Acute ICV infusions of sarthran (AT(1)R antagonist) or Tempol produced greater sympathoinhibition in Aldo-treated than in Veh-treated rats. Thus aldosterone upregulates key elements of brain RAS and induces oxidative stress in the hypothalamus. Aldosterone may increase sympathetic nerve activity by these mechanisms.
Asunto(s)
Aldosterona/farmacología , Química Encefálica/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Electrofisiología , Técnica del Anticuerpo Fluorescente , Frecuencia Cardíaca/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiología , Inmunohistoquímica , Inyecciones Intraventriculares , Masculino , Antagonistas de Receptores de Mineralocorticoides , Peptidil-Dipeptidasa A/biosíntesis , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Superóxidos/metabolismoRESUMEN
BACKGROUND CONTEXT: Spinal manipulation (SM) is a form of manual therapy used clinically to treat patients with low back and neck pain. The most common form of this maneuver is characterized as a high-velocity (duration <150 ms), low-amplitude (segmental translation <2 mm, rotation <4 degrees , and applied force 220-889 N) impulse thrust (high-velocity, low-amplitude spinal manipulation [HVLA-SM]). Clinical skill in applying an HVLA-SM lies in the practitioner's ability to control the duration and magnitude of the load (ie, the rate of loading), the direction in which the load is applied, and the contact point at which the load is applied. Control over its mechanical delivery is presumably related to its clinical effects. Biomechanical changes evoked by an HVLA-SM are thought to have physiological consequences caused, at least in part, by changes in sensory signaling from paraspinal tissues. PURPOSE: If activation of afferent pathways does contribute to the effects of an HVLA-SM, it seems reasonable to anticipate that neural discharge might increase or decrease in a nonlinear fashion as the thrust duration approaches a threshold value. We hypothesized that the relationship between the duration of an impulsive thrust to a vertebra and paraspinal muscle spindle discharge would be nonlinear with an inflection near the duration of an HVLA-SM delivered clinically (<150 ms). In addition, we anticipated that muscle spindle discharge would be more sensitive to larger amplitude thrusts. STUDY DESIGN/SETTING: A neurophysiological study of spinal manipulation using the lumbar spine of a feline model. METHODS: Impulse thrusts (duration: 12.5, 25, 50, 100, 200, and 400 ms; amplitude 1 or 2 mm posterior to anterior) were applied to the spinous process of the L6 vertebra of deeply anesthetized cats while recording single unit activity from dorsal root filaments of muscle spindle afferents innervating the lumbar paraspinal muscles. A feedback motor was used in displacement control mode to deliver the impulse thrusts. The motor's drive arm was securely attached to the L6 spinous process via a forceps. RESULTS: As thrust duration became shorter, the discharge of the lumbar paraspinal muscle spindles increased in a curvilinear fashion. A concave-up inflection occurred near the 100-ms duration eliciting both a higher frequency discharge compared with the longer durations and a substantially faster rate of change as thrust duration was shortened. This pattern was evident in paraspinal afferents with receptive fields both close and far from the midline. Paradoxically, spindle afferents were almost twice as sensitive to the 1-mm compared with the 2-mm amplitude thrust (6.2 vs. 3.3 spikes/s/mm/s). This latter finding may be related to the small versus large signal range properties of muscle spindles. CONCLUSIONS: The results indicate that the duration and amplitude of a spinal manipulation elicit a pattern of discharge from paraspinal muscle spindles different from slower mechanical inputs. Clinically, these parameters may be important determinants of an HVLA-SM's therapeutic benefit.
Asunto(s)
Vértebras Lumbares/fisiología , Manipulación Quiropráctica/métodos , Husos Musculares/fisiología , Músculo Esquelético/fisiología , Soporte de Peso/fisiología , Animales , Gatos , Estimulación Eléctrica , Modelos Animales , Músculo Esquelético/inervación , Conducción Nerviosa/fisiología , Neuronas Aferentes/fisiología , Umbral Sensorial/fisiología , Raíces Nerviosas Espinales/fisiologíaRESUMEN
Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-alpha in heart failure (HF) rats. TNF-alpha and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E2 by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle (drinking water). Eplerenone-treated HF rats had lower plasma TNF-alpha, interleukin (IL)-1beta and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity (indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-alpha, IL-1beta, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+vehicle versus sham+vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF+eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E2 in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.
Asunto(s)
Citocinas/biosíntesis , Insuficiencia Cardíaca/fisiopatología , Hipotálamo/fisiopatología , Mediadores de Inflamación/metabolismo , Antagonistas de Receptores de Mineralocorticoides , Isquemia Miocárdica/complicaciones , Animales , Citocinas/antagonistas & inhibidores , Sinergismo Farmacológico , Ecocardiografía , Eplerenona , Etanercept , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/etiología , Inmunoglobulina G/farmacología , Masculino , Toxina del Pertussis/farmacología , Ratas , Ratas Sprague-Dawley , Receptores del Factor de Necrosis Tumoral , Espironolactona/análogos & derivados , Espironolactona/farmacologíaRESUMEN
OBJECTIVE: More than 90% of chiropractic patients receive high-velocity, low-amplitude spinal manipulation (HVLA-SM) as part of their chiropractic care. The purpose of the current study was determine how the duration of a lumbar HVLA-SM given under force control affects the discharge of paraspinal muscle spindle afferents. METHODS: Experiments were performed on deeply anesthetized adult cats treated in accordance with the Guiding Principles in the Care and Use of Animals approved by the American Physiological Society. Muscle spindle afferents were identified in the dorsal roots. Neural activity was recorded from individual spindles located in the low back predominately from multifidus and longissimus muscles. Spinal manipulative loads were applied to the L6 vertebra. Force-time profiles were half-sine waves with impulse durations of 25, 50, 100, 200, 400, and 800 milliseconds, delivered at constant magnitudes of 33%, 66%, or 100% body weight. The relationships between spinal manipulation duration and muscle spindle responses were determined using a randomized block design. RESULTS: Mean instantaneous discharge frequency increased with decreasing impulse duration. There appeared to be a threshold effect for impulse duration below which the increase in muscle spindle discharge changed greatly with decreasing impulse duration and above which the discharge did not substantially change with decreasing impulse duration. This threshold was in the vicinity of the duration of an HVLA-SM applied clinically (Asunto(s)
Manipulación Quiropráctica/métodos
, Husos Musculares/fisiología
, Músculo Esquelético/fisiología
, Columna Vertebral
, Animales
, Gatos
, Electrofisiología
, Factores de Tiempo