RESUMO
Renal sympathetic (efferent) nerves play an important role in the regulation of renal function, including glomerular filtration, sodium reabsorption, and renin release. The kidney is also innervated by sensory (afferent) nerves that relay information to the brain to modulate sympathetic outflow. Hypertension and other cardiometabolic diseases are linked to overactivity of renal sympathetic and sensory nerves, but our mechanistic understanding of these relationships is limited. Clinical trials of catheter-based renal nerve ablation to treat hypertension have yielded promising results. Therefore, a greater understanding of how renal nerves control the kidney under physiological and pathophysiological conditions is needed. In this review, we provide an overview of the current knowledge of the anatomy of efferent and afferent renal nerves and their functions in normal and pathophysiological conditions. We also suggest further avenues of research for development of novel therapies targeting the renal nerves.
Assuntos
Vias Aferentes/fisiologia , Hipertensão/fisiopatologia , Rim/inervação , Rim/fisiologia , Animais , Ablação por Cateter/métodos , Humanos , Rim/fisiopatologiaRESUMO
PURPOSE: Young women are typically thought to be protected from cardiovascular disease (CVD) before menopause. However, posttraumatic stress disorder (PTSD) increases CVD risk in women by up to threefold. Data in predominantly male cohorts point to physiological mechanisms such as vascular and autonomic derangements as contributing to increased CVD risk. The purpose of the study reported here was to determine whether young women diagnosed with PTSD, compared to those without, present with arterial stiffness and impaired autonomic control of the heart. METHODS: A total of 73 healthy young women, ranging in age from 18 to 40 years, with a history of trauma exposure were included in this study, 32 with and 41 without a clinical PTSD diagnosis. We measured resting pulse wave velocity (PWV), central hemodynamics, augmentation pressure and augmentation index (AI) via pulse wave analysis using applanation tonometry. Heart rate variability was also assessed via peripheral arterial tone. RESULTS: In comparison to controls, women with PTSD showed higher central arterial pressure (mean ± standard deviation: systolic blood pressure 104 ± 8 vs. 97 ± 8 mmHg, p < 0.001; diastolic blood pressure 72 ± 7 vs. 67 ± 7 mmHg, p = 0.003), PWV (6 ± 0.3 vs. 5 ± 0.6 m/s, p < 0.001) and AI (22 ± 13 vs. 15 ± 12%, p = 0.007) but lower standard deviation of normal-to-normal intervals (SDNN; 44 ± 17 vs. 54 ± 18 ms, p = 0.005) and root mean square of successive differences between normal heartbeats (RMSSD; 37 ± 17 vs. 51 ± 22 ms, p = 0.002). CONCLUSION: PTSD in young women is associated with higher brachial and central pressures, increased arterial stiffness and blunted parasympathetic control of the heart. These findings illustrate potential mechanisms underlying high risk for CVD in young women with PTSD, suggesting possible treatment targets for this at-risk group.
Assuntos
Doenças Cardiovasculares , Transtornos de Estresse Pós-Traumáticos , Rigidez Vascular , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Rigidez Vascular/fisiologia , Análise de Onda de Pulso , Pressão Sanguínea/fisiologiaRESUMO
Renal denervation (RDN) is a potential therapy for drug-resistant hypertension. However, whether its effects are mediated by ablation of efferent or afferent renal nerves is not clear. Previous studies have implicated that renal inflammation and the sympathetic nervous system are driven by the activation of afferent and efferent renal nerves. RDN attenuated the renal inflammation and sympathetic activity in some animal models of hypertension. In the 2 kidney,1 clip (2K1C) model of renovascular hypertension, RDN also decreased sympathetic activity; however, mechanisms underlying renal and central inflammation are still unclear. We tested the hypothesis that the mechanisms by which total RDN (TRDN; efferent + afferent) and afferent-specific RDN (ARDN) reduce arterial pressure in 2K1C rats are the same. Male Sprague-Dawley rats were instrumented with telemeters to measure mean arterial pressure (MAP), and after 7 days, a clip was placed on the left renal artery. Rats underwent TRDN, ARDN, or sham surgery of the clipped kidney and MAP was measured for 6 wk. Weekly measurements of water intake (WI), urine output (UO), and urinary copeptin were conducted, and urine was analyzed for cytokines/chemokines. Neurogenic pressor activity (NPA) was assessed at the end of the protocol calculated by the depressor response after intraperitoneal injection of hexamethonium. Rats were euthanized and the hypothalamus and kidneys removed for measurement of cytokine content. MAP, NPA, WI, and urinary copeptin were significantly increased in 2K1C-sham rats, and these responses were abolished by both TRDN and ARDN. 2K1C-sham rats presented with renal and hypothalamic inflammation and these responses were largely mitigated by TRDN and ARDN. We conclude that RDN attenuates 2K1C hypertension primarily by ablation of afferent renal nerves which disrupts bidirectional renal neural-immune pathways.NEW & NOTEWORTHY Hypertension resulting from reduced perfusion of the kidney is dependent on renal sensory nerves, which are linked to inflammation in the kidney and hypothalamus. Afferent renal nerves are required for chronic increases in both water intake and vasopressin release observed following renal artery stenosis. Findings from this study suggest an important role of renal sensory nerves that has previously been underestimated in the pathogenesis of 2K1C hypertension.
Assuntos
Hipertensão Renovascular , Hipertensão , Nefrite , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Rim , Sistema Nervoso Simpático , Hipotálamo , Inflamação , Pressão Sanguínea/fisiologiaRESUMO
Atrial natriuretic peptide (NP) and BNP increase cGMP, which reduces blood pressure and cardiac hypertrophy by activating guanylyl cyclase (GC)-A, also known as NPR-A or Npr1. Although GC-A is highly phosphorylated, and dephosphorylation inactivates the enzyme, the significance of GC-A phosphorylation to heart structure and function remains unknown. To identify in vivo processes that are regulated by GC-A phosphorylation, we substituted glutamates for known phosphorylation sites to make GC-A8E/8E mice that express an enzyme that cannot be inactivated by dephosphorylation. GC-A activity, but not protein, was increased in heart and kidney membranes from GC-A8E/8E mice. Activities were threefold higher in female compared to male cardiac ventricles. Plasma cGMP and testosterone were elevated in male and female GC-A8E/8E mice, but aldosterone was only increased in mutant male mice. Plasma and urinary creatinine concentrations were decreased and increased, respectively, but blood pressure and heart rate were unchanged in male GC-A8E/8E mice. Heart weight to body weight ratios for GC-A8E/8E male, but not female, mice were 12% lower with a 14% reduction in cardiomyocyte cross-sectional area. Subcutaneous injection of fsANP, a long-lived ANP analog, increased plasma cGMP and decreased aldosterone in male GC-AWT/WT and GC-A8E/8E mice at 15 min, but only GC-A8E/8E mice had elevated levels of plasma cGMP and aldosterone at 60 min. fsANP reduced ventricular ERK1/2 phosphorylation to a greater extent and for a longer time in the male mutant compared to WT mice. Finally, ejection fractions were increased in male but not female hearts from GC-A8E/8E mice. We conclude that increased phosphorylation-dependent GC-A activity decreases cardiac ERK activity, which results in smaller male hearts with improved systolic function.
Assuntos
Cardiomegalia , Sistema de Sinalização das MAP Quinases , Fosforilação , Receptores do Fator Natriurético Atrial , Caracteres Sexuais , Animais , Cardiomegalia/enzimologia , Cardiomegalia/genética , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Receptores do Fator Natriurético Atrial/genética , Receptores do Fator Natriurético Atrial/metabolismoRESUMO
In Italy, chronic pain affects more than a quarter of the population, whereas the average European prevalence is 21%. This high prevalence might be due to the high percentage of Italian people who do not receive treatment, even after the passing of law 38/2010 (the right to access pain management in Italy), which created a regional network for the diagnosis and treatment of noncancer chronic pain. Italian epidemiologic studies on chronic pain are scanty, and this observational, multicenter, cross-sectional study is the first to investigate the clinical characteristics of patients who attended the pain management clinics in the Latium Region, Italy, for the management of their noncancer chronic pain. A total of 1,606 patients (mean age 56.8 years, standard deviation ± 11.4), 67% women, were analyzed. Severe pain was present in 54% of the sample. Women experienced pain and had it in two or more sites more often than men (57% vs. 50%, p = .02; and 55.2% vs. 45.9%, p < .001, respectively). Chronic pain was musculoskeletal (45%), mixed (34%), and neuropathic (21%). In more than 60% of the cases, chronic pain was continuous, and in 20% it had lasted for more than 48 months; long-lasting pain was often neuropathic. Low back (33.4%) and lower limbs (28.2%) were the main locations. Severe intensity of pain was statistically significantly associated with female gender (odds ratio [OR] 1.39; 95% confidence interval [CI] 1.06-1.84); with International Classification of Diseases, Ninth Revision, codes for chronic pain syndrome (OR 2.14; 95% CI 1.55-2.95); and with continuous pain (OR 2.02; 95% CI 1.54-2.66). Neuropathic pain and mixed pain were significantly associated with number of sites, and a trend seemed to be present (OR 2.11 and 3.02 for 2 and 3 + sites; 95% CI 1.59-2.79 and 2.00-4.55, respectively).
Assuntos
Dor Crônica/terapia , Clínicas de Dor/estatística & dados numéricos , Adulto , Idoso , Dor Crônica/epidemiologia , Estudos Transversais , Epidemiologia , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Clínicas de Dor/organização & administração , Prevalência , Fatores de RiscoRESUMO
Lesions of the anteroventral third ventricle (AV3V region) are known to prevent many forms of experimental hypertension, including mineralocorticoid [deoxycorticosterone acetate (DOCA)-salt] hypertension in the rat. However, AV3V lesions include the organum vasculosum of the lamina terminalis (OVLT), portions of the median preoptic nucleus, and efferent fibers from the subfornical organ (SFO), thereby limiting the ability to define the individual contribution of these structures to the prevention of experimental hypertension. Having previously reported that the SFO does not play a significant role in the development of DOCA-salt hypertension, the present study was designed to test the hypothesis that the OVLT is necessary for DOCA-salt hypertension in the rat. In uninephrectomized OVLT-lesioned (OVLTx; n = 6) and sham-operated ( n = 4) Sprague-Dawley rats consuming a 0.1% NaCl diet and 0.9% NaCl drinking solution, 24-h mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg sc per rat). No differences in control MAP were observed between groups. The chronic pressor response to DOCA was attenuated in OVLTx rats such that MAP increased to 133 ± 3 mmHg in sham-operated rats by day 21 of DOCA compared with 120 ± 4 mmHg (means ± SE) in OVLTx rats. These results support the hypothesis that the OVLT is an important brain site of action for the pathogenesis of DOCA-salt hypertension in the rat.
Assuntos
Pressão Arterial , Acetato de Desoxicorticosterona , Hipertensão/prevenção & controle , Organum Vasculosum/cirurgia , Cloreto de Sódio na Dieta , Animais , Monitorização Ambulatorial da Pressão Arterial/métodos , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Nefrectomia , Organum Vasculosum/patologia , Organum Vasculosum/fisiopatologia , Ratos Sprague-Dawley , Telemetria , Fatores de TempoRESUMO
Recent preclinical studies show renal denervation (RDNx) may be an effective treatment for hypertension; however, the mechanism remains unknown. We have recently reported total RDNx (TRDNx) and afferent-selective RDNx (ARDNx) similarly attenuated the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Whereas TRDNx abolished renal inflammation, ARDNx had a minimal effect despite an identical antihypertensive effect. Although this study established that ARDNx attenuates the development of DOCA-salt hypertension, it is unknown whether this mechanism remains operative once hypertension is established. The current study tested the hypothesis that TRDNx and ARDNx would similarly decrease mean arterial pressure (MAP) in the DOCA-salt hypertensive rat, and only TRDNx would mitigate renal inflammation. After 21 days of DOCA-salt treatment, male Sprague-Dawley rats underwent TRDNx ( n = 16), ARDNx ( n = 16), or Sham ( n = 14) treatment and were monitored for 14 days. Compared with baseline, TRDNx and ARDNx decreased MAP similarly (TRDNx -14 ± 4 and ARDNx -15 ± 6 mmHg). After analysis of diurnal rhythm, rhythm-adjusted mean and amplitude of night/day cycle were also reduced in TRDNx and ARDNx groups compared with Sham. Notably, no change in renal inflammation, injury, or function was detected with either treatment. We conclude from these findings that: 1) RDNx mitigates established DOCA-salt hypertension; 2) the MAP responses to RDNx are primarily mediated by ablation of afferent renal nerves; and 3) renal nerves do not contribute to the maintenance of renal inflammation in DOCA-salt hypertension.
Assuntos
Pressão Arterial , Hipertensão/fisiopatologia , Rim/inervação , Nefrite/fisiopatologia , Neurônios Aferentes , Animais , Ritmo Circadiano , Denervação , Acetato de Desoxicorticosterona , Hipertensão/induzido quimicamente , Masculino , Nefrite/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Over the past several decades, studies of the sympathetic nervous system in humans, sheep, rabbits, rats, and mice have substantially increased mechanistic understanding of cardiovascular function and dysfunction. Recently, interest in sympathetic neural mechanisms contributing to blood pressure control has grown, in part because of the development of devices or surgical procedures that treat hypertension by manipulating sympathetic outflow. Studies in animal models have provided important insights into physiological and pathophysiological mechanisms that are not accessible in human studies. Across species and among laboratories, various approaches have been developed to record, quantify, analyze, and interpret sympathetic nerve activity (SNA). In general, SNA demonstrates "bursting" behavior, where groups of action potentials are synchronized and linked to the cardiac cycle via the arterial baroreflex. In humans, it is common to quantify SNA as bursts per minute or bursts per 100 heart beats. This type of quantification can be done in other species but is only commonly reported in sheep, which have heart rates similar to humans. In rabbits, rats, and mice, SNA is often recorded relative to a maximal level elicited in the laboratory to control for differences in electrode position among animals or on different study days. SNA in humans can also be presented as total activity, where normalization to the largest burst is a common approach. The goal of the present paper is to put together a summary of "best practices" in several of the most common experimental models and to discuss opportunities and challenges relative to the optimal measurement of SNA across species.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/guidelines-for-measuring-sympathetic-nerve-activity/.
Assuntos
Potenciais de Ação/fisiologia , Barorreflexo/fisiologia , Técnicas de Diagnóstico Neurológico/normas , Nervos Periféricos/fisiologia , Guias de Prática Clínica como Assunto , Sistema Nervoso Simpático/fisiologia , Animais , Humanos , Coelhos , Ratos , Ovinos , Especificidade da EspécieRESUMO
RATIONALE: Inflammation and adaptive immunity play a crucial role in the development of hypertension. Angiotensin II and probably other hypertensive stimuli activate the central nervous system and promote T-cell activation and end-organ damage in peripheral tissues. OBJECTIVE: To determine if renal sympathetic nerves mediate renal inflammation and T-cell activation in hypertension. METHODS AND RESULTS: Bilateral renal denervation using phenol application to the renal arteries reduced renal norepinephrine levels and blunted angiotensin II-induced hypertension. Bilateral renal denervation also reduced inflammation, as reflected by decreased accumulation of total leukocytes, T cells, and both CD4+ and CD8+ T cells in the kidney. This was associated with a marked reduction in renal fibrosis, albuminuria, and nephrinuria. Unilateral renal denervation, which partly attenuated blood pressure, only reduced inflammation in the denervated kidney, suggesting that this effect is pressure independent. Angiotensin II also increased immunogenic isoketal-protein adducts in renal dendritic cells (DCs) and increased surface expression of costimulation markers and production of interleukin (IL)-1α, IL-1ß, and IL-6 from splenic DCs. Norepinephrine also dose dependently stimulated isoketal formation in cultured DCs. Adoptive transfer of splenic DCs from angiotensin II-treated mice primed T-cell activation and hypertension in recipient mice. Renal denervation prevented these effects of hypertension on DCs. In contrast to these beneficial effects of ablating all renal nerves, renal afferent disruption with capsaicin had no effect on blood pressure or renal inflammation. CONCLUSIONS: Renal sympathetic nerves contribute to DC activation, subsequent T-cell infiltration and end-organ damage in the kidney in the development of hypertension.
Assuntos
Angiotensina II/toxicidade , Hipertensão/imunologia , Imunidade Celular/fisiologia , Rim/imunologia , Rim/inervação , Simpatectomia , Animais , Hipertensão/patologia , Imunidade Celular/efeitos dos fármacos , Rim/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição AleatóriaRESUMO
Clinical data suggest that renal denervation (RDNX) may be an effective treatment for human hypertension; however, it is unclear whether this therapeutic effect is due to ablation of afferent or efferent renal nerves. We have previously shown that RDNX lowers arterial pressure in hypertensive Dahl salt-sensitive (S) rats to a similar degree observed in clinical trials. In addition, we have recently developed a method for selective ablation of afferent renal nerves (renal-CAP). In the present study, we tested the hypothesis that the antihypertensive effect of RDNX in the Dahl S rat is due to ablation of afferent renal nerves by comparing the effect of complete RDNX to renal-CAP during two phases of hypertension in the Dahl S rat. In the early phase, rats underwent treatment after 3 wk of high-NaCl feeding when mean arterial pressure (MAP) was â¼ 140 mmHg. In the late phase, rats underwent treatment after 9 wk of high NaCl feeding, when MAP was â¼ 170 mmHg. RDNX reduced MAP â¼ 10 mmHg compared with sham surgery in both the early and late phase, whereas renal-CAP had no antihypertensive effect. These results suggest that, in the Dahl S rat, the antihypertensive effect of RDNX is not dependent on pretreatment arterial pressure, nor is it due to ablation of afferent renal nerves.
Assuntos
Pressão Arterial , Denervação Autônoma/métodos , Hipertensão/fisiopatologia , Hipertensão/cirurgia , Rim/inervação , Vias Aferentes/fisiopatologia , Vias Aferentes/cirurgia , Animais , Modelos Animais de Doenças , Vias Eferentes/fisiopatologia , Vias Eferentes/cirurgia , Hipertensão/etiologia , Masculino , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta , Fatores de TempoRESUMO
BACKGROUND: Centers for Medicare and Medicaid Services define laparoscopic ventral hernia repair (LVHR) as outpatient procedure. We identified our institutional length of stay (LOS) to be above the National Surgical Quality Improvement Program (NSQIP) benchmark of 1 day [interquartile range (IQR) 2 days]. This study was undertaken to investigate risk factors associated with prolonged hospital stay and design an intervention to decrease median LOS. METHODS: This study analyzed institutional NSQIP data on patients who underwent elective LVHR from 2006 to 2011 to define factors associated with prolonged LOS, defined as LOS > 2 days. Modifiable factors identified in the initial analysis were included in a clinical care pathway to impact LOS. We repeated the NSQIP data analysis after implementation (4/2011-9/2012) to assess the effect of our intervention. Analysis was by univariate, ANOVA and logistic regression models. RESULTS: During the pre-implementation period, 80 patients with a median age of 54 years (31-84) stayed a median of 2 days (IQR 3). On univariate analysis, factors associated with prolonged LOS included operative time, mesh size, amount of narcotics used and female gender. In multivariate analysis, operative time and narcotics used were associated with a prolonged LOS, C statistic = 0.88. Introduction of a clinical pathway focusing on non-narcotic pain relief resulted in a decrease in mean narcotic usage from 223 to 63 mg morphine equivalents/patient (p < 0.0001), decrease in median LOS to 1 day (IQR 2) (p = 0.027), in line with NSQIP benchmarks, a slight decrease in complications and a 10% decrease in hospital cost. CONCLUSION: High narcotic use and long operative times are independent predictors of prolonged LOS in our patient population. Introduction of a standardized clinical care pathway designed to reduce perioperative narcotic use resulted in shorter LOS, improved quality and cost savings for patients undergoing LVHR.
Assuntos
Procedimentos Clínicos , Hérnia Ventral/cirurgia , Laparoscopia , Tempo de Internação , Melhoria de Qualidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos/uso terapêutico , Uso de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota , Duração da Cirurgia , Dor Pós-Operatória/tratamento farmacológicoRESUMO
Salt sensitivity of arterial pressure (salt-sensitive hypertension) is a serious global health issue. The causes of salt-sensitive hypertension are extremely complex and mathematical models can elucidate potential mechanisms that are experimentally inaccessible. Until recently, the only mathematical model for long-term control of arterial pressure was the model of Guyton and Coleman; referred to as the G-C model. The core of this model is the assumption that sodium excretion is driven by renal perfusion pressure, the so-called 'renal function curve'. Thus, the G-C model dictates that all forms of hypertension are due to a primary shift of the renal function curve to a higher operating pressure. However, several recent experimental studies in a model of hypertension produced by the combination of a high salt intake and administration of angiotensin II, the AngII-salt model, are inconsistent with the G-C model. We developed a new mathematical model that does not limit the cause of salt-sensitive hypertension solely to primary renal dysfunction. The model is the first known mathematical counterexample to the assumption that all salt-sensitive forms of hypertension require a primary shift of renal function: we show that in at least one salt-sensitive form of hypertension the requirement is not necessary. We will refer to this computational model as the 'neurogenic model'. In this Symposium Review we discuss how, despite fundamental differences between the G-C model and the neurogenic model regarding mechanisms regulating sodium excretion and vascular resistance, they generate similar haemodynamic profiles of AngII-salt hypertension. In addition, the steady-state relationships between arterial pressure and sodium excretion, a correlation that is often erroneously presented as the 'renal function curve', are also similar in both models. Our findings suggest that salt-sensitive hypertension is not due solely to renal dysfunction, as predicted by the G-C model, but may also result from neurogenic dysfunction.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Hipertensão/fisiopatologia , Modelos Neurológicos , Equilíbrio Hidroeletrolítico , Animais , HumanosRESUMO
Renal denervation has been shown to lower arterial pressure in some hypertensive patients, yet it remains unclear whether this is due to ablation of afferent or efferent renal nerves. To investigate the role of afferent renal nerves in arterial pressure regulation, previous studies have used methods that disrupt both renal and nonrenal afferent signaling. The present study was conducted to develop and validate a technique for selective ablation of afferent renal nerves that does not disrupt other afferent pathways. To do this, we adapted a technique for sensory denervation of the adrenal gland by topical application of capsaicin and tested the hypothesis that exposure of the renal nerves to capsaicin (renal-CAP) causes ablation of afferent but not efferent renal nerves. Renal-CAP had no effect on renal content of the efferent nerve markers tyrosine hydroxylase and norepinephrine; however, the afferent nerve marker, calcitonin gene-related peptide was largely depleted from the kidney 10 days after intervention, but returned to roughly half of control levels by 7 wk postintervention. Moreover, renal-CAP abolished the cardiovascular responses to acute pharmacological stimulation of afferent renal nerves. Renal-CAP rats showed normal weight gain, as well as cardiovascular and fluid balance regulation during dietary sodium loading. To some extent, renal-CAP did blunt the bradycardic response and increase the dipsogenic response to increased salt intake. Lastly, renal-CAP significantly attenuated the development of deoxycorticosterone acetate-salt hypertension. These results demonstrate that renal-CAP effectively causes selective ablation of afferent renal nerves in rats.
Assuntos
Capsaicina/farmacologia , Denervação , Rim/efeitos dos fármacos , Rim/inervação , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiopatologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Denervação/métodos , Modelos Animais de Doenças , Hipertensão/fisiopatologia , Rim/metabolismo , Masculino , Ratos Sprague-Dawley , Cloreto de Sódio na DietaRESUMO
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) may increase the risk for cardiac dysfunction. The present study aimed to determine whether, in children, NAFLD is associated with subclinical left ventricular (LV) structural and functional abnormalities independently of metabolic risk factors. We performed a complete echocardiographic study including tissue Doppler imaging, magnetic resonance imaging (MRI) for measurement of hepatic fat fraction (HFF) and abdominal fat mass distribution, along with lipid profile, insulin sensitivity, and high-sensitivity C-reactive protein in 108 obese children, 54 with (HFF ≥5%) and 54 without NAFLD, and 18 lean healthy subjects. The three groups were matched for age, gender, and pubertal status, and obese children with NAFLD were matched for body mass index/standard deviation score with those without NAFLD. Forty-one of the children with NAFLD underwent liver biopsy. Compared to controls and children without liver involvement, those with NAFLD had features of LV diastolic dysfunction, including higher E-to-e' ratio and lower e' tissue velocity. The Tei index (reflecting the combined systolic and diastolic LV function) was also significantly higher in NAFLD children. Among children with biopsy-proven NAFLD, 26 had definite nonalcoholic steatohepatitis (NASH) and 15 were not-NASH. Patients with definite-NASH had significantly lower e' velocity and significantly higher E-to-e' and Tei index (P < 0.001, respectively) than those without NASH. In multiple logistic regression analysis, NAFLD was the only statistically significant variable associated with increased E-to-e' ratio, whereas NAFLD and systolic blood pressure were significantly associated with increased Tei index. CONCLUSION: Asymptomatic obese children with NAFLD exhibit features of early LV diastolic and systolic dysfunction, and these abnormalities are more severe in those with NASH.
Assuntos
Fígado Gorduroso/complicações , Fígado Gorduroso/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Disfunção Ventricular Esquerda/epidemiologia , Adolescente , Biópsia , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Criança , Comorbidade , Estudos Transversais , Ecocardiografia , Fígado Gorduroso/metabolismo , Feminino , Humanos , Resistência à Insulina/fisiologia , Lipídeos/sangue , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Hepatopatia Gordurosa não Alcoólica , Obesidade/metabolismo , Prevalência , Análise de Regressão , Fatores de Risco , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/patologiaRESUMO
In 1998, a systemic fetal cytokine response, defined as a plasma interleukin-6 (IL-6) value above 11 pg/mL, was reported to be a major independent risk factor for the subsequent development of neonatal morbid events even after adjustments for gestational age and other confounders. Since then, the body of literature investigating the use of blood concentrations of IL-6 as a hallmark of the fetal inflammatory response syndrome (FIRS), a diagnostic marker of early-onset neonatal sepsis (EONS) and a risk predictor of white matter injury (WMI), has grown rapidly. In this article, we critically review: IL-6 biological functions; current evidence on the association between IL-6, preterm birth, FIRS and EONS; IL-6 reference intervals and dynamics in the early neonatal period; IL-6 response during the immediate postnatal period and perinatal confounders; accuracy and completeness of IL-6 diagnostic studies for EONS (according to the Standards for Reporting of Diagnostic Accuracy statement); and recent breakthroughs in the association between fetal blood IL-6, EONS, and WMI.
Assuntos
Feto/imunologia , Interleucina-6/sangue , Interleucina-6/fisiologia , Sepse/diagnóstico , Confiabilidade dos Dados , Feminino , Sangue Fetal/imunologia , Idade Gestacional , Humanos , Recém-Nascido , Interleucina-6/imunologia , Leucoencefalopatias/etiologia , Gravidez , Nascimento Prematuro/imunologia , Valores de Referência , Sepse/etiologia , Sepse/imunologia , Síndrome de Resposta Inflamatória Sistêmica/sangueRESUMO
Secretion of proteins and neurotransmitters from large dense core vesicles (LDCVs) is a highly regulated process. Adrenal LDCV formation involves the granin proteins chromogranin A (CgA) and chromogranin B (CgB); CgA- and CgB-derived peptides regulate catecholamine levels and blood pressure. We investigated function of the granin VGF (nonacronymic) in LDCV formation and the regulation of catecholamine levels and blood pressure. Expression of exogenous VGF in nonendocrine NIH 3T3 fibroblasts resulted in the formation of LDCV-like structures and depolarization-induced VGF secretion. Analysis of germline VGF-knockout mouse adrenal medulla revealed decreased LDCV size in noradrenergic chromaffin cells, increased adrenal norepinephrine and epinephrine content and circulating plasma epinephrine, and decreased adrenal CgB. These neurochemical changes in VGF-knockout mice were associated with hypertension. Germline knock-in of human VGF1-615 into the mouse Vgf locus rescued the hypertensive knockout phenotype, while knock-in of a truncated human VGF1-524 that lacks several C-terminal peptides, including TLQP-21, resulted in a small but significant increase in systolic blood pressure compared to hVGF1-615 mice. Finally, acute and chronic administration of the VGF-derived peptide TLQP-21 to rodents decreased blood pressure. Our studies establish a role for VGF in adrenal LDCV formation and the regulation of catecholamine levels and blood pressure.
Assuntos
Pressão Sanguínea , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Vesículas Secretórias/metabolismo , Medula Suprarrenal/metabolismo , Angiotensina Amida/sangue , Animais , Células Cromafins/metabolismo , Cromogranina A/metabolismo , Citoplasma/metabolismo , Epinefrina/sangue , Técnicas de Introdução de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células NIH 3T3 , Fatores de Crescimento Neural , Neurotransmissores/metabolismo , Fragmentos de Peptídeos/metabolismo , FenótipoRESUMO
Angiotensin II (ANG II)-induced hypertension is a commonly studied model of experimental hypertension, particularly in rodents, and is often generated by subcutaneous delivery of ANG II using Alzet osmotic minipumps chronically implanted under the skin. We have observed that, in a subset of animals subjected to this protocol, mean arterial pressure (MAP) begins to decline gradually starting the second week of ANG II infusion, resulting in a blunting of the slow pressor response and reduced final MAP. We hypothesized that this variability in the slow pressor response to ANG II was mainly due to factors unique to Alzet pumps. To test this, we compared the pressure profile and changes in plasma ANG II levels during subcutaneous ANG II administration (150 ng·kg(-1)·min(-1)) using either Alzet minipumps, iPrecio implantable pumps, or a Harvard external infusion pump. At the end of 14 days of ANG II, MAP was highest in the iPrecio group (156 ± 3 mmHg) followed by Harvard (140 ± 3 mmHg) and Alzet (122 ± 3 mmHg) groups. The rate of the slow pressor response, measured as daily increases in pressure averaged over days 2-14 of ANG II, was similar between iPrecio and Harvard groups (2.7 ± 0.4 and 2.2 ± 0.4 mmHg/day) but was significantly blunted in the Alzet group (0.4 ± 0.4 mmHg/day) due to a gradual decline in MAP in a subset of rats. We also found differences in the temporal profile of plasma ANG II between infusion groups. We conclude that the gradual decline in MAP observed in a subset of rats during ANG II infusion using Alzet pumps is mainly due to pump-dependent factors when applied in this particular context.
Assuntos
Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Infusões Subcutâneas/métodos , Angiotensina II/administração & dosagem , Angiotensina II/sangue , Animais , Bombas de Infusão , Infusões Subcutâneas/instrumentação , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Infections which complicate rheumatic diseases such as Rheumatoid Arthritis (RA) and Spondyloarthropathy (SpA) (Psoriatic Arthritis [PA] and Ankylosing Spondylitis [AS]), may cause significant morbidity and mortality. However, among the studies on the incidence rate (IR) of infections in such patients, very few have involved controls and the results have been controversial, probably due to methodological difficulties.To estimate infection rates in RA and SpA patients under disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids (CS) and tumor necrosis factor (TNF)α antagonists, alone or combined, a single-centre retrospective observational cohort study has been performed. PATIENTS AND METHODS: Incidence rates/100 patient-years of any infections were evaluated in RA and SpA outpatients observed in the period November 1, 2003 through December 31, 2009 and stratified according to therapy. Infection incidence rate ratios (IRR) were calculated using Poisson regression models which adjusted for demographic/clinical characteristics of the patients. RESULTS: Three hundred and thirtyone infections [318 (96.1%) non-serious and 13 (3.9%) serious] have been registered among 176 of the 341 patients (52%). The IR/100 patient-years of all infections was 36.3 ranging from 12.4 (DMARDs + CS) to 62.7 (anti-TNFα + CS). The most frequent infection site was respiratory tract, and bacteria were responsible for three quarters of all infections. In the multivariate analysis, adding anti-TNFα to DMARDs doubled the IRR compared to DMARDs alone, anti-TNFα + CS significantly tripled it, whereas anti-TNFα + CS + DMARDs only increased the risk 2.5 times. The degree of disease activity was strongly and significantly associated with the infection risk (severe or moderate versus mild, IRR = 4). Female sex was significantly associated with increased infection risk, while duration of disease and anti-influenza vaccination were protective, the latter even for cutaneous/soft-tissue (mainly herpetic) infections. CONCLUSION: The combination anti-TNFα with CS was found to be the most pro-infective treatment, whereas DMARDs alone were relatively safe. Physicians, therefore, should be aware that there may be an increased risk of infection when using anti-TNFα and CS therapy together. Anti-influenza vaccination appears to provide broad protection, adding evidence to support its use in these patients, and deserves further study.
Assuntos
Corticosteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Doenças Transmissíveis/etiologia , Espondiloartropatias/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Demografia , Feminino , Humanos , Vacinas contra Influenza/uso terapêutico , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco , Espondiloartropatias/complicações , VacinaçãoRESUMO
The importance of the sympathetic nervous system in essential hypertension has been recognized in 2 eras. The first was in early decades of the 20th century, through to the 1960s. Here, the sympathetic nervous system was identified as a target for the treatment of hypertension, and an extensive range of antiadrenergic therapies were developed. Then, after a period of lapsed interest, in a second era from 1985 on, the development of precise measures of human sympathetic nerve firing and transmitter release allowed demonstration of the importance of neural mechanisms in the initiation and maintenance of the arterial blood pressure elevation in hypertension. This led to the development of a device treatment of hypertension, catheter-based renal denervation, which we will discuss.
Assuntos
Hipertensão , Rim , Simpatectomia , Sistema Nervoso Simpático , Humanos , Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Hipertensão/cirurgia , Rim/inervação , Rim/fisiopatologia , Simpatectomia/métodos , Sistema Nervoso Simpático/fisiopatologiaRESUMO
Catheter based renal denervation has recently been FDA approved for the treatment of hypertension. Traditionally, the anti-hypertensive effects of renal denervation have been attributed to the ablation of the efferent sympathetic renal nerves. In recent years the role of the afferent sensory renal nerves in the regulation of blood pressure has received increased attention. In addition, afferent renal denervation is associated with reductions in sympathetic nervous system activity. This suggests that reductions in sympathetic drive to organs other than the kidney may contribute to the non-renal beneficial effects observed in clinical trials of catheter based renal denervation. In this review we will provide an overview of the role of the afferent renal nerves in the regulation of renal function and the development of pathophysiologies, both renal and non-renal. We will also describe the central projections of the afferent renal nerves, to give context to the responses seen following their ablation and activation. Finally, we will discuss the emerging role of the kidney as an interoceptive organ. We will describe the potential role of the kidney in the regulation of interoceptive sensitivity and in this context, speculate on the possible pathological consequences of altered renal function.