RESUMEN
Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+ current (INa) and repolarizing K+ current (IK) carried by voltage gated K+ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na+ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.
Asunto(s)
Fibrilación Atrial/metabolismo , Remodelación Atrial/fisiología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 1/complicaciones , Insulina/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/etiología , Fibrilación Atrial/fisiopatología , Remodelación Atrial/inmunología , Células Cultivadas , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animales de Enfermedad , Ecocardiografía , Electrocardiografía , Atrios Cardíacos/citología , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Atrios Cardíacos/fisiopatología , Humanos , Insulina/administración & dosificación , Insulina/genética , Canal de Potasio Kv1.5/metabolismo , Masculino , Ratones , Ratones Transgénicos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/fisiología , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Técnicas de Placa-Clamp , Potasio/metabolismo , Cultivo Primario de Células , Sodio/metabolismo , Estreptozocina/toxicidadRESUMEN
The renin angiotensin system (RAS) regulates fluid balance, blood pressure and maintains vascular tone. The potent vasoconstrictor angiotensin II (Ang II) produced by angiotensin-converting enzyme (ACE) comprises the classical RAS. The non-classical RAS involves the conversion of Ang II via ACE2 into the vasodilator Ang (1-7) to counterbalance the effects of Ang II. Furthermore, ACE2 converts AngA into another vasodilator named alamandine. The over activation of the classical RAS (increased vasoconstriction) and depletion of the non-classical RAS (decreased vasodilation) results in vascular dysfunction. Vascular dysfunction is the leading cause of atherosclerosis and cardiovascular disease (CVD). Additionally, local RAS is expressed in various tissues and regulates cellular functions. RAS dysregulation is involved in other several diseases such as inflammation, renal dysfunction and even cancer growth. An approach in restoring vascular dysfunction and other pathological diseases is to either increase the activity of ACE2 or reduce the effect of the classical RAS by counterbalancing Ang II effects. The antitrypanosomal agent, diminazene aceturate (DIZE), is one approach in activating ACE2. DIZE has been shown to exert beneficial effects in CVD experimental models of hypertension, myocardial infarction, type 1 diabetes and atherosclerosis. Thus, this review focuses on DIZE and its effect in several tissues such as blood vessels, cardiac, renal, immune and cancer cells.
Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , Diminazeno/análogos & derivados , Activadores de Enzimas/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/fisiopatología , Diminazeno/efectos adversos , Diminazeno/uso terapéutico , Activación Enzimática , Activadores de Enzimas/efectos adversos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/fisiopatologíaRESUMEN
B-type natriuretic peptide (BNP) exhibits roles in natriuresis and diuresis, making it an ideal drug that may aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these have demonstrated beneficial outcomes. The current challenge for BNP research in acute HF lies in addressing a failure of concept and a reluctance to abandon an ineffective research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP, as well as better integration of basic and clinical science.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Péptido Natriurético Encefálico/farmacología , Enfermedad Aguda , Humanos , Péptido Natriurético Encefálico/uso terapéuticoRESUMEN
The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that senses and integrates environmental information into cellular regulation and homeostasis. Accumulating evidence has suggested a master role of mTOR signalling in many fundamental aspects of cell biology and organismal development. mTOR deregulation is implicated in a broad range of pathological conditions, including diabetes, cancer, neurodegenerative diseases, myopathies, inflammatory, infectious, and autoimmune conditions. Here, we review recent advances in our knowledge of mTOR signalling in mammalian physiology. We also discuss the impact of mTOR alteration in human diseases and how targeting mTOR function can treat human diseases.
Asunto(s)
Homeostasis , Complejos Multiproteicos/metabolismo , Neoplasias/fisiopatología , Enfermedades Neurodegenerativas/fisiopatología , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , HumanosRESUMEN
Idiopathic Pulmonary Arterial Hypertension (IPAH) is a deadly and disabling disease characterized by severe vascular remodeling of small pulmonary vessels by fibroblasts, myofibroblasts and vascular smooth muscle cell proliferation. Recent studies suggest that the Natriuretic Peptide Clearance Receptor (NPR-C) signaling pathways may play a crucial role in the development of IPAH. Reduced expression or function of NPR-C signaling in pulmonary artery smooth muscle cells may contribute to the pulmonary vascular remodeling, which is characteristic of this disease. The likely mechanisms may involve an impaired interaction between NPR-C, specific growth factors and other signal transduction pathways including but not limited to Gqα/mitogen-activated protein kinase (MAPK)/PI3K and AKT signaling. The resulting failure of growth suppression in pulmonary artery smooth muscle cells provides critical clues to the cellular pathobiology of IPAH. The reciprocal regulation of NPR-C signaling in models of tissue remodeling may thus provide new insights to our understanding of IPAH.
Asunto(s)
Hipertensión Pulmonar Primaria Familiar/genética , Mutación , Receptores del Factor Natriurético Atrial/genética , Transducción de Señal , Hipertensión Pulmonar Primaria Familiar/metabolismo , Humanos , Receptores del Factor Natriurético Atrial/metabolismo , Remodelación VascularRESUMEN
Atherosclerosis is a major contributor to morbidity and mortality worldwide. With therapeutic consequences in mind, several risk scores are being used to differentiate individuals with low, intermediate or high cardiovascular (CV) event risk. The most appropriate management of intermediate risk individuals is still not known, therefore, novel biomarkers are being sought to help re-stratify them as low or high risk. This narrative review is presented in two parts. Here, in Part 1, we summarise current knowledge on serum (serological) biomarkers of atherosclerosis. Among novel biomarkers, high sensitivity C-reactive protein (hsCRP) has emerged as the most promising in chronic situations, others need further clinical studies. However, it seems that a combination of serum biomarkers offers more to risk stratification than either biomarker alone. In Part 2, we address genetic and imaging markers of atherosclerosis, as well as other developments relevant to risk prediction.
Asunto(s)
Aterosclerosis/sangre , Proteína C-Reactiva/metabolismo , Biomarcadores/sangre , Humanos , Inflamación/sangre , Factores de RiesgoRESUMEN
This is Part 2 of a two-part review summarising current knowledge on biomarkers of atherosclerosis. Part 1 addressed serological biomarkers. Here, in part 2 we address genetic and imaging markers, and other developments in predicting risk. Further improvements in risk stratification are expected with the addition of genetic risk scores. In addition to single nucleotide polymorphisms (SNPs), recent advances in epigenetics offer DNA methylation profiles, histone chemical modifications, and micro-RNAs as other promising indicators of atherosclerosis. Imaging biomarkers are better studied and already have a higher degree of clinical applicability in cardiovascular (CV) event prediction and detection of preclinical atherosclerosis. With new methodologies, such as proteomics and metabolomics, discoveries of new clinically applicable biomarkers are expected.
Asunto(s)
Aterosclerosis , Biomarcadores/sangre , Diagnóstico por Imagen/métodos , Marcadores Genéticos , Aterosclerosis/sangre , Aterosclerosis/diagnóstico , Aterosclerosis/genética , HumanosRESUMEN
Atrial fibrillation (AF) is prevalent in hypertension and elevated angiotensin II (Ang II); however, the mechanisms by which Ang II leads to AF are poorly understood. Here, we investigated the basis for this in mice treated with Ang II or saline for 3â¯weeks. Ang II treatment increased susceptibility to AF compared to saline controls in association with increases in P wave duration and atrial effective refractory period, as well as reductions in right and left atrial conduction velocity. Patch-clamp studies demonstrate that action potential (AP) duration was prolonged in right atrial myocytes from Ang II treated mice in association with a reduction in repolarizing K+ currents. In contrast, APs in left atrial myocytes from Ang II treated mice showed reductions in upstroke velocity and overshoot, as well as greater prolongations in AP duration. Ang II reduced Na+ current (INa) in the left, but not the right atrium. This reduction in INa was reversible following inhibition of protein kinase C (PKC) and PKCα expression was increased selectively in the left atrium in Ang II treated mice. The transient outward K+ current (Ito) showed larger reductions in the left atrium in association with a shift in the voltage dependence of activation. Finally, Ang II caused fibrosis throughout the atria in association with changes in collagen expression and regulators of the extracellular matrix. This study demonstrates that hypertension and elevated Ang II cause distinct patterns of electrical and structural remodeling in the right and left atria that collectively create a substrate for AF.
Asunto(s)
Potenciales de Acción , Angiotensina II/metabolismo , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/etiología , Remodelación Atrial , Angiotensina II/farmacología , Animales , Biomarcadores , Presión Sanguínea , Ecocardiografía , Electrocardiografía , Inmunohistoquímica , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratones , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismoRESUMEN
Several epidemiological studies reported an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol levels and atherosclerotic cardiovascular disease (ASCVD). However, therapeutic interventions targeted at raising HDL-cholesterol failed to improve cardiovascular outcomes, suggesting that HDL components distinct from cholesterol may account for the anti-atherothrombotic effects attributed to this lipoprotein. Sphingosine-1-phosphate (S1P) and the acute phase protein serum amyloid A (SAA) have been identified as integral constituents of HDL particles. Evidence suggests that S1P and SAA levels within HDL particles may be affected by inflammation and oxidative stress, which are coexisting processes underlying ASCVD. Because SAA, an inflammation-related marker, and S1P, an anti-atherothrombotic marker, have relatively clear opposite characteristics among the HDL-associated proteins, the approach of assessing the two markers simultaneously may provide new insights in clinical practice (S1P/SAA Index). This review focuses on evidence in support of the concept that the S1P/SAA Index may affect the HDL atheroprotective properties and may, therefore represent a potential target for therapeutic interventions.
Asunto(s)
HDL-Colesterol/sangre , HDL-Colesterol/química , Cardiopatías/sangre , Lisofosfolípidos/química , Proteína Amiloide A Sérica/química , Esfingosina/análogos & derivados , Cardiopatías/complicaciones , Humanos , Esfingosina/químicaRESUMEN
Obesity is a complex condition classically characterised by excessive body fat accumulation and represents one of the most important public health problems worldwide. Although several epidemiological studies have shown that elevated BMI is associated with higher morbidity, and with increased rate of death from all causes and from cardiovascular disease, accumulating evidence suggests that being overweight or obese may be protective (the so-called obesity paradox), at least in chronic diseases. These observations, not only question the validity of the BMI system, but also raise the intriguing question of whether we should redefine what the normal range of BMI is in individuals suffering from a chronic disease. In the present article, we review the available information on the association between elevated BMI and increased morbidity and mortality including obesity-related paradoxes, explore key aspects of the role and limitations of BMI as a measure of increased adiposity and outline potential solutions to address the current controversies regarding the impact of obesity on human health.
Asunto(s)
Índice de Masa Corporal , Obesidad/diagnóstico , Composición Corporal , Humanos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
Evidence suggests that high-density lipoprotein (HDL) components distinct from cholesterol, such as sphingosine-1-phosphate (S1P), may account for the anti-atherothrombotic effects attributed to this lipoprotein. The current method for the determination of plasma levels of S1P as well as levels associated with HDL particles is still cumbersome an assay method to be worldwide practical. Recently, a simplified protocol based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the sensitive and specific quantification of plasma levels of S1P with good accuracy has been reported. This work utilized a triple quadrupole (QqQ)-based LC-MS/MS system. Here we adapt that method for the determination of plasma levels of S1P using a quadrupole time of flight (Q-Tof) based LC-MS system. Calibration curves were linear in the range of 0.05 to 2 µM. The lower limit of quantification (LOQ) was 0.05 µM. The concentration of S1P in human plasma was determined to be 1 ± 0.09 µM (n = 6). The average accuracy over the stated range of the method was found to be 100 ± 5.9% with precision at the LOQ better than 10% when predicting the calibration standards. The concentration of plasma S1P in the prepared samples was stable for 24 h at room temperature. We have demonstrated the quantification of plasma S1P using Q-Tof based LC-MS with very good sensitivity, accuracy, and precision that can used for future studies in this field.
Asunto(s)
Cromatografía Liquida/métodos , Lisofosfolípidos/sangre , Esfingosina/análogos & derivados , Espectrometría de Masas en Tándem/métodos , Calibración , Humanos , Lipoproteínas HDL/sangre , Reproducibilidad de los Resultados , Esfingosina/sangreRESUMEN
BACKGROUND: Presence of macro- and microvascular complications in patients with diabetes mellitus (DM) is not only related to chronic hyperglycemia represented by glycated hemoglobin (HbA1c) but also to acute glycemic fluctuations (glycemic variability, GV). The association between GV and DM complications is not completely clear. Aim of our study was to evaluate GV by MAGE index in patients with type 2 DM and to verify association of MAGE index with presence of macro- and microvascular DM complications. METHODS: 99 patients with type 2 DM were included in the study. Every patient had done big glycemic profile, from which MAGE index was calculated. Anthropometric measurements, evaluation of HbA1c and fasting plasma glucose (FPG) and assessment for macrovascular (coronary artery disease - CAD; peripheral artery disease - PAD; cerebral stroke - CS) and microvascular (diabetic retinopathy - DR; nephropathy - DN; peripheral neuropathy - DPPN) DM complications were done. RESULTS: Average MAGE index value was 5.15 ± 2.88 mmol/l. We found no significant differences in MAGE index values in subgroups according to presence of neither CAD, CS, PAD nor DR, DN, DPPN. MAGE index value significantly positively correlated with FPG (p < 0.01) and HbA1c (p < 0.001) and negatively with weight (p < 0.05). CONCLUSION: In our study we failed to show association of MAGE index with presence of macrovascular and microvascular complications in patients with type 2 DM. However, this negative result does not necessarily disprove importance of glycemic variability in pathogenesis of diabetic complications.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Angiopatías Diabéticas/diagnóstico , Hemoglobina Glucada/análisis , Índice Glucémico , Distribución por Edad , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Estudios de Cohortes , Diabetes Mellitus Tipo 2/diagnóstico , Angiopatías Diabéticas/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Distribución por SexoRESUMEN
Modulation of Ca(2+) homoeostasis in cardiac myocytes plays a major role in beat-to-beat regulation of heart function. Previous studies suggest that sphingosine-1-phosphate (S1P), a biologically active sphingomyelin metabolite, regulates Ca(2+) handling in cardiac myocytes, but the underlying mechanism is unclear. In the present study, we tested the hypothesis that S1P-induced functional alteration of intracellular Ca(2+) handling includes the L-type calcium channel current (ICa,L) via a signalling pathway involving P21-activated kinase 1 (Pak1). Our results show that, in rat ventricular myocytes, S1P (100 nM) does not affect the basal activity of ICa,L but is able to partially reverse the effect of the ß-adrenergic agonist Isoproterenol (ISO, 100 nM) on ICa,L. S1P (25 nM) also significantly prevents ISO (5 nM)-induced Ca(2+) waves and diastolic Ca(2+) release in these cells. Our further molecular characterisation demonstrates that Pak1 activity is increased in myocytes treated with S1P (25 nM) compared with those myocytes without treatment of S1P. By immunoprecipitation we demonstrate that Pak1 and protein phosphatase 2A (PP2A) are associated in ventricular tissue indicating their functional interaction. Thus the results indicate that S1P attenuates ß-adrenergic stress-induced alteration of intracellular Ca(2+) release and L-type Ca(2+) channel current at least in part via Pak1-PP2A-mediated signalling.
Asunto(s)
Canales de Calcio Tipo L/metabolismo , Señalización del Calcio/efectos de los fármacos , Calcio/metabolismo , Ventrículos Cardíacos/metabolismo , Lisofosfolípidos/farmacología , Miocitos Cardíacos/metabolismo , Esfingosina/análogos & derivados , Animales , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteína Fosfatasa 2/metabolismo , Ratas , Esfingosina/farmacologíaRESUMEN
BACKGROUND: Assessment of coronary flow is only performed during pharmacological tests. Supine bicycle tests permit the visualization of coronary flow assessments during exercise. PURPOSE: To assess the parameters of coronary flow in the left anterior descending artery (LAD) during exercise, which could be a sign of significant LAD narrowing. MATERIAL AND METHODS: A total of 253 patients were enrolled: Group 1, 186 non-selective participants before undergoing a coronary angiography; and Group 2, 67 controls without coronary artery disease (CAD). All the patients performed a supine bicycle echocardiography test. Coronary flow velocities and coronary flow velocity reserve (CFVR) were measured at the mid-segment of the LAD during exercise. Patients in Group 1 underwent a coronary angiography. RESULTS: In comparison with participants without significant LAD stenosis, patients with LAD lesions had a lower ΔV (16 ± 21 vs. 27 ± 20 cm/s, P < 0.04) and a lower CFVR (1.5 ± 0.8 vs. 2.0 ± 0.6, P < 0.004). In comparison with patients without significant proximal LAD stenosis, the patients with proximal LAD lesions had a lower flow velocity at the peak of exercise (49 ± 32 vs. 61 ± 19 cm/s, P < 0.02), a lower ΔV (13 ± 19 vs. 26 ± 22 cm/s, P < 0.004), and a lower CFVR (1.4 ± 0.6 vs. 1.9 ± 0.7, P < 0.0001). In comparison with the control group, the patients with LAD stenosis had a lower flow velocity at the peak of exercise, a lower ΔV, and a lower CFVR. CONCLUSION: Non-invasive CFVR measurement in the LAD could provide valuable additional information to a conventional echocardiography exercise test. In routine clinical practice, CFVR is sufficient for a diagnosis of severe stenosis.
Asunto(s)
Velocidad del Flujo Sanguíneo , Circulación Coronaria , Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/fisiopatología , Ecocardiografía Doppler de Pulso , Ecocardiografía de Estrés , Prueba de Esfuerzo , Ciclismo/fisiología , Estudios de Casos y Controles , Angiografía Coronaria , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Biomechanical stress and inflammatory biomarkers relate to global contractility dysfunction; however, adding these biomarkers into a risk model constructed on clinical data does not improve its prediction value in chronic heart failure (CHF). AIM: The aim of this study was to evaluate whether biomarkers predict declining of left ventricular global contractility function in diabetic patients with ischemia-induced CHF. PATIENTS AND METHODS: The study retrospectively evolved 54 diabetic patients who had systolic or diastolic ischemia-induced CHF that was defined as left-ventricular ejection fraction (LVEF) ≤45% or 46-55% respectively assessed by quantitative echocardiography and other conventional criteria according to current clinical guidelines. Two-dimensional transthoracic echocardiography and tissue Doppler imaging were performed according to a conventional method. Radial, longitudinal, and circumferential strain and strain rate values were obtained by speckle-tracking Imaging analysis of both LV short axis and long axis views. Serum adiponectin, NT-pro brain natriuretic peptide (BNP), osteoprotegerin, and hs- C-reactive protein (CRP) were determined at baseline by ELISA. RESULTS: We found lower global longitudinal strain and strain rate in diabetic patients with LVEF <45% than these in diabetic patients that did not have LVEF (Ð =0.001 for all cases). Multivariate logistic regression analysis showed that NT-proBNP (r=0.432; P=0.001 and r=0.402; P=0.001, respectively), osteoprotegerin (r=0.422; P=0.001 and r=0.401; P=0.001, respectively), hs-CRP (r=0.408; P=0.001 and r=0.404; P=0.001, respectively) were independently inversely associated with global longitudinal strain and strain rate in CHF patients. CONCLUSION: We suggest that osteoprotegerin may be useful in improving the NT-proBNP based model as predictor of decreased global contractility function in diabetic patients with CHF.
Asunto(s)
Diabetes Mellitus/sangre , Diabetes Mellitus/fisiopatología , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/fisiopatología , Osteoprotegerina/sangre , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/fisiopatología , Biomarcadores/sangre , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Estudios Retrospectivos , Factores de Riesgo , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/tratamiento farmacológicoRESUMEN
Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes mellitus that impairs autonomic regulation of heart rate (HR). This has been attributed to damage to the nerves that modulate spontaneous pacemaker activity in the sinoatrial node (SAN). Our objective was to test the hypothesis that impaired parasympathetic regulation of HR in diabetes is due to reduced responsiveness of the SAN to parasympathetic agonists. We used the Akita mouse model of type 1 diabetes to study the effects of the parasympathetic agonist carbachol (CCh) on SAN function using intracardiac programmed stimulation, high resolution optical mapping and patch-clamping of SAN myocytes. CCh decreased HR by 30% and increased corrected SAN recovery time (cSNRT) by 123% in wildtype mice. In contrast, CCh only decreased HR by 12%, and only increased cSNRT by 37% in Akita mice. These alterations were due to smaller effects of CCh on SAN electrical conduction and spontaneous action potential firing in isolated SAN myocytes. Voltage clamp experiments demonstrate that the acetylcholine-activated K(+) current (IKACh) is reduced in Akita SAN myocytes due to enhanced desensitization and faster deactivation kinetics. These IKACh alterations were normalized by treating Akita SAN myocytes with PI(3,4,5)P3 or an inhibitor of regulator of G-protein signaling 4 (RGS4). There was no difference in the effects of CCh on the hyperpolarization-activated current (If) between wildtype and Akita mice. Our study demonstrates that Akita diabetic mice demonstrate impaired parasympathetic regulation of HR and SAN function due to reduced responses of the SAN to parasympathetic agonists. Our experiments demonstrate a key role for insulin-dependent phosphoinositide 3-kinase (PI3K) signaling in the parasympathetic dysfunction seen in the SAN in diabetes.
Asunto(s)
Sistema Nervioso Parasimpático/fisiopatología , Nodo Sinoatrial/inervación , Acetilcolina/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Carbacol/farmacología , Cardiotónicos/farmacología , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/fisiopatología , Modelos Animales de Enfermedad , Corazón/efectos de los fármacos , Corazón/fisiopatología , Insulina/administración & dosificación , Insulina/farmacología , Ratones , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Proteínas RGS/antagonistas & inhibidores , Proteínas RGS/metabolismo , Nodo Sinoatrial/efectos de los fármacosRESUMEN
The sphingosine-1-phosphate (S1P) receptor modulator, fingolimod (FTY720), has been used for the treatment of patients with relapsing forms of multiple sclerosis, but atrioventricular (AV) conduction block have been reported in some patients after the first dose. The underlying mechanism of this AV node conduction blockade is still not well-understood. In this study, we hypothesize that expression of this particular arrhythmia might be related to a direct effect of FTY720 on AV node rather than a parasympathetic mimetic action. We, therefore, investigated the effect of FTY720 on AV nodal, using in vitro rat model preparation, under both basal as well as ischaemia/reperfusion conditions. We first look at the expression pattern of S1P receptors on the AV node using real-time PCR. Although all three S1P receptor isoforms were expressed in AVN tissues, S1P1 receptor isoform expression level was higher than S1P2 and S1P3. The effect of 25 nM FTY720 on cycle length (CL) was subsequently studied via extracellular potentials recordings. FTY720 caused a mild to moderate prolongation in CL by an average 9% in AVN (n = 10, P < 0.05) preparations. We also show that FTY720 attenuated both ischaemia and reperfusion induced AVN rhythmic disturbance. To our knowledge, these remarkable findings have not been previously reported in the literature, and stress the importance for extensive monitoring period in certain cases, especially in patients taking concurrently AV node blocker agents.
Asunto(s)
Nodo Atrioventricular/efectos de los fármacos , Clorhidrato de Fingolimod/farmacología , Lisofosfolípidos/farmacología , Esfingosina/análogos & derivados , Animales , Nodo Atrioventricular/fisiopatología , Disección , Regulación de la Expresión Génica/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptores de Lisoesfingolípidos/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatología , Esfingosina/farmacologíaRESUMEN
Natriuretic peptides (NPs) are critical regulators of the cardiovascular system that are currently viewed as possible therapeutic targets for the treatment of heart disease. Recent work demonstrates potent NP effects on cardiac electrophysiology, including in the sinoatrial node (SAN) and atria. NPs elicit their effects via three NP receptors (NPR-A, NPR-B and NPR-C). Among these receptors, NPR-C is poorly understood. Accordingly, the goal of this study was to determine the effects of NPR-C ablation on cardiac structure and arrhythmogenesis. Cardiac structure and function were assessed in wild-type (NPR-C(+/+)) and NPR-C knockout (NPR-C(-/-)) mice using echocardiography, intracardiac programmed stimulation, patch clamping, high-resolution optical mapping, quantitative polymerase chain reaction and histology. These studies demonstrate that NPR-C(-/-) mice display SAN dysfunction, as indicated by a prolongation (30%) of corrected SAN recovery time, as well as an increased susceptibility to atrial fibrillation (6% in NPR-C(+/+) vs. 47% in NPR-C(-/-)). There were no differences in SAN or atrial action potential morphology in NPR-C(-/-) mice; however, increased atrial arrhythmogenesis in NPR-C(-/-) mice was associated with reductions in SAN (20%) and atrial (15%) conduction velocity, as well as increases in expression and deposition of collagen in the atrial myocardium. No differences were seen in ventricular arrhythmogenesis or fibrosis in NPR-C(-/-) mice. This study demonstrates that loss of NPR-C results in SAN dysfunction and increased susceptibility to atrial arrhythmias in association with structural remodelling and fibrosis in the atrial myocardium. These findings indicate a critical protective role for NPR-C in the heart.
Asunto(s)
Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Receptores del Factor Natriurético Atrial/genética , Nodo Sinoatrial/metabolismo , Potenciales de Acción , Animales , Células Cultivadas , Colágeno/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/fisiología , Receptores del Factor Natriurético Atrial/metabolismo , Nodo Sinoatrial/fisiopatologíaRESUMEN
The B-type natriuretic peptide (BNP), a member of the family of vasoactive peptides, is a potent natriuretic, diuretic, and vasodilatory peptide that contributes to blood pressure and volume homeostasis. These attributes make BNP an ideal drug that could aid in diuresing a fluid-overloaded patient who had poor or worsening renal function. Despite the potential benefits of BNP, accumulating evidence suggests that simply increasing the amount of circulating BNP does not necessarily increase natriuresis in patients with heart failure (HF). Moreover, despite high BNP levels, natriuresis falls when HF progresses from a compensated to a decompensated state, suggesting the emergence of renal resistance to BNP. Although likely multifactorial, several mechanisms have been proposed to explain renal hyporesponsiveness in HF, including, but not limited to, decreased renal BNP availability, down-regulation of natriuretic peptide receptors, and altered BNP intracellular signal transduction pathways. Thus, a better understanding of renal hyporesponsiveness in HF is required to devise strategies to develop novel agents and technologies that directly restore renal BNP efficiency. It is hoped that development of these new therapeutic approaches will serve to limit sodium retention in patients with HF, which may ultimately delay the progression to overt HF.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Riñón/fisiopatología , Péptido Natriurético Encefálico/metabolismo , Animales , Insuficiencia Cardíaca/metabolismo , Humanos , Riñón/metabolismo , Natriuresis/fisiología , Péptidos Natriuréticos/metabolismo , Transducción de Señal/fisiologíaRESUMEN
The B-type natriuretic peptide (BNP) may favour natriuresis and diuresis, making it an ideal drug to aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these has resulted in a better outcome. The current challenge for BNP research in acute HF lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP as well as a better integration of basic and clinical science.