RESUMEN
Exercise intolerance is a hallmark symptom of heart failure and to a large extent stems from reductions in cardiac output that occur due to the inherent ventricular dysfunction coupled with enhanced muscle metaboreflex-induced functional coronary vasoconstriction, which limits increases in coronary blood flow. This creates a further mismatch between O2 delivery and O2 demand, which may activate the cardiac sympathetic afferent reflex (CSAR), causing amplification of the already increased sympathetic activity in a positive-feedback fashion. We used our chronically instrumented conscious canine model to evaluate if chronic ablation of afferents responsible for the CSAR would attenuate the gain of muscle metaboreflex before and after induction of heart failure. After afferent ablation, the gain of the muscle metaboreflex control of mean arterial pressure was significantly reduced before (-239.5 ± 16 to -95.2 ± 8 mmHg/L/min) and after the induction of heart failure (-185.6 ± 14 to -95.7 ± 12 mmHg/L/min). Similar results were observed for the strength (gain) of muscle metaboreflex control of heart rate, cardiac output, and ventricular contractility. Thus, we conclude that the CSAR contributes significantly to the strength of the muscle metaboreflex in normal animals with heart failure serving as an effective positive-feedback amplifier thereby further increasing sympathetic activity.NEW & NOTEWORTHY The powerful pressor responses from the CSAR arise via O2 delivery versus O2 demand imbalance. Muscle metaboreflex activation (MMA) simultaneously elicits coronary vasoconstriction (which is augmented in heart failure) and profound increases in cardiac work thereby upsetting oxygen balance. Whether MMA activates the CSAR thereby amplifying MMA responses is unknown. We observed that removal of the CSAR afferents attenuated the strength of the muscle metaboreflex in normal and subjects with heart failure.
Asunto(s)
Insuficiencia Cardíaca , Músculo Esquelético , Animales , Perros , Humanos , Retroalimentación , Vasoconstricción , Reflejo/fisiología , Frecuencia Cardíaca , Presión SanguíneaRESUMEN
Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex-induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express transient receptor potential vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultrapotent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1-sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4-L6) of RTX (2 µg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex-induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min), and stroke work (2.27 ± 0.2 L·mmHg vs. 1.01 ± 0.2 L·mmHg). Effects were maintained until 78 ± 14 days post-RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 µg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre-RTX vs. +19.7 ± 3.1 mmHg post-RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.
Asunto(s)
Gasto Cardíaco/efectos de los fármacos , Diterpenos/farmacología , Miembro Posterior/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Animales , Presión Arterial/efectos de los fármacos , Gasto Cardíaco/fisiología , Diterpenos/administración & dosificación , Perros , Corazón/efectos de los fármacos , Corazón/fisiopatología , Miembro Posterior/fisiopatología , Isquemia/fisiopatología , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Flujo Sanguíneo Regional/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Vasoconstricción/fisiologíaRESUMEN
INTRODUCTION: Epilepsy is a debilitating neurological condition characterized by spontaneous seizures as well as significant comorbid behavioral abnormalities. In addition to seizures, epileptic patients exhibit interictal spikes far more frequently than seizures, often, but not always observed in the same brain areas. The exact relationship between spiking and seizures as well as their respective effects on behavior are not well understood. In fact, spiking without overt seizures is seen in various psychiatric conditions including attention-deficit hyperactivity disorder. METHODS: In order to study the effects of spiking and seizures on behavior in an epileptic animal model, we used long-term video-electroencephalography recordings at six cortical recording sites together with behavioral activity monitoring. Animals received unilateral injections of tetanus toxin into either the somatosensory or motor cortex. RESULTS: Somatosensory cortex-injected animals developed progressive spiking ipsilateral to the injection site, while those receiving the injection into the motor cortex developed mostly contralateral spiking and spontaneous seizures. Animals with spiking but no seizures displayed a hyperactive phenotype, while animals with both spiking and seizures displayed a hypoactive phenotype. Not all spikes were equivalent as spike location strongly correlated with distinct locomotor behaviors including ambulatory distance, vertical movements, and rotatory movement. CONCLUSIONS: Together, our results demonstrate relationships between brain region-specific spiking, seizures, and behaviors in rodents that could translate into a better understanding for patients with epileptic behavioral comorbidities and other neuropsychiatric disorders.
Asunto(s)
Epilepsia , Animales , Encéfalo , Electroencefalografía , Epilepsia/complicaciones , Humanos , Convulsiones/inducido químicamente , Corteza SomatosensorialRESUMEN
Underperfusion of active skeletal muscle causes metabolites to accumulate and stimulate group III and IV skeletal muscle afferents, which triggers a powerful pressor response termed the muscle metaboreflex. Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in healthy individuals increases arterial pressure mainly via substantial increases in cardiac output (CO). The increases in CO occur via the combination of tachycardia and increased ventricular contractility. Importantly, MMA also elicits substantial central blood volume mobilization, which allows the ventricular responses to sustain the increases in CO. Otherwise preload would fall and the increases in CO could not be maintained. In subjects with systolic heart failure (HF), the ability to increase CO during exercise and MMA is markedly reduced, which has been attributed to impaired ventricular contractility. Whether the ability to maintain preload during MMA in HF is preserved is unknown. Using a conscious chronically instrumented canine model, we observed that MMA in HF is able to raise central blood volume similarly as in normal subjects. Therefore, the loss of the ability to raise CO during MMA in HF is not because of the loss of the ability to mobilize blood volume centrally. NEW & NOTEWORTHY In normal subjects during dynamic exercise muscle metaboreflex activation elicits large increases in cardiac output that occur via increases in heart rate, ventricular contractility, and, importantly, marked central blood volume mobilization that acts to maintain ventricular preload, thereby allowing the changes in cardiac function to maintain the increases in cardiac output. In subjects with heart failure, the ability to raise cardiac output during muscle metaboreflex activation is impaired. We investigated whether this is because of the inability to maintain ventricular preload. We found that this reflex is still able to elicit large increases in central blood volume, and therefore the limited ability to raise cardiac output likely stems from ventricular dysfunction and not the ability to maintain preload.
Asunto(s)
Volumen Sanguíneo , Gasto Cardíaco , Células Quimiorreceptoras/metabolismo , Tolerancia al Ejercicio , Insuficiencia Cardíaca/fisiopatología , Contracción Muscular , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/inervación , Reflejo , Animales , Presión Arterial , Presión Venosa Central , Modelos Animales de Enfermedad , Perros , Femenino , Insuficiencia Cardíaca/metabolismo , Frecuencia Cardíaca , Homeostasis , Masculino , Músculo Esquelético/metabolismo , Carrera , Factores de TiempoRESUMEN
Two powerful reflexes controlling cardiovascular function during exercise are the muscle metaboreflex and arterial baroreflex. In heart failure (HF), the strength and mechanisms of these reflexes are altered. Muscle metaboreflex activation (MMA) in normal subjects increases mean arterial pressure (MAP) primarily via increases in cardiac output (CO), whereas in HF the mechanism shifts to peripheral vasoconstriction. Baroreceptor unloading increases MAP via peripheral vasoconstriction, and this pressor response is blunted in HF. Baroreceptor unloading during MMA in normal animals elicits an enormous pressor response via combined increases in CO and peripheral vasoconstriction. The mode of interaction between these reflexes is intimately dependent on the parameter (e.g., MAP and CO) being investigated. The interaction between the two reflexes when activated simultaneously during dynamic exercise in HF is unknown. We activated the muscle metaboreflex in chronically instrumented dogs during mild exercise (via graded reductions in hindlimb blood flow) followed by baroreceptor unloading [via bilateral carotid occlusion (BCO)] before and after induction of HF. We hypothesized that BCO during MMA in HF would cause a smaller increase in MAP and a larger vasoconstriction of ischemic hindlimb vasculature, which would attenuate the restoration of blood flow to ischemic muscle observed in normal dogs. We observed that BCO during MMA in HF increases MAP by substantial vasoconstriction of all vascular beds, including ischemic active muscle, and that all cardiovascular responses, except ventricular function, exhibit occlusive interaction. We conclude that vasoconstriction of ischemic active skeletal muscle in response to baroreceptor unloading during MMA attenuates restoration of hindlimb blood flow. NEW & NOTEWORTHY We found that baroreceptor unloading during the muscle metaboreflex in heart failure results in occlusive interaction (except for ventricular function) with significant vasoconstriction of all vascular beds. In addition, restoration of blood flow to ischemic active muscle, via preferentially larger vasoconstriction of nonischemic beds, is significantly attenuated in heart failure.
Asunto(s)
Presión Arterial , Barorreflejo , Células Quimiorreceptoras/metabolismo , Metabolismo Energético , Insuficiencia Cardíaca/fisiopatología , Músculo Esquelético/inervación , Músculo Esquelético/metabolismo , Presorreceptores/fisiopatología , Adaptación Fisiológica , Animales , Gasto Cardíaco , Modelos Animales de Enfermedad , Perros , Femenino , Insuficiencia Cardíaca/metabolismo , Miembro Posterior , Masculino , Contracción Muscular , Flujo Sanguíneo Regional , Factores de Tiempo , VasoconstricciónRESUMEN
When oxygen delivery to active muscle is insufficient to meet the metabolic demand during exercise, metabolites accumulate and stimulate skeletal muscle afferents, inducing a reflex increase in blood pressure, termed the muscle metaboreflex. In healthy individuals, muscle metaboreflex activation (MMA) during submaximal exercise increases arterial pressure primarily via an increase in cardiac output (CO), as little peripheral vasoconstriction occurs. This increase in CO partially restores blood flow to ischemic muscle. However, we recently demonstrated that MMA induces sympathetic vasoconstriction in ischemic active muscle, limiting the ability of the metaboreflex to restore blood flow. In heart failure (HF), increases in CO are limited, and metaboreflex-induced pressor responses occur predominantly via peripheral vasoconstriction. In the present study, we tested the hypothesis that vasoconstriction of ischemic active muscle is exaggerated in HF. Changes in hindlimb vascular resistance [femoral arterial pressure ÷ hindlimb blood flow (HLBF)] were observed during MMA (via graded reductions in HLBF) during mild exercise with and without α1-adrenergic blockade (prazosin, 50 µg/kg) before and after induction of HF. In normal animals, initial HLBF reductions caused metabolic vasodilation, while reductions below the metaboreflex threshold elicited reflex vasoconstriction, in ischemic active skeletal muscle, which was abolished after α1-adrenergic blockade. Metaboreflex-induced vasoconstriction of ischemic active muscle was exaggerated after induction of HF. This heightened vasoconstriction impairs the ability of the metaboreflex to restore blood flow to ischemic muscle in HF and may contribute to the exercise intolerance observed in these patients. We conclude that sympathetically mediated vasoconstriction of ischemic active muscle during MMA is exaggerated in HF. NEW & NOTEWORTHY We found that muscle metaboreflex-induced vasoconstriction of the ischemic active skeletal muscle from which the reflex originates is exaggerated in heart failure. This results in heightened metaboreflex activation, which further amplifies the reflex-induced vasoconstriction of the ischemic active skeletal muscle and contributes to exercise intolerance in patients.
Asunto(s)
Metabolismo Energético , Insuficiencia Cardíaca/fisiopatología , Isquemia/fisiopatología , Contracción Muscular , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/inervación , Reflejo , Vasoconstricción , Animales , Presión Arterial , Gasto Cardíaco , Modelos Animales de Enfermedad , Perros , Femenino , Insuficiencia Cardíaca/metabolismo , Miembro Posterior , Isquemia/metabolismo , Masculino , Músculo Esquelético/metabolismo , Oxígeno/sangre , Receptores Adrenérgicos alfa 1/metabolismo , VasodilataciónRESUMEN
The muscle metaboreflex is a powerful pressor reflex induced by the activation of chemically sensitive muscle afferents as a result of metabolite accumulation. During submaximal dynamic exercise, the rise in arterial pressure is primarily due to increases in cardiac output, since there is little systemic vasoconstriction. Indeed, in normal animals, we have often shown a small, but significant, peripheral vasodilation during metaboreflex activation, which is mediated, at least in part, by release of epinephrine and activation of vascular ß2-receptors. We tested whether this vasodilation is in part due to increased release of nitric oxide caused by the rise in cardiac output eliciting endothelium-dependent flow-mediated vasodilation. The muscle metaboreflex was activated via graded reductions in hindlimb blood flow during mild exercise with and without nitric oxide synthesis blockade [NG-nitro-l-arginine methyl ester (l-NAME); 5 mg/kg]. We assessed the role of increased cardiac output in mediating peripheral vasodilation via the slope of the relationship between the rise in nonischemic vascular conductance (conductance of all vascular beds excluding hindlimbs) vs. the rise in cardiac output. l-NAME increased mean arterial pressure at rest and during exercise. The metaboreflex-induced increases in mean arterial pressure were unaltered by l-NAME, whereas the increases in cardiac output and nonischemic vascular conductance were attenuated. However, the slope of the relationship between nonischemic vascular conductance and cardiac output was not affected by l-NAME, indicating that the rise in cardiac output did not elicit vasodilation via increased release of nitric oxide. Thus, although nitric oxide is intrinsic to the vascular tonus, endothelial-dependent flow-mediated vasodilation plays little role in the small peripheral vasodilation observed during muscle metaboreflex activation.
Asunto(s)
Conductividad Eléctrica , Endotelio Vascular/fisiología , Músculo Esquelético/fisiología , Óxido Nítrico/metabolismo , Reflejo/fisiología , Animales , Perros , Femenino , MasculinoRESUMEN
The muscle metaboreflex and arterial baroreflex regulate arterial pressure through distinct mechanisms. During submaximal exercise muscle metaboreflex activation (MMA) elicits a pressor response virtually solely by increasing cardiac output (CO) while baroreceptor unloading increases mean arterial pressure (MAP) primarily through peripheral vasoconstriction. The interaction between the two reflexes when activated simultaneously has not been well established. We activated the muscle metaboreflex in chronically instrumented canines during dynamic exercise (via graded reductions in hindlimb blood flow; HLBF) followed by simultaneous baroreceptor unloading (via bilateral carotid occlusion; BCO). We hypothesized that simultaneous activation of both reflexes would result in an exacerbated pressor response owing to both an increase in CO and vasoconstriction. We observed that coactivation of muscle metaboreflex and arterial baroreflex resulted in additive interaction although the mechanisms for the pressor response were different. MMA increased MAP via increases in CO, heart rate (HR), and ventricular contractility whereas baroreflex unloading during MMA caused further increases in MAP via a large decrease in nonischemic vascular conductance (NIVC; conductance of all vascular beds except the hindlimb vasculature), indicating substantial peripheral vasoconstriction. Moreover, there was significant vasoconstriction within the ischemic muscle itself during coactivation of the two reflexes but the remaining vasculature vasoconstricted to a greater extent, thereby redirecting blood flow to the ischemic muscle. We conclude that baroreceptor unloading during MMA induces preferential peripheral vasoconstriction to improve blood flow to the ischemic active skeletal muscle.
Asunto(s)
Presión Arterial/fisiología , Barorreflejo/fisiología , Gasto Cardíaco/fisiología , Isquemia/fisiopatología , Músculo Esquelético/irrigación sanguínea , Contracción Miocárdica/fisiología , Flujo Sanguíneo Regional/fisiología , Vasoconstricción/fisiología , Animales , Arterias Carótidas , Perros , Femenino , Frecuencia Cardíaca , Miembro Posterior/irrigación sanguínea , Masculino , Presorreceptores , ReflejoRESUMEN
Metabolite accumulation due to ischemia of active skeletal muscle stimulates group III/IV chemosensitive afferents eliciting reflex increases in arterial blood pressure and sympathetic activity, termed the muscle metaboreflex. We and others have previously demonstrated sympathetically mediated vasoconstriction of coronary, renal, and forelimb vasculatures with muscle metaboreflex activation (MMA). Whether MMA elicits vasoconstriction of the ischemic muscle from which it originates is unknown. We hypothesized that the vasodilation in active skeletal muscle with imposed ischemia becomes progressively restrained by the increasing sympathetic vasoconstriction during MMA. We activated the metaboreflex during mild dynamic exercise in chronically instrumented canines via graded reductions in hindlimb blood flow (HLBF) before and after α1-adrenergic blockade [prazosin (50 µg/kg)], ß-adrenergic blockade [propranolol (2 mg/kg)], and α1 + ß-blockade. Hindlimb resistance was calculated as femoral arterial pressure/HLBF. During mild exercise, HLBF must be reduced below a threshold level before the reflex is activated. With initial reductions in HLBF, vasodilation occurred with the imposed ischemia. Once the muscle metaboreflex was elicited, hindlimb resistance increased. This increase in hindlimb resistance was abolished by α1-adrenergic blockade and exacerbated after ß-adrenergic blockade. We conclude that metaboreflex activation during submaximal dynamic exercise causes sympathetically mediated α-adrenergic vasoconstriction in ischemic skeletal muscle. This limits the ability of the reflex to improve blood flow to the muscle.
Asunto(s)
Isquemia/fisiopatología , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Esfuerzo Físico , Vasoconstricción/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Presión Arterial , Perros , Femenino , Miembro Posterior/irrigación sanguínea , Masculino , Músculo Esquelético/efectos de los fármacos , Neuronas Aferentes/metabolismo , Prazosina/farmacología , Propranolol/farmacología , Reflejo , Flujo Sanguíneo Regional , Sistema Nervioso Simpático , Resistencia Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
High-fructose diet is known to produce cardiovascular and metabolic pathologies. The objective was to determine whether the timing of high fructose (10% liquid solution) intake affect the metabolic and cardiovascular outcomes. Male C57BL mice with radiotelemetric probes were divided into four groups: (1) 24 h water (control); (2) 24 h fructose (F24); (3) 12 h fructose during the light phase (F12L); (4) 12 h fructose during the dark phase (F12D). All fructose groups had higher fluid intake. Body weight was increased in mice on restricted access with no difference in total caloric intake. Fasting glycemia was higher in groups with restricted access. F24 mice showed a fructose-induced blood pressure increase during the dark period. Blood pressure circadian rhythms were absent in F12L mice. Results suggest that the timing of fructose intake is an important variable in the etiology of cardiovascular and metabolic pathologies produced by high fructose consumption.
Asunto(s)
Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Fructosa/farmacología , Animales , Glucemia/metabolismo , Ingestión de Líquidos/efectos de los fármacos , Prueba de Tolerancia a la Glucosa , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , TelemetríaRESUMEN
OBJECTIVE: Epilepsy is a disease characterized by chronic seizures, but is associated with significant comorbidities between seizures including cognitive impairments, hyperactivity, and depression. To study this interictal state, we characterized the electrical, molecular, and behavior effects of chronic, neocortical interictal spiking in rats. METHODS: A single injection of tetanus toxin into somatosensory cortex generated chronic interictal spiking measured by long-term video EEG monitoring and was correlated with motor activity. The cortical pattern of biomarker activation and the effects of blocking MAPK signaling on interictal spiking and behavior were determined. RESULTS: Interictal spiking in this model increases in frequency, size, and becomes repetitive over time, but is rarely associated with seizures. Interictal spiking was sufficient to produce the same molecular and cellular pattern of layer 2/3-specific CREB activation and plasticity gene induction as is seen in the human interictal state. Increasing spike frequency was associated with hyperactivity, demonstrated by increased ambulatory activity and preferential circling toward the spiking hemisphere. Loud noises induced epileptic discharges, identical to spontaneous discharges. Treatment with a selective MAPK inhibitor prevented layer 2/3 CREB activation, reduced the frequency of epileptic discharges, and normalized behavioral abnormalities, but had no effect on seizures induced by electrical kindling. INTERPRETATION: These results provide insights into the development of interictal epileptic spiking, their relationship to behavior, and suggest that interictal and ictal activities utilize distinct molecular pathways. This model, that parallels recent observations in humans, will be useful to develop therapeutics against interictal spiking and its behavioral comorbidities.
Asunto(s)
Conducta Animal/efectos de los fármacos , Ondas Encefálicas/efectos de los fármacos , Epilepsia/fisiopatología , Actividad Motora/efectos de los fármacos , Corteza Somatosensorial/fisiopatología , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Electroencefalografía/efectos de los fármacos , Excitación Neurológica , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Masculino , Neurotoxinas/farmacología , Ratas , Ratas Sprague-Dawley , Corteza Somatosensorial/efectos de los fármacos , Toxina Tetánica/farmacologíaRESUMEN
Consumption of high levels of fructose in humans and animals leads to metabolic and cardiovascular dysfunction. There are questions as to the role of the autonomic changes in the time course of fructose-induced dysfunction. C57/BL male mice were given tap water or fructose water (100 g/l) to drink for up to 2 mo. Groups were control (C), 15-day fructose (F15), and 60-day fructose (F60). Light-dark patterns of arterial pressure (AP) and heart rate (HR), and their respective variabilities were measured. Plasma glucose, lipids, insulin, leptin, resistin, adiponectin, and glucose tolerance were quantified. Fructose increased systolic AP (SAP) at 15 and 60 days during both light (F15: 123 ± 2 and F60: 118 ± 2 mmHg) and dark periods (F15: 136 ± 4 and F60: 136 ± 5 mmHg) compared with controls (light: 111 ± 2 and dark: 117 ± 2 mmHg). SAP variance (VAR) and the low-frequency component (LF) were increased in F15 (>60% and >80%) and F60 (>170% and >140%) compared with C. Cardiac sympatho-vagal balance was enhanced, while baroreflex function was attenuated in fructose groups. Metabolic parameters were unchanged in F15. However, F60 showed significant increases in plasma glucose (26%), cholesterol (44%), triglycerides (22%), insulin (95%), and leptin (63%), as well as glucose intolerance. LF of SAP was positively correlated with SAP. Plasma leptin was correlated with triglycerides, insulin, and glucose tolerance. Results show that increased sympathetic modulation of vessels and heart preceded metabolic dysfunction in fructose-consuming mice. Data suggest that changes in autonomic modulation may be an initiating mechanism underlying the cluster of symptoms associated with cardiometabolic disease.
Asunto(s)
Fructosa/efectos adversos , Intolerancia a la Glucosa/metabolismo , Sistema Nervioso Simpático/fisiopatología , Animales , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Modelos Animales de Enfermedad , Intolerancia a la Glucosa/inducido químicamente , Intolerancia a la Glucosa/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Insulina/sangre , Resistencia a la Insulina/fisiología , Leptina/sangre , Lípidos/sangre , Masculino , Ratones , Sistema Nervioso Simpático/metabolismoRESUMEN
AIM: To determine whether pharmacological blockade of angiotensin (Ang) AT1 receptors alters the cardiovascular, metabolic, and angiotensin-converting enzyme (ACE and ACE2) responses to a fructose diet in mice. METHODS: C57BL male mice were fed with a 60% fructose diet for 8 weeks in combination with losartan treatment on week 9 (30 mg/kg per day). Blood pressure (BP), heart rate (HR), and autonomic balance were monitored using radiotelemetry with spectral analysis. Renal ACE and ACE2 activity and protein levels as well as Ang II and Ang 1-7 were measured. RESULTS: Fructose impaired glucose tolerance and increased plasma cholesterol and insulin. These effects were not corrected by losartan treatment. Fructose increased BP and HR but only during the dark period. Short-term losartan treatment decreased BP by 16% in the fructose group but had no effect in controls. This was accompanied by a decrease in BP variance and its low-frequency component. Fructose increased Ang II (plasma and kidney) and ACE 2 (renal activity and protein expression). Losartan alone increased plasma Ang II in plasma and ACE2 in kidney. There were no changes in renal Ang 1-7 levels. CONCLUSIONS: Losartan reversed the pressor effect of a high fructose diet, demonstrating that there are prominent interactions between a dietary regimen that produces glucose intolerance and an antihypertensive drug that antagonizes Ang signaling. The mechanism of change may be via renal Ang II rather than the ACE2/Ang 1-7 pathway because the fructose losartan combination resulted in lowered renal Ang II without changes in Ang 1-7.
Asunto(s)
Antihipertensivos/farmacología , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Fructosa/farmacología , Losartán/farmacología , Peptidil-Dipeptidasa A/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Análisis de Varianza , Animales , Presión Sanguínea/efectos de los fármacos , Western Blotting , Colesterol/sangre , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Frecuencia Cardíaca/efectos de los fármacos , Insulina/sangre , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The db/db mice serve as a good model for type 2 diabetes characterized by hyperinsulinaemia and progressive hyperglycaemia. There are limited and conflicting data on the cardiovascular changes in this model. The aim of the present study was to characterize the cardiovascular and autonomic phenotype of male db/db mice and evaluate the role of angiotensin II AT(1) receptors. Radiotelemetry was used to monitor 24 h blood pressure (BP) in mice for 8 weeks. Parameters measured were mean arterial pressure (MAP), heart rate (HR) and their variabilities. In 8-week-old db/db mice, the MAP and BP circadian rhythms were not different from age-matched control mice, while HR and locomotor activity were decreased. With ageing, MAP gradually increased in db/db mice, and the 12 h light values did not dip significantly from the 12 h dark periods. In 14-week-old mice, MAP was increased during light (101 +/- 1 versus 117 +/- 2 mmHg, P < 0.01; control versus db/db mice) and dark phases (110 +/- 1.7 versus 121 +/- 3.1 mmHg, P < 0.01; control versus db/db mice). This increase in MAP was associated with a significant increase in plasma angiotensin-converting enzyme activity and angiotensin II levels. Chronic treatment with losartan (10 mg kg(-1) day(-1)) blocked the increase in MAP in db/db mice, with no effect in control animals. Spectral analysis was used to monitor autonomic cardiovascular function. The circadian rhythm observed in systolic arterial pressure variance and its low-frequency component in control mice was absent in db/db mice. There were no changes in HR variability and spontaneous baroreflex sensitivity between control and db/db mice. The results document an age-related increase in MAP in db/db mice, which can be reduced by antagonism of angiotensin II AT(1) receptors, and alterations in autonomic balance and components of the renin-angiotensin system.
Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Sistema Cardiovascular/fisiopatología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Receptores de Leptina/genética , Envejecimiento/genética , Envejecimiento/fisiología , Angiotensina II/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Sistema Nervioso Autónomo/efectos de los fármacos , Barorreflejo/genética , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Sistema Cardiovascular/efectos de los fármacos , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/etiología , Complicaciones de la Diabetes/genética , Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Frecuencia Cardíaca/fisiología , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Hipertensión/genética , Hipertensión/fisiopatología , Losartán/farmacología , Masculino , Ratones , Ratones Mutantes , Actividad Motora/fisiología , Peptidil-Dipeptidasa A/sangre , Fenotipo , Receptor de Angiotensina Tipo 1/fisiologíaRESUMEN
We investigated the effect of exercise training on blood pressure, heart rate, and arterial baro- and chemoreflex sensitivity in diabetic rats (streptozotocin, 50 mg/kg iv). Male Wistar rats (251+/-10 g) were divided into 4 groups (n=8, each group): sedentary normotensive (SC), sedentary diabetic (SD), trained normotensive (TC), and trained diabetic (TD). Trained groups underwent exercise training on a treadmill (10 weeks). Exercise training induced resting bradycardia (340+/-5 vs. 316+/-8 bpm) and improvement in baroreflex tachycardic response (3.4+/-0.31 vs. 2.7+/-0.06 bpm/mmHg in SC) and chemoreflex bradycardic (145+/-12 vs. 78+/-7 bpm in SC) and pressor (49+/-5 vs. 22+/-3 mmHg in SC) responses in control rats. Diabetic-induced hypotension (SC: 107+/-2 vs. SD: 93+/-2 mmHg) and bradycardia (SC: 340+/-5 vs. SD: 276+/-7 bpm) were reversed by exercise training. Baroreflex tachycardic and bradycardic responses impaired in SD rats (SD: 2.1+/-0.18 and 1.3+/-0.08 vs. SC: 2.7+/-0.06 and 1.3+/-0.08 bpm/mmHg) were enhanced in TD rats (2.5+/-0.1 and 1.7+/-0.06 bpm/mmHg). Chemoreflex bradycardic and pressor responses, attenuated in SD rats (23+/-9 bpm and 7+/-1 mmHg) in relation to SC rats, were improved by exercise (TD: 84+/-15 bpm and 32+/-5 mmHg). The improvement in arterial baro- and chemoreflex-mediated control of circulation in trained control and diabetic rats reinforces the role of exercise in the management of cardiovascular risk in healthy and diabetic individuals.