RESUMEN
The sensitization and hypertonicity of visceral afferents are highly relevant to the development and progression of cardiovascular and respiratory disease states. In this review, we described the evidence that the inflammatory process regulates visceral afferent sensitivity and tonicity, affecting the control of the cardiovascular and respiratory system. Some inflammatory mediators like nitric oxide, angiotensin II, endothelin-1, and arginine vasopressin may inhibit baroreceptor afferents and contribute to the baroreflex impairment observed in cardiovascular diseases. Cytokines may act directly on peripheral afferent terminals that transmit information to the central nervous system (CNS). TLR-4 receptors, which recognize lipopolysaccharide, were identified in the nodose and petrosal ganglion and have been implicated in disrupting the blood-brain barrier, which can potentiate the inflammatory process. For example, cytokines may cross the blood-brain barrier to access the CNS. Additionally, pro-inflammatory cytokines such as IL-1ß, IL-6, TNF-α and some of their receptors have been identified in the nodose ganglion and carotid body. These pro-inflammatory cytokines also sensitize the dorsal root ganglion or are released in the nucleus of the solitary tract. In cardiovascular disease, pro-inflammatory mediators increase in the brain, heart, vessels, and plasma and may act locally or systemically to activate/sensitize afferent nervous terminals. Recent evidence demonstrated that the carotid body chemoreceptor cells might sense systemic pro-inflammatory molecules, supporting the novel proposal that the carotid body is part of the afferent pathway in the central anti-inflammatory reflexes. The exact mechanisms of how pro-inflammatory mediators affects visceral afferent signals and contribute to the pathophysiology of cardiovascular diseases awaits future research.
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Enfermedades Cardiovasculares , Humanos , Núcleo Solitario/metabolismo , Inflamación/metabolismo , Citocinas/metabolismo , Mediadores de InflamaciónRESUMEN
Our understanding of central nervous system regulation of the set-point of arterial pressure remains incomplete, especially in conditions of hypertension. The ventrolateral periaqueductal gray (vlPAG) is of particular interest given that its acute activation induces hypotension and sympatho-inhibition in anaesthetised, normotensive animals, and recent preliminary studies have shown that vlPAG stimulation can reduce blood pressure in refractory hypertensive patients. To assist our mechanistic understanding, we investigated whether electrical stimulation of the vlPAG had depressor actions in a model of neurogenic hypertension, the spontaneously hypertensive (SH) rat. We found that electrical stimulation of the lateral and vlPAG (2-6 V, 20-40 Hz, 0.18-0.2 ms pulse width) decreased arterial pressure (-19 ± 4 mm Hg, n = 8) and heart rate (median - 18 bpm) in anaesthetised SH rats. In contrast, in conscious freely-moving SH rats fitted with blood pressure telemetry, stimulation of this same region produced failed to evoked a hypotensive response (n = 13; either no change, n = 9; or an increase in arterial pressure of 23 ± 4 mm Hg, n = 4). The hypotensive action of the vlPAG observed in anaesthetised animals has been attributed to inhibition of pre-sympathetic neurones originating in the rostral ventrolateral medulla. We therefore used an un-anaesthetised, decerebrate SH rat preparation to investigate whether activation of vlPAG neurons produced sympatho-inhibition that might be below the threshold at which a peripheral vascular response could be observed. Only sympatho-excitatory responses to electrical and excitatory amino acid microinjections were observed, and these were evoked from both the dorsal and ventral PAG; no responses were evoked from the vlPAG. We conclude that the vlPAG is not a reliable antihypertensive locus in the awake SH rat. We discuss the potential importance of the state-dependency of the hypotensive response that can be evoked from the vlPAG, which has important implications for translating to humans.
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Hipertensión , Hipotensión , Animales , Presión Arterial , Presión Sanguínea/fisiología , Humanos , Hipertensión/metabolismo , Microinyecciones , Sustancia Gris Periacueductal/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Sprague-DawleyRESUMEN
Heart rate variability (HRV) is a crucial indicator of cardiovascular health. Low HRV is correlated with disease severity and mortality in heart failure. Heart rate increases and decreases with each breath in normal physiology termed respiratory sinus arrhythmia (RSA). RSA is highly evolutionarily conserved, most prominent in the young and athletic and is lost in cardiovascular disease. Despite this, current pacemakers either pace the heart in a metronomic fashion or sense activity in the sinus node. If RSA has been lost in cardiovascular disease current pacemakers cannot restore it. We hypothesized that restoration of RSA in heart failure would improve cardiac function. Restoration of RSA in heart failure was assessed in an ovine model of heart failure with reduced ejection fraction. Conscious 24 h recordings were made from three groups, RSA paced (n = 6), monotonically paced (n = 6) and heart failure time control (n = 5). Real-time blood pressure, cardiac output, heart rate and diaphragmatic EMG were recorded in all animals. Respiratory modulated pacing was generated by a proprietary device (Ceryx Medical) to pace the heart with real-time respiratory modulation. RSA pacing substantially increased cardiac output by 1.4 L/min (20%) compared to contemporary (monotonic) pacing. This increase in cardiac output led to a significant decrease in apnoeas associated with heart failure, reversed cardiomyocyte hypertrophy, and restored the T-tubule structure that is essential for force generation. Re-instating RSA in heart failure improves cardiac function through mechanisms of reverse re-modelling; the improvement observed is far greater than that seen with current contemporary therapies. These findings support the concept of re-instating RSA as a regime for patients who require a pacemaker.
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Insuficiencia Cardíaca , Arritmia Sinusal Respiratoria , Disfunción Ventricular Izquierda , Animales , Arritmia Sinusal , Insuficiencia Cardíaca/terapia , Frecuencia Cardíaca/fisiología , Humanos , Arritmia Sinusal Respiratoria/fisiología , OvinosRESUMEN
NEW FINDINGS: What is the central question of this study? Does chronic reduction of neuronally generated nitric oxide in the hypothalamic paraventricular nucleus affect the set-point regulation of blood pressure and sympathetic activity destined to the kidneys? What is the main finding and its importance? Within the hypothalamic paraventricular nucleus, nitric oxide generated by neuronal nitric oxide synthase plays a major constitutive role in suppressing long term the levels of both ongoing renal sympathetic activity and arterial pressure in conscious Wistar rats. This finding unequivocally demonstrates a mechanism by which the diencephalon exerts a tonic influence on sympathetic discharge to the kidney and may provide the basis for both blood volume and osmolality homeostasis. ABSTRACT: The paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in cardiovascular and neuroendocrine regulation. Application of nitric oxide donors to the PVN stimulates GABAergic transmission, and may suppress sympathetic nerve activity (SNA) to lower arterial pressure. However, the role of endogenous nitric oxide within the PVN in regulating renal SNA chronically remains to be established in conscious animals. To address this, we used our previously established lentiviral vectors to knock down neuronal nitric oxide synthase (nNOS) selectively in the PVN of conscious Wistar rats. Blood pressure and renal SNA were monitored simultaneously and continuously for 21 days (n = 14) using radio-telemetry. Renal SNA was normalized to maximal evoked discharge and expressed as a percentage change from baseline. The PVN was microinjected bilaterally with a neurone-specific tetracycline-controllable lentiviral vector, expressing a short hairpin miRNA30 interference system targeting nNOS (n = 7) or expressing a mis-sense as control (n = 7). Recordings continued for a further 18 days. The vectors also expressed green fluorescent protein, and successful expression in the PVN and nNOS knockdown were confirmed histologically post hoc. Knockdown of nNOS expression in the PVN resulted in a sustained increase in blood pressure (from 95 ± 2 to 104 ± 3 mmHg, P < 0.05), with robust concurrent sustained activation of renal SNA (>70%, P < 0.05). The study reveals a major role for nNOS-derived nitric oxide within the PVN in chronic set-point regulation of cardiovascular autonomic activity in the conscious, normotensive rat.
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Presión Sanguínea/fisiología , Riñón/metabolismo , Óxido Nítrico Sintasa de Tipo I/metabolismo , Núcleo Hipotalámico Paraventricular/enzimología , Sistema Nervioso Simpático/metabolismo , Animales , Masculino , Neuronas/metabolismo , Óxido Nítrico Sintasa de Tipo I/genética , ARN Interferente Pequeño , Ratas , Ratas WistarRESUMEN
Left atrial enlargement (LAE) has adverse prognostic implications in hypertension. We sought to determine the accuracy of five electrocardiogram (ECG) criteria for LAE in hypertension relative to cardiac magnetic resonance (CMR) gold standard and investigate the effect of concomitant obesity. One hundred and thirty consecutive patients (age: 51.4±15.1 years, 47% male, 51% obese, systolic blood pressure (BP): 171±29 mm Hg, diastolic BP: 97±15 mm Hg) referred for CMR (1.5 T) from a tertiary hypertension clinic were included. Patients with concomitant cardiac pathology were excluded. ECGs were assessed blindly for the following: (1) P-wave >110 ms, (2) P-mitrale, (3) P-wave axis <30°, (4) area of negative P-terminal force in V1 >40 ms.mm and (5) positive P-terminal force in augmented vector left (aVL) >0.5 mm. Left atrial volume ≥55 ml m-2, measured blindly by CMR, was defined as LAE. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy and area under the receiver operator curve were calculated. The prevalence of LAE by CMR was 26%. All the individual ECG LAE criteria were more specific than sensitive, with specificities ranging from 70% (P-axis <30o) to 99% (P-mitrale). Obesity attenuated the specificity of most of the individual ECG LAE criteria. Obesity correlated with significant lower specificity (48% vs 65%, P<0.05) and a trend towards lower sensitivity (59 vs 43%, P=0.119) when ≥1 ECG LAE criteria were present. Individual ECG criteria of LAE in hypertension are specific, but not sensitive, at identifying LAE. The ECG should not be used to excluded LAE in hypertension, particularly in obese subjects.
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Electrocardiografía , Atrios Cardíacos/patología , Hipertensión/patología , Obesidad/complicaciones , Adulto , Anciano , Técnicas de Imagen Cardíaca , Femenino , Atrios Cardíacos/diagnóstico por imagen , Humanos , Hipertensión/complicaciones , Hipertensión/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Obesidad/diagnóstico por imagenRESUMEN
The brain is an exceptionally energetically demanding organ with little metabolic reserve, and multiple systems operate to protect and preserve the brain blood supply. But how does the brain sense its own perfusion? In this review, we discuss how the brain may harness the cardiovascular system to counter threats to cerebral perfusion sensed via intracranial pressure (ICP), cerebral oxygenation and ischaemia. Since the work of Cushing over 100 years ago, the existence of brain baroreceptors capable of eliciting increases in sympathetic outflow and blood pressure has been hypothesized. In the clinic, this response has generally been thought to occur only in extremis, to perfuse the severely ischaemic brain as cerebral autoregulation fails. We review evidence that pressor responses may also occur with smaller, physiologically relevant increases in ICP. The incoming brain oxygen supply is closely monitored by the carotid chemoreceptors; however, hypoxia and other markers of ischaemia are also sensed intrinsically by astrocytes or other support cells within brain tissue itself and elicit reactive hyperaemia. Recent studies suggest that astrocytic oxygen signalling within the brainstem may directly affect sympathetic nerve activity and blood pressure. We speculate that local cerebral oxygen tension is a major determinant of the mean level of arterial pressure and discuss recent evidence that this may be the case. We conclude that intrinsic intra- and extra-cranial mechanisms sense and integrate information about hypoxia/ischaemia and ICP and play a major role in determining the long-term level of sympathetic outflow and arterial pressure, to optimize cerebral perfusion.
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Isquemia Encefálica/fisiopatología , Encéfalo/irrigación sanguínea , Circulación Cerebrovascular/fisiología , Presión Intracraneal/fisiología , Accidente Cerebrovascular/fisiopatología , Presión Sanguínea/fisiología , Hemodinámica/fisiología , HumanosRESUMEN
KEY POINTS: We have developed a simple analytical method for quantifying the transduction of sympathetic activity into vascular tone. This method demonstrates that as women age, the transfer of sympathetic nerve activity into vascular tone is increased, so that for a given level of sympathetic activity there is more vasoconstriction. In men, this measure decreases with age. Test-re-test analysis demonstrated that the new method is a reliable estimate of sympathetic transduction. We conclude that increased sympathetic vascular coupling contributes to the age-related increase in blood pressure that occurs in women only. This measure is a reliable estimate of sympathetic transduction in populations with high sympathetic nerve activity. Thus, it will provide information regarding whether treatment targeting the sympathetic nervous system, which interrupts the transfer of sympathetic nerve activity into vascular tone, will be effective in reducing blood pressure in hypertensive patients. This may provide insight into which populations will respond to certain types of anti-hypertensive medication. ABSTRACT: Sex and age differences in the sympathetic control of resting blood pressure (BP) may be due to differences in the transduction of sympathetic nerve activity (SNA) into vascular tone. Current methods for dynamically quantifying transduction focus on the relationship between SNA and vasoconstriction during a pressor stimulus, which increases BP and may be contra-indicated in patients. We describe a simple analytical method for quantifying transduction under resting conditions. We performed linear regression analysis of binned muscle SNA burst areas against diastolic BP (DBP). We assessed whether the slope of this relationship reflects the transduction of SNA into DBP. To evaluate this, we investigated whether this measure captures differences in transduction in different populations. Specifically, we (1) quantified transduction in young men (YM), young women (YW), older men (OM) and postmenopausal women (PMW); and (2) measured changes in transduction during ß-blockade using propranolol in YW, YM and PMW. YM had a greater transduction vs. OM (0.10 ± 0.01 mmHg (% s)(-1) , n = 23 vs. 0.06 ± 0.01 mmHg (% s)(-1) , n = 18; P = 0.003). Transduction was lowest in YW (0.02 ± 0.01 mmHg (% s)(-1) , n = 23) and increased during ß-blockade (0.11 ± 0.01 mmHg (% s)(-1) ; P < 0.001). Transduction in PMW (0.07 ± 0.01 mmHg (% s)(-1) , n = 23) was greater compared to YW (P = 0.001), and was not altered during ß-blockade (0.06 ± 0.01 mmHg (% s)(-1) ; P = 0.98). Importantly, transduction increased in women with age, but decreased in men. Transduction in women intersected that in men at 55 ± 1.5 years. This measure of transduction captures age- and sex-differences in the sympathetic regulation of DBP and may be valuable in quantifying transduction in disease. In particular, this measure may help target treatment strategies in specific hypertensive subpopulations.
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Envejecimiento/fisiología , Sistema Nervioso Simpático/fisiología , Adolescente , Antagonistas Adrenérgicos beta/farmacología , Adulto , Anciano , Presión Sanguínea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Propranolol/farmacología , Posición Supina , Sistema Nervioso Simpático/efectos de los fármacos , Adulto JovenRESUMEN
The synthesis of arginine vasopressin (AVP) in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus is sensitive to increased plasma osmolality and a decreased blood volume, and thus is robustly increased by both dehydration (increased plasma osmolality and decreased blood volume) and salt loading (increased plasma osmolality). Both stimuli result in functional remodelling of the SON and PVN, a process referred to as functional-related plasticity. Such plastic changes in the brain have recently been associated with altered patterns of DNA methylation at CpG (cytosine-phosphate-guanine) residues, a process considered to be important for the regulation of gene transcription. In this regard, the proximal Avp promoter contains a number of CpG sites and is recognised as one of four CpG islands for the Avp gene, suggesting that methylation may be regulating Avp transcription. In the present study, we show that, in an immortalised hypothalamic cell line 4B, the proximal Avp promoter is highly methylated, and treatment of these cells with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine to demethylate DNA dramatically increases basal and stimulated Avp biosynthesis. We report no changes in the expression of DNA methyltransferases, Dnmt1 and Dnmt3a, whereas there is decreased expression of the demethylating enzyme ten-eleven-translocation 2, Tet2, in the SON by dehydration and salt loading. We found higher methylation of the SON Avp promoter in dehydrated but not salt-loaded rats. By analysis of individual CpG sites, we observed hypomethylation, hypermethylation and no change in methylation of specific CpGs in the SON Avp promoter of the dehydrated rat. Using reporter gene assays, we show that mutation of individual CpGs can result in altered Avp promoter activity. We propose that methylation of the SON Avp promoter is necessary to co-ordinate the duel inputs of increased plasma osmolality and decreased blood volume on Avp transcription in the chronically dehydrated rat.
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Metilación de ADN/genética , Deshidratación/genética , Epigénesis Genética/genética , Regiones Promotoras Genéticas/genética , Cloruro de Sodio/metabolismo , Vasopresinas/genética , Animales , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular , ADN (Citosina-5-)-Metiltransferasa 1/biosíntesis , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Decitabina , Desmetilación/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Mutación , Concentración Osmolar , Ratas , Cloruro de Sodio/farmacologíaRESUMEN
Electrocardiograph (ECG) criteria for left ventricular hypertrophy (LVH) are a widely used clinical tool. We recalibrated six ECG criteria for LVH against gold-standard cardiac magnetic resonance (CMR) and assessed the impact of obesity. One hundred and fifty consecutive tertiary hypertension clinic referrals for CMR (1.5 T) were reviewed. Patients with cardiac pathology potentially confounding hypertensive LVH were excluded (n=22). The final sample size was 128 (age: 51.0±15.2 years, 48% male). LVH was defined by CMR. From a 12-lead ECG, Sokolow-Lyon voltage and product, Cornell voltage and product, Gubner-Ungerleidger voltage and Romhilt-Estes score were evaluated, blinded to the CMR. ECG diagnostic performance was calculated. LVH by CMR was present in 37% and obesity in 51%. Obesity significantly reduced ECG sensitivity, because of significant attenuation in mean ECG values for Cornell voltage (22.2±5.7 vs 26.4±9.4 mm, P<0.05), Cornell product (2540±942 vs 3023±1185 mm ⢠ms, P<0.05) and for Gubner-Ungerleider voltage (18.2±7.1 vs 23.3±1.2 mm, P<0.05). Obesity also significantly reduced ECG specificity, because of significantly higher prevalence of LV remodeling (no LVH but increased mass-to-volume ratio) in obese subjects without LVH (36% vs 16%, P<0.05), which correlated with higher mean ECG LVH criteria values. Obesity-specific partition values were generated at fixed 95% specificity; Cornell voltage had highest sensitivity in non-obese (56%) and Sokolow-Lyon product in obese patients (24%). Obesity significantly lowers ECG sensitivity at detecting LVH, by attenuating ECG LVH values, and lowers ECG specificity through changes associated with LV remodeling. Our obesity-specific ECG partition values could improve the diagnostic performance in obese patients with hypertension.
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Electrocardiografía/normas , Hipertensión/complicaciones , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Obesidad/complicaciones , Adulto , Anciano , Femenino , Humanos , Hipertrofia Ventricular Izquierda/etiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Sensory information arising from the upper neck is important in the reflex control of posture and eye position. It has also been linked to the autonomic control of the cardiovascular and respiratory systems. Whiplash associated disorders (WAD) and cervical dystonia, which involve disturbance to the neck region, can often present with abnormalities to the oromotor, respiratory and cardiovascular systems. We investigated the potential neural pathways underlying such symptoms. Simulating neck afferent activity by electrical stimulation of the second cervical nerve in a working heart brainstem preparation (WHBP) altered the pattern of central respiratory drive and increased perfusion pressure. Tracing central targets of these sensory afferents revealed projections to the intermedius nucleus of the medulla (InM). These anterogradely labelled afferents co-localised with parvalbumin and vesicular glutamate transporter 1 indicating that they are proprioceptive. Anterograde tracing from the InM identified projections to brain regions involved in respiratory, cardiovascular, postural and oro-facial behaviours--the neighbouring hypoglossal nucleus, facial and motor trigeminal nuclei, parabrachial nuclei, rostral and caudal ventrolateral medulla and nucleus ambiguus. In brain slices, electrical stimulation of afferent fibre tracts lateral to the cuneate nucleus monosynaptically excited InM neurones. Direct stimulation of the InM in the WHBP mimicked the response of second cervical nerve stimulation. These results provide evidence of pathways linking upper cervical sensory afferents with CNS areas involved in autonomic and oromotor control, via the InM. Disruption of these neuronal pathways could, therefore, explain the dysphagic and cardiorespiratory abnormalities which may accompany cervical dystonia and WAD.
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Fenómenos Fisiológicos Cardiovasculares , Bulbo Raquídeo/fisiología , Bulbo Raquídeo/ultraestructura , Músculos del Cuello/inervación , Músculos del Cuello/fisiología , Respiración , Vías Aferentes/fisiología , Animales , Tronco Encefálico/fisiología , Tronco Encefálico/ultraestructura , Sistema Cardiovascular/inervación , Estimulación Eléctrica , Nervio Hipogloso/fisiología , Masculino , Ratones , Músculos del Cuello/citología , Neuronas/metabolismo , Neuronas/fisiología , Neuronas/ultraestructura , Nervio Frénico/fisiología , Ratas Wistar , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
Astrocytes produce and release L-lactate as a potential source of energy for neurons. Here we present evidence that L-lactate, independently of its caloric value, serves as an astrocytic signalling molecule in the locus coeruleus (LC). The LC is the principal source of norepinephrine to the frontal brain and thus one of the most influential modulatory centers of the brain. Optogenetically activated astrocytes release L-lactate, which excites LC neurons and triggers release of norepinephrine. Exogenous L-lactate within the physiologically relevant concentration range mimics these effects. L-lactate effects are concentration-dependent, stereo-selective, independent of L-lactate uptake into neurons and involve a cAMP-mediated step. In vivo injections of L-lactate in the LC evokes arousal similar to the excitatory transmitter, L-glutamate. Our results imply the existence of an unknown receptor for this 'glio-transmitter'.
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Neuronas Adrenérgicas/metabolismo , Astrocitos/metabolismo , Ácido Láctico/metabolismo , Locus Coeruleus/metabolismo , Norepinefrina/metabolismo , Animales , Neuroglía/metabolismo , Neuronas/metabolismo , Ratas , Transducción de SeñalRESUMEN
The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the regulation of sympathetic nerve activity, which is significantly elevated in chronic heart failure (CHF). Fractalkine (FKN) and its cognate receptor, CX3CR1, are constitutively expressed in the central nervous system, but their role and physiological significance are not well known. The aims of the present study were to determine whether FKN plays a cardiovascular role within the PVN and to investigate how the actions of FKN might be altered in CHF. We show that both FKN and CX3CR1 are expressed on neurons in the PVN of rats, suggesting that they may have a physiological function in this brain nucleus. Unilateral microinjection of FKN directly into the PVN of anaesthetized rats elicited a significant dose-related decrease in blood pressure (1.0 nmol, -5 ± 3 mmHg; 2.5 nmol, -13 ± 2 mmHg; 5.0 nmol, -22 ± 3 mmHg; and 7.5 nmol, -32 ± 3 mmHg) and a concomitant increase in heart rate (1.0 nmol, 6 ± 3 beats min(-1); 2.5 nmol, 11 ± 3 beats min(-1); 5 nmol, 18 ± 4 beats min(-1); and 7.5 nmol, 27 ± 5 beats min(-1)) compared with control saline microinjections. In order to determine whether FKN signalling is altered in rats with CHF, we first performed quantitative RT-PCR and Western blot analysis and followed these experiments with functional studies in rats with CHF and sham-operated control rats. We found a significant increase in CX3CR1 mRNA and protein expression, as determined by quantitative RT-PCR and Western blot analysis, respectively, in the PVN of rats with CHF compared with sham-operated control rats. We also found that the blood pressure effects of FKN (2.5 nmol in 50 nl) were significantly attenuated in rats with CHF (change in mean arterial pressure, -6 ± 3 mmHg) compared with sham-operated control rats (change in mean arterial pressure, -16 ± 6 mmHg). These data suggest that FKN and its receptor, CX3CR1, modulate cardiovascular function at the level of the PVN and that the actions of FKN within this nucleus are altered in heart failure.
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Sistema Cardiovascular/fisiopatología , Quimiocina CX3CL1/metabolismo , Insuficiencia Cardíaca/fisiopatología , Hipotálamo/fisiopatología , Núcleo Hipotalámico Paraventricular/fisiopatología , Animales , Presión Sanguínea/genética , Presión Sanguínea/fisiología , Sistema Cardiovascular/metabolismo , Quimiocina CX3CL1/genética , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Frecuencia Cardíaca/genética , Frecuencia Cardíaca/fisiología , Hipotensión/genética , Hipotensión/metabolismo , Hipotensión/fisiopatología , Hipotálamo/metabolismo , Masculino , Microinyecciones/métodos , Núcleo Hipotalámico Paraventricular/metabolismo , Ratas , Ratas Sprague-Dawley , Taquicardia/genética , Taquicardia/metabolismo , Taquicardia/fisiopatologíaRESUMEN
The magnocellular neurones (MCN) of the supraoptic nucleus (SON) undergo reversible changes during dehydration. We hypothesise that alterations in steady-state transcript levels might be partially responsible for this plasticity. In turn, regulation of transcript abundance might be mediated by transcription factors. We have previously used microarrays to identify changes in the expression of mRNAs encoding transcription factors in response to water deprivation. We observed down-regulation of 11 and up-regulation of 31 transcription factor transcripts, including members of the activator protein-1 gene family, namely c-fos, c-jun, fosl1 and junD. Because JunD expression and regulation within the SON has not been previously described, we have used in situ hybridisation and the quantitative reverse transcriptase-polymerase chain reaction to confirm the array results, demonstrating a significant increase in JunD mRNA levels following 24 and 72 h of water deprivation. Western blot and immunohistochemistry revealed a significant increase in JunD protein expression following dehydration. Double-staining fluorescence immunohistochemistry with a neurone-specific marker (NeuN) demonstrated that JunD staining is predominantly neuronal. Additionally, JunD immunoreactivity is observed primarily in vasopressin-containing neurones with markedly less staining seen in oxytocin-containing MCNs. Furthermore, JunD is highly co-expressed with c-Fos in MCNs of the SON following dehydration. These results suggest that JunD plays a role in the regulation of gene expression within MCNs of the SON in association with other Fos and Jun family members.
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Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Núcleo Supraóptico/metabolismo , Vasopresinas/metabolismo , Privación de Agua/fisiología , Animales , Expresión Génica , Masculino , Neuronas/fisiología , Especificidad de Órganos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Núcleo Supraóptico/citología , Regulación hacia Arriba/genéticaRESUMEN
The nucleus of the solitary tract (NTS), an integral vasomotor region located in the hindbrain, is important for cardiovascular homeostasis. Fractalkine (FKN) and its cognate receptor, CX3CR1, are constitutively expressed in the normal rat brain. The physiological significance of this cytokine and its receptor are not well established. In this study, we sought to identify the expression of FKN and CX3CR1 in subnuclei of the NTS and to elucidate their functional relevance. Using immunohistochemistry, we found expression of FKN and CX3CR1 throughout the entire rostro-caudal axis of the NTS in normal adult male Sprague-Dawley rats. When FKN was unilaterally microinjected directly into the commissural and sub-postremal, but not rostral, NTS, blood pressure and heart rate were significantly decreased when compared with saline controls. The FKN-induced depressor and bradycardic responses were inhibited by pretreatment with a phosphoinositide 3-kinase inhibitor, LY294002. These data suggest that the cytokine, FKN, and its receptor, CX3CR1, may modulate cardiovascular responses in the NTS of normal healthy rats via the phosphoinositide 3-kinase intracellular signaling pathway.
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Fenómenos Fisiológicos Cardiovasculares , Quimiocina CX3CL1/biosíntesis , Receptores de Quimiocina/biosíntesis , Núcleo Solitario/metabolismo , Animales , Western Blotting , Receptor 1 de Quimiocinas CX3C , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Quimiocina CX3CL1/farmacología , Inmunohistoquímica , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
The elucidation of the genomes of a large number of mammalian species has produced a huge amount of data on which to base physiological studies. These endeavours have also produced surprises, not least of which has been the revelation that the number of protein coding genes needed to make a mammal is only 22 333 (give or take). However, this small number belies an unanticipated complexity that has only recently been revealed as a result of genomic studies. This complexity is evident at a number of levels: (i) cis-regulatory sequences; (ii) noncoding and antisense mRNAs, most of which have no known function; (iii) alternative splicing that results in the generation of multiple, subtly different mature mRNAs from the precursor transcript encoded by a single gene; and (iv) post-translational processing and modification. In this review, we examine the steps being taken to decipher genome complexity in the context of gene expression, regulation and function in the hypothalamic-neurohypophyseal system (HNS). Five unique stories explain: (i) the use of transcriptomics to identify genes involved in the response to physiological (dehydration) and pathological (hypertension) cues; (ii) the use of mass spectrometry for single-cell level identification of biological active peptides in the HNS, and to measure in vitro release; (iii) the use of transgenic lines that express fusion transgenes enabling (by cross-breeding) the generation of double transgenic lines that can be used to study vasopressin (AVP) and oxytocin (OXT) neurones in the HNS, as well as their neuroanatomy, electrophysiology and activation upon exposure to any given stimulus; (iv) the use of viral vectors to demonstrate that somato-dendritically released AVP plays an important role in cardiovascular homeostasis by binding to V1a receptors on local somata and dendrites; and (v) the use of virally-mediated optogenetics to dissect the role of OXT and AVP in the modulation of a wide variety of behaviours.
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Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Neuropéptidos/genética , Neuropéptidos/fisiología , Animales , Animales Modificados Genéticamente/fisiología , Arginina Vasopresina/fisiología , Barorreflejo/genética , Barorreflejo/fisiología , Perfilación de la Expresión Génica/métodos , Genoma , Humanos , Hipertensión/genética , Hipertensión/fisiopatología , Oxitocina/fisiologíaRESUMEN
We conducted a theoretical study of the physiological significance of respiratory sinus arrhythmia (RSA), a phenomenon used as an index of cardiac vagal tone and wellbeing, whereby the heart rate (HR) increases during inspiration and decreases during expiration. We first tested the hypothesis that RSA improves gas exchange efficiency but found that although gas exchange efficiency improved with slow and deep breathing and with increased mean heart rate, this was unrelated to RSA. We then formulated and tested a new hypothesis: that RSA minimizes the work done by the heart while maintaining physiological levels of arterial carbon dioxide. We tested the new hypothesis using two methods. First, the HR for which the work is minimized was calculated using techniques from optimal control theory. This calculation was done on simplified models that we derived from a previously published model of gas exchange in mammals. We found that the calculated HR was remarkably similar to RSA and that this became more profound under slow and deep breathing. Second, the HR was prescribed and the work done by the heart was calculated by conducting a series of numerical experiments on the previously published gas exchange model. We found that cardiac work was minimized for RSA-like HR functions, most profoundly under slow and deep breathing. These findings provide novel insights into potential reasons for and benefits of RSA under physiological conditions.
Asunto(s)
Arritmia Sinusal/fisiopatología , Corazón/fisiopatología , Modelos Cardiovasculares , Mecánica Respiratoria/fisiología , Animales , Arritmia Sinusal/metabolismo , Dióxido de Carbono/metabolismo , Frecuencia Cardíaca/fisiología , Humanos , Modelos Teóricos , Perfusión , Intercambio Gaseoso Pulmonar/fisiología , Ventilación PulmonarRESUMEN
A neurogenic component to primary hypertension (hypertension) is now well established. Along with raised vasomotor tone and increased cardiac output, the chronic activation of the sympathetic nervous system in hypertension has a diverse range of pathophysiological consequences independent of any increase in blood pressure. This review provides a perspective on the actions and interactions of angiotensin II, inflammation and vascular dysfunction/brain hypoperfusion in the pathogenesis and progression of neurogenic hypertension. The optimisation of current treatment strategies and the exciting recent developments in the therapeutic targeting of the sympathetic nervous system to control hypertension (for example, catheter-based renal denervation and carotid baroreceptor stimulation) will be outlined.