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ABSTRACT: In normal rats, central administration of orexin, or certain stress exposures, can induce significant increases in blood pressure and sympathetic nerve activity (SNA), which can be blocked by orexin receptor antagonists. The resting blood pressure is, however, unaffected by such antagonists, but is significantly lower in rodents with total loss of orexin, e.g., prepro-orexin knockout mice and orexin neuron-ablated orexin/ataxin-3 transgenic rats. We hypothesize that orexin is involved in the pathophysiology and maintenance of high blood pressure in the spontaneously hypertensive rat (SHR), a model of primary hypertension. To test this hypothesis we measured orexin-A mRNA expression in the rostral ventrolateral medulla (RVLM) and antagonized both orexin receptors using an orally administered potent dual orexin receptor antagonist, Almorexant (Almxt), in SHRs and normotensive Wistar-Kyoto (WKY) rats. In SHRs, there was a strong trend towards an increased orexin-A mRNA expression in the RVLM, and blocking orexin receptors markedly lowered blood pressure (from 182/152±5/6 to 149/119±9/8 mmHg (P<0.001)), heart rate (P< 0.001), sympathetic vasomotor tone (P<0.001), and norepinephrine levels in cerebrospinal fluid and plasma (P<0.002). The significant anti-hypertensive effects of Almxt were observed in wakefulness and NREM sleep during both dark and light cycle only in SHR. Blocking orexin receptors had no effect on blood pressure and sympathetic tone in normotensive WKY rats. Our study links the orexin system to the pathogenesis of high blood pressure in SHR and suggests that modulation of the orexin system could be a potential target in treating some forms of hypertension.
The Journal of Physiology 05/2013; · 4.72 Impact Factor
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ABSTRACT: Breathing movements in mammals are driven by rhyth-mic neural activity generated within spatially and func-tionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcir-cuits of this CPG from recent multidisciplinary experi-mental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site-and mechanism-specific interventions to treat various disorders of the neural control of breathing.
Trends in Neurosciences 05/2013; · 14.23 Impact Factor
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[show abstract]
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ABSTRACT: Breathing movements in mammals are driven by rhyth-mic neural activity generated within spatially and func-tionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcir-cuits of this CPG from recent multidisciplinary experi-mental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site-and mechanism-specific interventions to treat various disorders of the neural control of breathing.
Trends in Neurosciences 05/2013; · 14.23 Impact Factor
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Zhiying Shan,
Jasenka Zubcevic,
Peng Shi,
Joo Y Jun,
Ying Dong,
Tatiane M Murça,
Gwyneth J Lamont,
Adolfo Cuadra,
Wei Yuan,
Yanfei Qi,
Qiuhong Li, Julian F R Paton,
Michael J Katovich,
Colin Sumners,
Mohan K Raizada
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ABSTRACT: AT1 receptor subtype a (AT1Ra) expression is increased in the nucleus of the solitary tract (NTS) in spontaneously hypertensive rat (SHR) compared with Wistar Kyoto controls. However, the chronic role of AT1Ra in the NTS for cardiovascular control is not well understood. In this study, we investigated the hypothesis that the NTS AT1Ra is involved in the neural regulation of the peripheral inflammatory status and linked with hypertension. Transduction of brain neuronal cultures with recombinant adeno-associated virus type 2 (AAV2)-AT1R-small hairpin RNA (shRNA) resulted in a 72% decrease in AT1Ra mRNA and attenuated angiotensin II-induced increase in extracellular signal-regulated kinase 1/2 phosphorylation and neuronal firing. Specific NTS microinjection of AAV2-AT1R-shRNA vector in the SHR resulted in a ≈30 mm Hg increase in the mean arterial pressure compared with control vector-injected animals (Sc-shRNA: 154±4 mm Hg; AT1R-shRNA: 183±10 mm Hg) and induced a resetting of the baroreflex control of heart rate to higher mean arterial pressure. In addition, AAV2-AT1R-shRNA-treated SHRs exhibited a 74% decrease in circulating endothelial progenitor cells (CD90(+), CD4(-)/CD5(-)/CD8(-)) and a 300% increase in the circulating inflammatory cells, including CD4(+)(+)CD8(+), CD45(+)/3(+) T lymphocytes, and macrophages (CD68(+)). As a result, the endothelial progenitor cell/inflammatory cells ratio was decreased by 8- to 15-fold in the AT1R-shRNA-treated SHR. However, identical injection of AAV2-AT1R-shRNA into the NTS of Wistar Kyoto rats had no effect on mean arterial pressure and inflammatory cells. These observations suggest that increased expression of the AT1Ra in SHR NTS may present a counterhypertensive mechanism involving inflammatory/angiogenic cells.
Hypertension 04/2013; · 6.21 Impact Factor
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ABSTRACT: Breathing movements in mammals are driven by rhythmic neural activity generated within spatially and functionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial-functional organization of key neural microcircuits of this CPG from recent multidisciplinary experimental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site- and mechanism-specific interventions to treat various disorders of the neural control of breathing.
Trends in Neurosciences 03/2013; 36(3):152-1262. · 14.23 Impact Factor
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ABSTRACT: Breathing movements in mammals are driven by rhyth-mic neural activity generated within spatially and func-tionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcir-cuits of this CPG from recent multidisciplinary experi-mental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site-and mechanism-specific interventions to treat various disorders of the neural control of breathing. Introduction Breathing in mammals is the primal homeostatic process regulating levels of oxygen and carbon dioxide in the body that is critical for life. Respiratory movements occur auto-matically and continuously throughout life and are driven by the rhythmic motor activity generated within neural circuits in the brainstem and spinal cord. The underlying neural machinery is robust yet exquisitely flexible for physiological and behavioral integration. The respiratory neural control system not only performs a vital physiologi-cal function but is also engaged in volitional (e.g., speech and singing) and emotional (e.g., laughing and crying) motor behaviors. Understanding this neural circuitry may have far-reaching implications for other rhythmic motor behaviors and oscillatory circuits [1–3]. Respiratory movements, like other innate rhythmic motor behaviors such as locomotion, are produced by semi-autonomous neural networks referred to as central pattern generators (CPGs). These networks are the basic neural substrates for rhythmic motor pattern generation and sensorimotor integration [4]. They consist of core circuits of excitatory and inhibitory interneurons that
Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Breathing movements in mammals are driven by rhyth-mic neural activity generated within spatially and func-tionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcir-cuits of this CPG from recent multidisciplinary experi-mental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site-and mechanism-specific interventions to treat various disorders of the neural control of breathing.
Trends in Neurosciences 03/2013; 36(3):152-162. · 14.23 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Breathing movements in mammals are driven by rhyth-mic neural activity generated within spatially and func-tionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcir-cuits of this CPG from recent multidisciplinary experi-mental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site-and mechanism-specific interventions to treat various disorders of the neural control of breathing.
Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Breathing movements in mammals are driven by rhyth-mic neural activity generated within spatially and func-tionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcir-cuits of this CPG from recent multidisciplinary experi-mental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site-and mechanism-specific interventions to treat various disorders of the neural control of breathing.
Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Breathing movements in mammals are driven by rhyth-mic neural activity generated within spatially and func-tionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcir-cuits of this CPG from recent multidisciplinary experi-mental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site-and mechanism-specific interventions to treat various disorders of the neural control of breathing.
Trends in Neurosciences 03/2013; 36(3):152. · 14.23 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Breathing movements in mammals are driven by rhyth-mic neural activity generated within spatially and func-tionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcir-cuits of this CPG from recent multidisciplinary experi-mental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site-and mechanism-specific interventions to treat various disorders of the neural control of breathing.
03/2013;
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[show abstract]
[hide abstract]
ABSTRACT: Breathing movements in mammals are driven by rhyth-mic neural activity generated within spatially and func-tionally organized brainstem neural circuits comprising the respiratory central pattern generator (CPG). This rhythmic activity provides homeostatic regulation of gases in blood and tissues and integrates breathing with other motor acts. We review new insights into the spatial–functional organization of key neural microcir-cuits of this CPG from recent multidisciplinary experi-mental and computational studies. The emerging view is that the microcircuit organization within the CPG allows the generation of multiple rhythmic breathing patterns and adaptive switching between them, depending on physiological or pathophysiological conditions. These insights open the possibility for site-and mechanism-specific interventions to treat various disorders of the neural control of breathing.
03/2013;
