Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats.

Key Points: Peripheral chemoreflex sensitization is a feature of renovascular hypertension. Carotid sinus nerve denervation (CSD) has recently been shown to relieve hypertension and reduce sympathetic activity in other rat models of hypertension. We show that CSD in renovascular hypertension halts further increases in blood pressure.

Physiological and pathophysiological interactions between the respiratory central pattern generator and the sympathetic nervous system.

Respiratory modulation seen in the sympathetic nerve activity (SNA) implies that the respiratory and sympathetic networks interact. During hypertension elicited by chronic intermittent hypoxia (CIH), the SNA displays an enhanced respiratory modulation reflecting strengthened interactions between the networks. In this chapter, we review a series of experimental and modeling studies that help elucidate possible mechanisms of sympatho-respiratory coupling.

Brainstem respiratory networks: building blocks and microcircuits.

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.

Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata.

Aims: Increased sympathetic tone in obstructive sleep apnoea results from recurrent episodes of systemic hypoxia and hypercapnia and might be an important contributor to the development of cardiovascular disease. In this study, we re-evaluated the role of a specific population of sympathoexcitatory catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata in the control of sympathetic vasomotor tone, arterial blood pressure, and hypercapnia-evoked sympathetic and cardiovascular responses.

Methods And Results: In anaesthetized rats in vivo and perfused rat working heart brainstem preparations in situ, C1 neurones were acutely silenced by application of the insect peptide allatostatin following cell-specific targeting with a lentiviral vector to express the inhibitory Drosophila allatostatin receptor.

Elevated vertebrobasilar artery resistance in neonatal spontaneously hypertensive rats.

There is a strong correlation between increased vertebral artery resistance and arterial blood pressure in humans. The reasons for this increased resistance at high systemic pressure remain unknown, but may include raised sympathetic activity. With the recent finding that prehypertensive spontaneously hypertensive (PHSH) rats, which have raised sympathetic nerve activity, but a blood pressure comparable to normotensive rat strains, we hypothesized that its vertebrobasilar vascular resistance would already be raised and, as a consequence, would exhibit a more responsive Cushing response (e.

Correction of respiratory disorders in a mouse model of Rett syndrome.

Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice.

Late-expiratory activity: emergence and interactions with the respiratory CpG.

The respiratory rhythm and motor pattern are hypothesized to be generated by a brain stem respiratory network with a rhythmogenic core consisting of neural populations interacting within and between the pre-Bötzinger (pre-BötC) and Bötzinger (BötC) complexes and controlled by drives from other brain stem compartments. Our previous large-scale computational model reproduced the behavior of this network under many different conditions but did not consider neural oscillations that were proposed to emerge within the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) and drive preinspiratory (or late-expiratory, late-E) discharges in the abdominal motor output. Here we extend the analysis of our previously published data and consider new data on the generation of abdominal late-E activity as the basis for extending our computational model.

Structural and functional architecture of respiratory networks in the mammalian brainstem.

Neural circuits controlling breathing in mammals are organized within serially arrayed and functionally interacting brainstem compartments extending from the pons to the lower medulla. The core circuit components that constitute the neural machinery for generating respiratory rhythm and shaping inspiratory and expiratory motor patterns are distributed among three adjacent structural compartments in the ventrolateral medulla: the Bötzinger complex (BötC), pre-Bötzinger complex (pre-BötC) and rostral ventral respiratory group (rVRG). The respiratory rhythm and inspiratory-expiratory patterns emerge from dynamic interactions between: (i) excitatory neuron populations in the pre-BötC and rVRG active during inspiration that form inspiratory motor output; (ii) inhibitory neuron populations in the pre-BötC that provide inspiratory inhibition within the network; and (iii) inhibitory populations in the BötC active during expiration that generate expiratory inhibition.

Spatial organization and state-dependent mechanisms for respiratory rhythm and pattern generation.

The brainstem respiratory network can operate in multiple functional states engaging different state-dependent neural mechanisms. These mechanisms were studied in the in situ perfused rat brainstem-spinal cord preparation using sequential brainstem transections and administration of riluzole, a pharmacological blocker of persistent sodium current (INaP). Dramatic transformations in the rhythmogenic mechanisms and respiratory motor pattern were observed after removal of the pons and subsequent medullary transactions down to the rostral end of pre-Bötzinger complex (pre-BötC).

Vascular-brain signaling in hypertension: role of angiotensin II and nitric oxide.

Paracrine signaling by nitric oxide (NO) released from microvasculature within the brain affects multiple neuronal functions. Reviewed here is a role in central cardiovascular control. Within the nucleus tractus solitarii (NTS), a major regulatory region for arterial pressure, angiotensin II stimulates NO generation from endothelial nitric oxide synthase (eNOS).

Ablation of NK1 receptor bearing neurons in the nucleus of the solitary tract blunts cardiovascular reflexes in awake rats.

The nucleus of the solitary tract (NTS) receives primary afferents involved in cardiovascular regulation. We investigated the role of NK(1)-receptor bearing neurons in the NTS on cardiovascular reflexes in awake rats fitted with chronic venous and arterial cannulae. These neurons were lesioned selectively with saporin conjugated with substance P (SP-SAP, 2 microM, bilateral injections of 20 nL in the subpostremal NTS, or 200 nL in both the subpostremal and the commissural NTS).

Respiratory rhythm generation during gasping depends on persistent sodium current.

In severe hypoxia, homeostatic mechanisms maintain function of the brainstem respiratory network. We hypothesized that hypoxia involves a transition from neuronal mechanisms of normal breathing (eupnea) to a rudimentary pattern of inspiratory movements (gasping). We provide evidence for hypoxia-driven transformation within the central respiratory oscillator, in which gasping relies on persistent sodium current, whereas eupnea does not depend on this cellular mechanism.

Cardiovascular responses to substance P in the nucleus tractus solitarii: microinjection study in conscious rats.

The cardiovascular effects of substance P (SP) microinjections in the nucleus tractus solitarii (NTS) were evaluated in conscious rats. We chose this model because it is an effective way to access some of the cardiovascular effects of neurotransmitters in the NTS without the inconvenience of blunting pathways with anesthetic agents or removing forebrain projections by decerebration. The cardiovascular responses to SP injections were also evaluated after chronic nodose ganglionectomy.