Carotid body overactivity induces respiratory neurone channelopathy contributing to neurogenic hypertension

Abstract

Why sympathetic activity rises in neurogenic hypertension remains unknown. It has been postulated that changes in the electrical excitability of medullary pre-sympathetic neurones are the main causal mechanism for the development of sympathetic overactivity in experimental hypertension. Here we review recent data suggesting that enhanced sympathetic activity in neurogenic hypertension is, at least in part, dependent on alterations in the electrical excitability of medullary respiratory neurones and their central modulation of sympatho-excitatory networks. We also present results showing a critical role for carotid body tonicity in the aetiology of enhanced central respiratory modulation of sympathetic activity in neurogenic hypertension. We propose a novel hypothesis of respiratory neurone channelopathy induced by carotid body overactivity in neurogenic hypertension that may contribute to sympathetic excess. Moreover, our data support the notion of targeting the carotid body as a potential novel therapeutic approach for reducing sympathetic vasomotor tone in neurogenic hypertension.

Chemoreception and neuroplasticity in respiratory circuits

“…HCN channels are primarily permeable to K + ions, and, hence, their downregulation positively affects the excitability. This is consistent with the recent idea of peripheral chemoreceptor mediated channelopathy within the respiratory network in SHRs (Moraes et al, 2015). …”

“…Interestingly, SHR and CIH rat models of hypertension share many common features: 1) in both models, strengthened respiratory-sympathetic coupling are suggested to be involved in the development/maintenance of arterial hypertension (Zoccal et al, 2008, Moraes et al, 2014); 2) the carotid body chemoreceptors play a pivotal role for the development of hypertension in both models (Fletcher et al, 1992, Abdala et al, 2012); 3) the sympathetic response to peripheral chemoreceptors are amplified in SHR and CIH rats (Braga et al, 2006, Simms et al, 2009, Tan et al, 2010, Moraes et al, 2014), suggesting a sensitization of processing of peripheral chemoreceptor inputs; 4) SHR also exhibit a late-expiratory component in the AbN, in the cervical sympathetic and in the pre-sympathetic RVLM neuronal activity at normal (5%) CO 2 levels strongly resembling respiratory pattern of control (Wistar) animals at 7% CO 2 (Zoccal et al, 2008, Moraes et al, 2013, Moraes et al, 2014); and 5) SH animals also have a lower apneic threshold compared to Wistar rats (Moraes et al, 2014) similar to CIH vs. control (Molkov et al, 2011). Based on these similarities, we hypothesize that CIH-conditioned animals have altered baseline respiratory patterns due to increased excitability of pre-I/I population in pre-BötC because of the reduced leak conductance of these neurons (Moraes et al, 2014, 2015). We further test this hypothesis using computational modeling.…”

“…On the other hand, experimental evidence in SHR suggests that the pre-I/I population in the pre-BötC becomes more excitable via a decrease in leak conductance (Moraes et al, 2014). We use this evidence to formulate the hypothesis that repetitive activation of peripheral and, hence, central chemoreceptors during CIH conditioning induces plasticity in this population as recently proposed (Moraes et al, 2015, Zoccal, 2015); specifically, we model the respiratory plasticity evoked by CIH as a decrease in the leak conductance of the pre-I/I population. The average leak conductance of these neurons was decreased from 2.9 nS in the control model to 2.3 nS in the CIH model.…”

“…The development of arterial hypertension in rats exposed to CIH is fully prevented by previous ablation of carotid body peripheral chemoreceptors (Fletcher et al, 1992), indicating that the plasticity in the neural circuitries of the peripheral chemoreflex, elicited by repeated stimulation during CIH (Moraes et al, 2015), may underpin the development of the observed respiratory and sympathetic changes. Therefore, it is important to understand the neural pathways engaged during peripheral chemoreceptor stimulation in order to identify potential neural mechanisms triggering active expiration and sympathetic overactivity in CIH rats.…”

Carotid body chemoreflex: a driver of autonomic abnormalities in sleep apnoea

“…Recently, Moraes, Machado and co-workers (Moraes et al , 2013) reported that a specific population of non-catecholaminergic respiratory-modulated pre-sympathetic neurons in RVLM of IH exposed rats exhibit augmented excitatory synaptic inputs from the respiratory network. The enhanced excitatory synaptic activity of these neurons by IH was due to altered properties of the ion channels in post-inspiratory neurons (Moraes et al , 2015). Collectively, these studies indicate that altered neuronal coupling between the respiratory and pre-sympathetic neurons in the RVLM is an important central mechanism contributing to activation of the sympathetic nervous system by IH.…”