Specific Respiratory Neuron Types Have Increased Excitability That Drive Presympathetic Neurones in Neurogenic Hypertension

Abstract

H igh sympathetic activity is associated with hypertension 1-6 and many other diseases including heart failure, 7,8 insulin resistance, 9 and obesity. 10,11 Sympathetic nerve activity increases progressively as blood pressure rises from normal to moderate to severe hypertension in humans. 12 Interestingly, in both animal models of hypertension 13 and in patients with hypertension 3,6 elevated sympathetic activity precedes hypertension. The mechanisms driving excessive sympathetic activity in hypertension remain unresolved. Likely mechanisms contributing include elevated reflex afferent drive from both peripheral chemoreceptors 14,15 and kidney, 16,17 saltangiotensin II, 18-21 inflammation, [22][23][24] and respiration. 13,[25][26][27][28][29] Respiratory modulation of sympathetic activity or respiratory-sympathetic coupling has been observed in many sympathetic postganglionic outflows. 13,21,[28][29][30][31][32][33] Clinical studies have purported that by controlling breathing depth and rate (using RespeRate) blood pressure can be lowered 34 in patients with hypertension. 35 Recently, we found that in the spontaneously hypertensive (SH) rats, a genetic animal model of hypertension, 13 as well in rats submitted to chronic intermittent hypoxia, 27,29,36 there is augmented coupling of the central respiratory network to sympathetic circuits. This is expressed as elevations in sympathetic bursts in the late inspiratory (or beginning of postinspiratory; post-I) phases in the thoracic sympathetic nerve relative to age/sex-matched normotensive rats and is present before rats develop hypertension. 13 Simms et al 13 focused only on phrenic (central inspiratory) related modulation of sympathetic nerve activity and did not consider changes in expiratory neuronal activity at either the motor or neuronal level, so the central neural mechanisms for enhancing this coupling are unknown. In other models of hypertension (angiotensin II-salt hypertension), rostral ventrolateral medulla (RVLM) presympathetic neurons also show enhanced respiratory-related activity, 28 suggesting that this fundamental mechanism exists in both genetic and environmental induced hypertensive animal models. The unknown issue is whether enhanced respiratory-sympathetic coupling reflects either enhanced excitability of RVLM premotor sympathetic Abstract-A major aspect of hypertension is excessive sympathetic activity but the reasons for this remain elusive.Sympathetic tone is increased in the spontaneously hypertensive (SH) rat reflecting, in part, enhanced respiratorysympathetic coupling. We aimed to identify which respiratory cells might have altered properties. Using the working heart-brain stem preparation, we monitored simultaneously sympathetic and respiratory nerve activity in combination with intracellular recordings of physiologically characterized medullary presympathetic or respiratory neurons. In SH rats, respiratory modulation of both inspiratory and postinspiratory phases of sympathetic activity was larger relative to Wistar rats. An additiona...

Chemoreception and neuroplasticity in respiratory circuits

“…Moreover, the late-E activity was present at rest in eucapnia in CIH-treated animals but never in untreated controls, and was eliminated by a reduction of CO 2 content in the perfusate (Molkov et al, 2011). The involvement of respiratory-sympathetic interactions in the development of hypertension in CIH rats is further supported by recent findings that late-E modulation in the pre-sympathetic neurons of rostral ventrolateral medulla (RVLM ) depends on synaptic inputs from bulbar respiratory neurons rather than on changes in their intrinsic properties (Moraes et al, 2013, Moraes et al, 2014). All together these data indicate that CIH-induced sympathetic overactivity is linked to the transition of expiration from a passive to an active process at rest.…”

“…In a different animal model of neurogenic hypertension, the spontaneously hypertensive rat (SHR), Moraes et al (2014) demonstrated that intrinsically bursting neurons in the pre-BötC were found to have altered electrophysiological properties. Specifically, the authors showed that pre-BötC pre-inspiratory neurons are more excitable due to significantly lower conductance of the leak current.…”

“…In the present study, we combined recent published studies (Braga et al, 2006, Zoccal et al, 2008, Molkov et al, 2011, Moraes et al, 2012a, McBryde et al, 2013, Moraes et al, 2014) and new experimental data obtained in the in situ arterially perfused preparation of decerebrate rats, as described in details below.…”

The nucleus of the solitary tract and the coordination of respiratory and sympathetic activities

“…Altogether, these findings indicate that neurogenic hypertension is causally associated with potentiation of peripheral chemoreflex, in which plastic changes of cNTS neurons receiving the afferent inputs from the carotid bodies importantly contribute to elevate baseline sympathetic activity and strength respiratory-sympathetic coupling. The contribution of amplified respiratory-sympathetic coupling for the development and maintenance of arterial hypertension in SHR rats is still under investigation and is matter of debate (Fatouleh and Macefield, 2011; Moraes et al, 2014). …”

Appeasing the Carotid Body After Chronic Intermittent Hypoxia

“…Indeed, our data point strongly to excitability of expiratory neural elements causing postinspiratory apnea. 11 There are 3 messages here: (1) there is a need for more detailed assessment of respiration-it is all too easy to measure inspiration only but the apnea is often caused by a dysfunction/prolongation of expiration (postinspiration and stage II expiration, Figure 11 ); (2) it is the strength of the expiratory neurone coupling to sympathetic neurones that appears exaggerated contributing to sympathetic over activity in hypertension, 12 including chronic intermittent hypoxia 13 ( Figure); and (3) postinspiratory activity also drives upper airway adductors that could contribute to obstructive apneas ( Figure). Thus, future studies should consider measuring expiratory and inspiratory activities.…”