Neural structures that mediate sympathoexcitation during hypoxia

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Abstract

The sympathetic adjustments triggered by acute mild hypoxia (sympathetic chemoreflex) are initiated by activation of peripheral chemoreceptors whereas more severe hypoxia activates the sympathetic outflow via direct effects on the brainstem. In both cases the rostral ventrolateral medulla (RVLM) plays a critical role in these responses. The first part of this review briefly describes the general input–output properties of the presympathetic neurons of RVLM before focusing on the neural pathways leading to their excitation in response to peripheral chemoreceptor stimulation. The extent to which the central respiratory network contributes to the sympathetic chemoreflex is then discussed before briefly alluding to its role in obstructive sleep apnea and other pathologies. The second half of the review examines the direct effects of hypoxia on RVLM neurons and whether this region and the presympathetic neurons in particular qualify as a physiological central oxygen sensor. The literature is also examined in the context of cerebral ischemia, the Cushing response and the genesis of certain forms of hypertension.

Introduction

At normal levels of resting arterial pressure, small reductions in blood PO2 are detected by peripheral chemoreceptors rather than by the brain itself. The neural responses to low levels of hypoxia include arousal, increased ventilation, aversive responses and autonomic adjustments that compensate for the direct vasodilating effect of hypoxia and redistribute flow to essential organs including the brain, heart and kidneys (Marshall, 1994). The sympathetic response to stimulation of peripheral chemoreceptors is excitatory with some regional differences. The primary autonomic responses triggered by activation of peripheral chemoreceptors can be considerably modified by secondary cardiopulmonary reflexes from baroreceptors and various lung afferents or by secondary changes in blood PCO2 (for review see Marshall, 1994). These secondary reflexes have an especially large influence on the cardiovagal response to hypoxia but relatively less impact on the sympathetic response (Marshall, 1994).

The first part of this review briefly summarizes our current understanding of the neural pathways involved in sympathetic tone generation. This description is limited to the pontomedullary networks which are known to contribute the most to the sympathoexcitatory effects of hypoxia. The second part of the review examines the neural pathways that mediate the primary effect of peripheral chemoreceptor stimulation on the sympathetic outflow. The neural pathways that mediate secondary cardiopulmonary feed-back (lung stretch receptors and central chemoreceptors) will not be considered.

The sympathetic system can also be activated directly by CNS hypoxia. This response is thought to require a much greater degree of systemic hypoxia, or it can be triggered by reductions in blood flow to the brainstem (Cushing response). The last part of this review describes the neural mechanisms involved in the sympathetic response to ischemia or central hypoxia and provides a brief discussion of the possible physiological and pathological relevance of these mechanisms.

Section snippets

Role of the ventrolateral medulla in sympathetic tone generation

The sympathetic preganglionic neurons that control circulation are regulated by a network of spinal interneurons (Poree and Schramm, 1992, Chau et al., 1997, Chizh et al., 1998). Yet, at least under most anesthetic conditions, this spinal circuitry is apparently unable to generate a significant vasomotor outflow and requires excitatory drives from supraspinal sources (Dampney, 1994a, Dampney, 1994b, Guyenet and Stornetta, 1998). Under anesthesia, the ventrolateral medulla is the principal

Neural pathways that mediate the effect of peripheral chemoreceptor stimulation on the sympathetic outflow

The vast majority of the data comes from work done in anesthetized, ventilated, paralysed and vagotomized animals in which secondary reflexes due to changes in ventilation and PCO2 can be minimized. Under these conditions moderate hypoxia or selective stimulation of the carotid bodies cause similar neural responses, namely a profound activation of the phrenic nerve discharge and of the sympathetic outflow to the heart and blood vessels (e.g. Fig. 4). The predominant role of the carotid bodies

Cerebral ischemia

Under anesthesia, cerebral ischemia caused by constricting an appropriate set of arteries (vertebral and carotid arteries in rat and rabbit) produces a dramatic increase in blood pressure which is due to activation of the sympathetic system. The response clearly originates in the lower brainstem because it is preserved after midpontine transection (Guyenet and Brown, 1986). It is obliterated by lesions of the RVLM, consistent with the finding that such lesions eliminate the major source of the

Summary and conclusion

The activation of peripheral chemoreceptors by hypoxia produces a specific pattern of activation of the sympathetic outflow and an increase in its respiratory synchronization. Under anesthesia, the response appears to be largely integrated within the most rostral part of the ventrolateral medulla and it is relayed to the cord by two types of RVLM presympathetic neurons (C1 and non-C1 cells) with some contribution from the A5 neurons of the ventrolateral pons. The bulk of the excitatory drive

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