Medullary pathways regulating sympathetic outflow: the need for more lateral thinking.

STUDIES CARRIED OUT more than 50 years ago demonstrated that electrical stimulation of sites within a large part of the dorsolateral reticular formation in the medulla oblongata can produce large increases in arterial pressure (1, 21). These early studies led to the view that neurons controlling the sympathetic outflow to the heart and blood vessels are distributed diffusely throughout this pontomedullary area. In the 1980s, however, attention shifted to the role of the ventrolateral medulla in cardiovascular regulation, when a series of functional and anatomical studies carried out by several laboratories led to the discovery that a discrete group of spinally projecting neurons within the rostral ventrolateral medulla (RVLM) is of crucial importance in the tonic and phasic control of sympathetic vasomotor activity and arterial pressure (for reviews, see Refs. 6, 8, 11). Around the same time, it was also discovered that there are neurons within the caudal ventrolateral medulla (CVLM) that, when excited, produce depressor and sympathoinhibitory effects (5, 6). Furthermore, experiments in the rat and rabbit demonstrated that some CVLM neurons are a critical component in the central baroreceptor reflex pathway by relaying baroreceptor inhibitory inputs to RVLM sympathetic premotor neurons (6, 8, 11). The fact that profound pressor effects can be produced by electrical stimulation of sites within a large part of the dorsolateral medulla is believed to reflect the fact that, at least to a large extent, these responses arise from excitation of axons of passage rather than neuronal cell bodies. Nevertheless, electrophysiological studies carried out by Drs. Barman and Gebber and their coworkers during the 1980s demonstrated that there are neurons within the dorsolateral reticular formation that have firing patterns indicative of neurons that regulate the sympathetic outflow to the heart and blood vessels. This group focused their attention on the medullary lateral tegmental field (LTF), which lies within the dorsolateral reticular formation and includes portions of the nucleus reticularis parvocellularis and nucleus reticularis ventralis (19). In these early studies, Drs. Barman and Gebber (9) demonstrated that many LTF neurons with sympathetic-related activity responded to baroreceptor inputs, either by a decrease in their firing rate or an increase. LTF neurons inhibited by baroreceptor inputs (putative sympathoexcitatory neurons) and those excited by baroreceptor inputs (putative sympathoinhbitory neurons) project to the regions containing sympathetic premotor neurons in the RVLM and midline raphe, respectively (2–4). A more recent study from the same group demonstrated that blockade of N-methyl-D-aspartate (NMDA) receptors in the LTF abolished baroreceptor reflex control of sympathetic activity (19), indicating for the first time that LTF neurons do not merely receive inputs from baroreceptors, but are an essential link in the central pathways mediating the baroreceptor-sympathetic reflex. This was an important observation, because until that time the generally accepted model of the medullary baroreceptor reflex pathway did not include LTF neurons as a critical component (6, 8, 11). The study by Orer et al. (19) also made a further observation: blockade of non-NMDA receptors in the LTF reduced the basal level of sympathetic discharge, but without affecting baroreflex control of sympathetic discharge. Thus this group has proposed that LTF sympathoexcitatory neurons play an important role in both the tonic and baroreflex control of the sympathetic vasomotor outflow, via activation of non-NMDA and NMDA receptors, respectively. The latest study by this group (20) in this issue of American Journal of Physiology-Regulatory, Integrative and Comparative Physiology shows that non-NMDA receptors in the LTF are also an important component of the central pathways subserving reflex sympathoexcitatory responses to some, but not all, stimuli. In particular, they found that blockade of non-NMDA receptors in the LTF significantly attenuated the reflex increase in cardiac and vertebral sympathetic nerve activity evoked by electrical stimulation of vagal afferents or by activation of arterial chemoreceptors. On the other hand, the reflex sympathoexcitation evoked by electrical stimulation of trigeminal or sciatic nerve afferents or of sites in the posterior hypothalamus or midbrain periaqueductal gray were not attenuated. As the authors point out, vagal and chemoreceptor afferent fibers (like baroreceptor afferent fibers) terminate in the nucleus of the solitary tract (NTS), whereas trigeminal and sciatic afferents do not, suggesting the possibility that, at least in the cat, the LTF may be a critical component in all sympathetic reflex pathways in which the primary afferents terminate in the NTS. How do these observations fit in with the currently accepted functional organization of cardiovascular reflex pathways in the medulla, which are based largely on experiments in the rat and rabbit? To take the example of the chemoreceptor-sympathetic reflex, an electrophysiological study in the rat by Koshiya and Guyenet (14) showed that about one-third of NTS neurons that were antidromically activated from the RVLM could be activated by chemoreceptor stimulation. Consistent with this, Hirooka et al. (12) showed that hypoxia in the conscious rabbit induced c-fos expression (indicative of neuronal activation) in a similar proportion of NTS neurons that were retrogradely labeled from the RVLM. These studies in the rat and rabbit thus support the hypothesis that chemosensitive neurons in the NTS convey excitatory inputs to RVLM sympathoexcitatory neurons via a direct pathway, rather than an indirect pathway including the LTF, as suggested by Orer and coworkers. These observations in the rat and rabbit would be compatible with the findings reported by Orer et al. (20) in the cat if there are separate parallel pathways by which chemoreceptor signals Address for reprint requests and other correspondence: R. A. L. Dampney, Dept. of Physiology, F13, The Univ. of Sydney, Sydney NSW 2006, Australia (E-mail: [email protected]). Am J Physiol Regul Integr Comp Physiol 286: R446–R448, 2004; 10.1152/ajpregu.00696.2003.