Sympathetic vasomotor tonetime to move beyond the Network Oscillator Hypothesis?

The following is the abstract of the article discussed in the subsequent letter:

	ABSTRACT

Barman, Susan M., Hakan S. Orer, and Gerard L. Gebber. Differential effects of an NMDA and a non-NMDA receptor antagonist on medullary lateral tegmental field neurons. Am J Physiol Regul Integr Comp Physiol 282: R100-R112, 2002.We microinotophoresed an N-methyl-D-aspartate (NMDA) and a non-NMDA receptor antagonist onto medullary lateral tegmental field (LTF) neurons, the naturally occurring discharges of which were correlated to the cardiac-related rhythm in sympathetic nerve discharge (SND) of dialurethane-anesthetized cats. Some of the neurons were classified as sympathoexcitatory, because their firing rage decreased during baroreceptor reflex activation. Microiontophoresis of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide I (NBQX), a non-NMDA receptor antagonist, reduced the mean firing rates of these neurons (51 ± 8% of control, P < 0.001, n = 20) without affecting their relationship to cardiac-related SND, as indicated by the lack of significant changes in the ratio of peak to background counts in arterial pulse (AP)-triggered histograms of LTF neuronal activity and the AP-LTF coherence value at the frequency of the heartbeat. In contrast, microiontophoresis of D()-2-amino-5-phosphonopentanoic acid, an NMDA receptor antagonist, onto LTF neurons reduced the ratio of peak to background counts in AP-triggered histograms to 57 ± 9% of control (P = 0.002, n =16) and the AP-LTF coherence value to 25 ± 10% of control (P = 0.001, n = 10). These data support the view that non-NMDA and NMDA receptors are involved in setting the basal level of activity of LTF sympathoexcitatory neurons and in synchronizing their discharges to the AP, respectively.

	LETTER

To the Editor: One of the major unsolved questions of regulatory physiology is how the central nervous system generates the basal sympathetic vasomotor activity that supports blood pressure, the "vasomotor tone." There is general agreement that the essential excitatory drive comes from premotor neurons in the rostral ventrolateral medulla (RVLM), so the major question becomes: what is the origin of their tonic activity? Recent theories include the "RVLM Pacemaker Hypothesis" (1) and the "Network Oscillator Hypothesis" (2, 3). The Pacemaker Hypothesis, although not excluded as a potential backup mechanism, fell into disfavor as the basis for vasomotor tone after intracellular recordings from RVLM neurons indicated that their ongoing spikes were driven synaptically rather than by intrinsic pacemaker currents (4). The inference was that basal RVLM neuron activity (and thus presumably vasomotor tone) is driven by a network. But is it a network of oscillators?

The Network Oscillator Hypothesis takes the fact that sympathetic nerve activity comes intrinsically in bursts (an early discovery of the Gebber laboratory) to indicate that the sources that drive it are oscillatory (2). Those sources are considered to be a network of variably coupled brain stem oscillator circuits (2, 3). Over the years, this principle has helped Barman, Gebber, and their colleagues identify neurons of several brain regions whose firing was correlated with sympathetic bursts and with particular frequency components of sympathetic nerve activity (3). The relative timing of spikes in relation to sympathetic bursts was used, with other data such as axonal projections, to map putative circuits. An area identified as a potential source of excitatory activity to the RVLM was the lateral tegmental field (LTF) of the medulla (2, 3). Direct experiments later showed that the LTF does indeed contribute a proportion of the tonic drive that supports blood pressure and sympathetic nerve activity (5).

In an illuminating paper published in this journal this year, Barman and colleagues (6) studied LTF neurons with sympathetic-related activity. Strikingly, they found that the tonic and rhythmic components of those neurons' activity could be dissociated. The rhythmic component was selectively reduced by N-methyl-D-aspartate (NMDA) antagonists while the tonic activity (mean firing rate) was preserved. Conversely, non-NMDA antagonists halved their mean firing rate while preserving the sympathetically linked rhythmic component of their activity (6). The rhythmic and tonic components of activity in these LTF neurons thus appeared to be driven by different synaptic inputs. Furthermore, we would suggest that the clean dissociation between them means that, at least in these neurons, the rhythmic inputs were not responsible for much of the tonic activity (i.e., their mean firing rate). We recently reached the same conclusion with respect to the bulbospinal output of RVLM premotor neurons (7).

We propose that it is time for this principle to be applied more generally. The tonic and rhythmic components of sympathetic drive cannot be assumed, without evidence, to be facets of the same process. The independent control of sympathetic burst amplitude and burst probability (8, 9) may be a further expression of the dissociation between tonic and phasic drives. We have to consider each in its own right.

As a corollary, we would point out that although the Network Oscillator Hypothesis is well suited to account for the origin of the rhythmic components of sympathetic vasomotor drive, an important subject in itself, it is not well suited to account for the tonic components that underlie sympathetic vasomotor tone.

	REFERENCES

1.   Guyenet, PG. Role of ventral medulla oblongata in blood pressure regulation. In: Central Regulation of Autonomic Functions, edited by Loewy AD, and Spyer KM.. Oxford: Oxford University Press, 1990, p. 145-167.

2.   Gebber, GL. Central determinants of sympathetic nerve discharge. In: Central Regulation of Autonomic Functions, edited by Loewy AD, and Spyer KM.. New York: Oxford University Press, 1990, p. 126-144.

3.   Barman, SM, and Gebber GL. "Rapid" rhythmic discharges of sympathetic nerves: sources, mechanisms of generation, and physiological relevance. J Biol Rhythms 15: 365-379, 2000[Abstract].

4.   Lipski, J, Kanjhan R, Kruszewska B, and Rong W. Properties of presympathetic neurones in the rostral ventrolateral medulla in the rat: an intracellular study "in vivo." J Physiol 490: 729-744, 1996[ISI].

5.   Barman, SM, Gebber GL, and Orer HS. Medullary lateral tegmental field: an important source of basal sympathetic nerve discharge in the cat. Am J Physiol Regul Integr Comp Physiol 278: R995-R1004, 2000[Abstract/Free Full Text].

6.   Barman, SM, Orer HS, and Gebber GL. Differential effects of an NMDA and a non-NMDA receptor antagonist on medullary lateral tegmental field neurons. Am J Physiol Regul Integr Comp Physiol 282: R100-R113, 2002[Abstract/Free Full Text].

7.   McAllen, RM, Trevaks D, and Allen AM. Analysis of firing correlations between sympathetic premotor neuron pairs in anesthetized cats. J Neurophysiol 85: 1697-1708, 2001[Abstract/Free Full Text].

8.   McAllen, RM, and Malpas SC. Sympathetic burst activity: characteristics and significance. Clin Exp Pharmacol Physiol 24: 791-799, 1997[ISI][Medline].

9.   Kienbaum, P, Karlssonn T, Sverrisdottir YB, Elam M, and Wallin BG. Two sites for modulation of human sympathetic activity by arterial baroreceptors? J Physiol 531: 861-869, 2001[Abstract/Free Full Text].

Robin McAllen, Andrew Allen, Simon Malpas 1 Howard Florey Institute of Experimental Physiology and Medicine University of Melbourne 3050 Australia; 2 Department of Physiology University of Auckland New Zealand

	REPLY

To the Editor: In their letter to the editor, McAllen et al. used our work (3) to argue that 1) the rhythmic discharges of sympathetic nerves arise from central sources distinct from those responsible for their nonoscillatory background (i.e., "tonic") activity and 2) network oscillators responsible in particular for the cardiac-related rhythm do not play an important role in the genesis of sympathetic vasomotor tone that supports blood pressure. We do not draw these inferences from our work.

As noted by McAllen et al., a fundamental aspect of the Network Oscillator Hypothesis is that driving sources of sympathetic nerve discharge (SND) have an inherent tendency to oscillate. The cardiac-related activity of sympathetic nerves and certain groups of brain stem neurons [e.g., neurons in the medullary lateral tegmental field (LTF) and rostral ventrolateral medulla (RVLM)] results from the entrainment of such oscillations (2- to 6-Hz range) to the cardiac cycle by pulse-synchronous baroreceptor nerve activity (1, 4). McAllen et al. apparently lost sight of this and, as a consequence, mistakenly equated the loss of a cardiac-related rhythm in our experiments with absence of an oscillation.

In the study (3) referred to by McAllen et al., we showed that microiontophoresis of an N-methyl-D-aspartate (NMDA) receptor antagonist onto individual LTF neurons reduced or eliminated their cardiac-related activity without changing their mean firing rate. McAllen et al. interpreted these data to indicate that the oscillatory component of their activity was selectively diminished. In actuality, our data showed that the oscillatory activity of LTF neurons persisted. Specifically, during the microiontophoresis of the NMDA receptor antagonist, the autospectrum of LTF neuronal activity contained a prominent peak whose frequency was near that of the heart rate (Fig. 8 in Ref. 3), and the interspike interval histogram contained a single sharp peak corresponding to a frequency in the 2- to 6-Hz band (Fig. 5 in Ref. 3). On this basis, we proposed that NMDA receptor blockade disrupted the entrainment of centrally generated 2- to 6-Hz oscillations to the cardiac cycle. An earlier study by us (5) served as the foundation for this proposal. In that study, we showed that the cardiac-related rhythm in SND was significantly reduced or eliminated by bilateral microinjection of an NMDA receptor antagonist into the LTF, but 2- to 6-Hz oscillations persisted (Figs. 1 and 2 in Ref. 5). We later showed that the 2- to 6-Hz oscillations of SND were not affected by blockade of NMDA receptors in the LTF of baroreceptor-denervated cats (Table 1 and Fig. 4 in Ref. 2). Thus the combined results of our studies (2, 3, 5) support the contention that activation of NMDA receptors in the LTF is critical for the entrainment, but not the generation, of the 2- to 6-Hz oscillations in SND.

McAllen et al. also misinterpreted our findings with iontophoresis of a non-NMDA receptor antagonist onto LTF neurons. They state that blockade of non-NMDA receptors selectively reduced the "tonic" activity of LTF neurons while sparing their rhythmic activity. In fact, cardiac-related power in the autospectrum of LTF neuronal activity was reduced in proportion to that at other frequencies (Fig. 3 in Ref. 3). Also, counts in the cardiac-related peak of the AP-triggered histogram of LTF neuronal activity were reduced proportionally to background counts (Fig. 2 in Ref. 3). Thus, in contrast to the statement by McAllen et al., cardiac-related rhythmic discharges and background activity of LTF neurons were similarly dependent on synaptic inputs acting on non-NMDA receptors. In two other studies (2, 5), we provided additional evidence that non-NMDA receptor blockade depressed oscillatory SND. First, microinjection of a non-NMDA receptor antagonist into the LTF reduced cardiac-related power in SND (Figs. 3 and 5 in Ref. 5). Second, microinjection of the antagonist into the LTF of baroreceptor-denervated cats significantly reduced power in the 2- to 6-Hz band of SND to 46% of control and lowered blood pressure significantly (Table 1 and Fig. 3 in Ref. 2). These observations are at odds with the view of McAllen et al. that network oscillators play little or no role in the genesis of sympathetic vasomotor tone that supports blood pressure. Thus our answer to the question posed by McAllen et al., "Sympathetic vasomotor tonetime to move beyond the Network Oscillator Hypothesis?", is a resounding no!

	FOOTNOTES

10.1152/ajpregu.00297.2002

	REFERENCES

1.   Barman, SM, and Gebber GL. "Rapid" rhythmic discharges of sympathetic nerves: sources, mechanisms of generation, and physiological relevance. J Biol Rhythms 15: 365-379, 2000[Abstract].

2.   Barman, SM, Gebber GL, and Orer HS. Medullary lateral tegmental field: an important source of basal sympathetic nerve discharge in the cat. Am J Physiol Regul Integr Comp Physiol 278: R995-R1004, 2000[Abstract/Free Full Text].

3.   Barman, SM, Orer HS, and Gebber GL. Differential effects of an NMDA and a non-NMDA receptor antagonist on medullary lateral tegmental field neurons. Am J Physiol Regul Integr Comp Physiol 282: R100-R113, 2002[Abstract/Free Full Text].

4.   Gebber, GL. Central determinants of sympathetic nerve discharge. In: Central Regulation of Autonomic Functions, edited by Loewy AD, and Spyer KM.. New York: Oxford Univ. Press, 1990, p. 126-144.

5.   Orer, HS, Barman SM, Gebber GL, and Sykes SM. Medullary lateral tegmental field: an important synaptic relay in the baroreceptor reflex pathway of the cat. Am J Physiol Regul Integr Comp Physiol 277: R1462-R1475, 1999[Abstract/Free Full Text].

Susan M. Barman, Gerard L. Gebber, Hakan S. Orer 1 Department of Pharmacology and Toxicology Michigan State University East Lansing, MI 48824; 2 Department of Pharmacology Faculty of Medicine Hacettepe University 06100 Ankara, Turkey