ReviewEffect of baroreceptor stimulation on the respiratory pattern: Insights into respiratory–sympathetic interactions☆
Introduction
Cardiac, sympathetic and respiratory activities are coordinated for effective and efficient gas exchange (Hayano et al., 1996). In this regard, the cardiovascular and respiratory systems can be envisioned as an integrated physiological system delivering oxygen to the tissues and removing carbon dioxide from the body (Koepchen et al., 1981, Richter and Spyer, 1990, Simms et al., 2010). The neural control of this system is located within the brainstem where respiratory rhythm and sympathetic premotor activity are generated. Moreover, the respiratory and sympathetic control circuits interact within the brainstem and various sensory afferents, including baroreceptor inputs, affect the neurones that generate and modulate both respiratory and sympathetic activities.
Sympathetic nerve activity (SNA) expresses respiratory modulation even after vagotomy and decerebration (Barman and Gebber, 1980, Haselton and Guyenet, 1989, Häbler et al., 1994, Richter and Spyer, 1990, Simms et al., 2009) supporting the idea of central coupling between respiratory and sympathetic networks. This coupling seems to be an important mechanism to: (i) optimize minute ventilation and cardiac output to increase the efficiency of oxygen uptake/perfusion at rest; and (ii) allow appropriate dynamic integrative cardiovascular and respiratory reflex responses essential for maintaining homeostasis (Hayano et al., 1996, Zoccal et al., 2009). Therefore, respiratory modulation may contribute to the dynamic control of SNA.
The respiratory rhythm and motor pattern is generated by a respiratory central pattern generator (CPG) located in the lower brainstem (Bianchi et al., 1995, Cohen, 1979, Lumsden, 1923). The pre-Bötzinger Complex (pre-BötC) located within the medullary ventrolateral respiratory column (VRC) is considered a major source of rhythmic inspiratory activity (Feldman and Del Negro, 2006, Koshiya and Smith, 1999, Rekling and Feldman, 1998, Smith et al., 1991). The pre-BötC, interacting with the adjacent Bötzinger Complex (BötC) containing mostly expiratory neurones (Ezure, 1990, Ezure et al., 2003, Jiang and Lipski, 1990, Tian et al., 1999), represents a core of the respiratory CPG (Bianchi et al., 1995, Cohen, 1979, Richter, 1996, Richter and Spyer, 2001, Rybak et al., 2004, Rybak et al., 2007, Rybak et al., 2008, Smith et al., 2007, Smith et al., 2009, Tian et al., 1999). This core circuitry generates primary respiratory oscillations defined by the intrinsic biophysical properties of respiratory neurones involved, the architecture of network interactions between respiratory neural populations within the pre-BötC and BötC, and inputs from other brainstem compartments, including the pons, retrotrapezoid nucleus (RTN), raphé, and nucleus tractus solitarii (NTS).
The NTS receives and integrates most of the peripheral cardiovascular and respiratory afferent inputs, including baroreceptor afferents. It mediates a variety of reflexive motor responses from the brainstem and spinal cord that provide homeodynamic control of breathing and cardiovascular functions (reviewed by Loewy and Spyer, 1990). The classical baroreflex control of SNA operates via NTS neurones mediating the baroreceptor projections to the caudal ventrolateral medulla (CVLM). Through this path, baroreceptor activation excites CVLM neurones which in turn inhibit the rostral ventrolateral medulla (RVLM) neurones and hence lower SNA (Dampney, 1994, Guyenet, 1990). This pathway provides a direct negative feedback control of SNA.
Respiratory activity is also modulated by the afferent baroreceptor activity possibly through the same NTS baro-sensitive neurones. For instance in vagally intact, decerebrate cats, the activities of approximately 50% of the respiratory-modulated neurones within the VRC responded to transient pressure pulses (Dick and Morris, 2004). Furthermore, expiratory propriobulbar activity was modulated to a greater extent than inspiratory propriobulbar activity (Dick and Morris, 2004). Because the overlap between respiratory and cardiovascular regulatory areas is extensive, we could not exclude the possibility that neurones with both the respiratory-modulated and arterial pulse-modulated activity were related to cardiovascular rather than to respiratory control or to both. To address this, we restricted our analysis to respiratory-modulated activity that was identified as either bulbospinal premotor or bulbar (laryngeal) motor neurones. Surprisingly, these neurones also exhibited arterial-pulse-pressure modulated activity (Dick et al., 2005). Thus, neurones with an identified respiratory function, modulating airway resistance, can express arterial-pulse modulated activity.
The aim of this study was to verify that activation of baroreceptor afferents can indeed affect the respiratory CPG and the respiratory pattern by altering BötC expiratory neurone firing. We performed systematic recordings of respiratory neurones within the VRC, specifically within the BötC/pre-BötC core of the respiratory network, to reveal possible neural interactions between the baro-afferent processing circuits and those determining the respiratory pattern.
Another important objective of this study was to examine the possibility of parallel pathways for the sympathetic baroreceptor reflex. Parallel pathways, one respiratory modulated and the other independent of respiration has been proposed and identified for the sympathetic chemo-reflex (Guyenet and Koshiya, 1995). The theoretical basis for parallel pathways was derived from the following logic. If respiratory modulation represents an important mechanism for control of SNA and, at the same time, baroreceptor activation can alter the respiratory pattern, then baroreceptor activation should affect SNA via its effects on the respiratory pattern independent of the direct baroreflex pathway from NTS to CVLM. This would provide a basis for suggesting that the sympathetic baroreceptor reflex provides negative feedback from baroreceptors to SNA through two pathways: one direct that is independent of the respiratory–sympathetic interactions, and the other indirect that depends on the effects of baroreceptor afferents on the respiratory pattern and hence on the respiratory modulation of SNA.
Finally, because transection of the pons significantly attenuates respiratory modulation of SNA (Baekey et al., 2008, Dick et al., 2009), we were interested in a possible role of the pons in the baroreceptor reflex mediated respiratory–sympathetic interactions and respiratory modulation of SNA. We used a computational model of the brainstem respiratory network that includes the pons (Smith et al., 2007) and extended it to incorporate VLM, RTN compartments and their corresponding neural populations. The extended model was used to simulate, investigate and predict the possible neural mechanisms involved in the baroreceptor reflex mediated respiratory–sympathetic interactions.
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Surgical and experimental procedures
This series of experiments were performed at two sites: the University of Bristol in Bristol, England, and Case Western Reserve University in Cleveland, OH, USA. For those experiments performed in England, all surgical and experimental procedures conformed to the UK Animals (Scientific Procedures) Act and were approved by the University of Bristol ethical review committee. Similarly, for the experiments done in the United States, the Institutional Animal Care and Use Committee (IACUC) of Case
Respiratory phase-dependent and pontine-dependent effects of transient baroreceptor stimulation on the respiratory pattern and on respiratory modulation of sympathetic nerve activity
In the intact arterially perfused in situ rat preparation, the thoracic sympathetic nerve activity (tSNA) usually exhibited a well-expressed positive inspiratory modulation reaching its peak in early post-inspiration (see Fig. 1A1–A3 before applied stimulations). The respiratory modulation of tSNA was significantly suppressed or eliminated after removal of the pons when phrenic nerve activity (PNA) transformed to a more apneustic-like pattern with prolonged inspiratory bursts and shortened
Respiratory modulation of sympathetic activity
In this study, we focus on two aspects of the respiratory modulation of SNA: the positive inspiratory (or IE with the peak during early post-inspiration) and the subsequent post-inspiration rapid off-set that can be recognized in our experimental recordings in situ (Fig. 1A1–A3). Our data support the anatomical evidence that sympatho-respiratory coupling occurs, at least partially, in the medulla (Pilowsky et al., 1990, Pilowsky et al., 1992, Pilowsky et al., 1994, Sun et al., 1997). However,
Acknowledgements
We gratefully acknowledge the support of NIH grants R33 HL087377, NS057815, HL090554, and HL033610; American Heart Association, SDG 073503N; and the British Heart Foundation. David Baekey was also funded by a Leverhulme Fellowship from the University of Bristol. J.F.R.P. was in receipt of a Royal Society Wolfsom Research Merit Award.
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This paper is part of a special issue entitled “Central cardiorespiratory regulation: physiology and pathology”, guest-edited by Thomas E. Dick and Paul M. Pilowsky.
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These authors contributed equally to this work.