Stretching our understanding of baroreflex control in humans: evidence of a positive feedback pulmonary baroreflex

Stretch-sensitive mechanoreceptors (or baroreceptors) are located ubiquitously throughout the vasculature (i.e. arterial, venous, pulmonary, heart, brain) and provide beat-to-beat afferent feedback to modulate peripheral sympathetic outflow and maintain blood pressure homeostasis. The classical view is that these afferent reflexes act in a negative feedback manner to increase sympathetic activity during acute reductions in blood pressure (e.g. standing) and vice versa. This oversimplified view negates the complexity of baroreceptor afferents. For example, the arterial baroreceptors are known to contain subpopulations of afferent fibres that demonstrate different excitation thresholds and sensitivities, dependent on the blood pressure stimulus (absolute vs. change). Low-pressure cardiac and pulmonary baroreceptors (often termed cardiopulmonary baroreceptors) are also conventionally characterized as a negative feedback mechanism that uniformly sense and respond to changes in central blood volume and pressure/distension. This is observed classically by increases in muscle sympathetic nerve activity (MSNA) responses to non-hypotensive lower body negative pressure. However, these low-pressure baroreceptors, located throughout the atria, ventricle and pulmonary circulation, can each possess unique reflex responses when investigated in isolation. Acknowledging potential species differences, stimulation of unmyelinated vagal afferents, mainly situated in the left ventricle, can evoke mild sympatho-inhibition (i.e. negative feedback response), whereas stimulation of myelinated vagal afferents located in the coronary arteries can decrease sympathetic activity (i.e. negative feedback response), while those at veno-atrial junctions can cause an increase in sympathetic outflow (i.e. positive feedback response) (Hainsworth, 2014). In addition, when controlling systemic arterial pressure, selective increases in pulmonary arterial pressure induce a reflex increase in sympathetic outflow in dogs (Moore et al. 2011). These latter findings indicate an intriguing and less appreciated positive feedback sympathetic reflex arising from pulmonary baroreceptors, which centrally may compete with simultaneously occurring negative feedback mechanisms to modulate efferent sympathetic responses. Indirect evidence in humans also supports the existence of paradoxical baroreflex control, given that a subpopulation of single-unit muscle sympathetic nerve fibres possess divergent discharge patterns during unloading and loading of these low-pressure cardiac and/or pulmonary baroreceptors (Millar et al. 2015). However, the isolation of pulmonary afferents in humans is challenging due to the proximity to cardiac baroreceptors, and close association with modulations in filling pressure and stimulation of the arterial baroreflex. Therefore, direct evidence in humans of a positive feedback sympathoexcitatory reflex from low-pressure pulmonary arterial baroreceptors remains lacking. In a recent issue of the Journal of Physiology, Simpson and colleagues developed a novel experimental approach to overcome the limitations of evaluating the independent contribution of the pulmonary arterial baroreceptors in humans (Simpson et al. 2020). Inhalation of nitric oxide was used to selectively reduce pulmonary arterial pressure via relaxation of pulmonary artery smooth muscle cells, a stimulus that exerts minimal effects on systemic arterial pressure. Using this novel stimulus, the authors hypothesized that reductions in pulmonary pressure would cause reflex inhibition of sympathetic outflow, in line with findings from animal models (Moore et al. 2011). Their study took place as part of the Global REACH 2018 study, and approximately 5 days following an expedition to high altitude (4383 m), direct recordings of peroneal nerve MSNA using microneurography were obtained in 13 lowlanders before and after selective reductions of pulmonary pressure. Echocardiography was used to estimate pulmonary artery systolic pressure, while heart rate and blood pressure were measured on a beat-to-beat basis via electrocardiography and finger photoplethysmography, respectively. To evaluate the interaction between the pulmonary and arterial baroreflexes, the gain or sensitivity of the relationship between MSNA and diastolic blood pressure was assessed using the modified-Oxford protocol, which consists of infusion of pharmacological stimuli to decrease (using sodium nitroprusside) and increase (using phenylephrine) systemic arterial pressure. This was also completed before and after selective reductions in pulmonary arterial pressure with inhaled nitric oxide. The main findings of the current study were that inhalation of nitric oxide: (1) concurrently decreased estimated pulmonary arterial systolic pressure and MSNA burst frequency (but not burst amplitude), and (2) did not alter the sensitivity of arterial baroreflex control of MSNA but caused a leftward and downward resetting. Collectively, these findings provided the first evidence of an independent contribution of the pulmonary arterial baroreceptors to alter muscle sympathetic outflow in a positive feedback manner at high altitude. The study by Simpson and colleagues was well designed and employed novel methodologies to isolate the contribution of pulmonary baroreflex function in humans. In general, pioneering studies like this hold considerable promise to advance the body of knowledge in the field, but often create more questions than answers. It is important to acknowledge that all measurements in the current study were performed at high altitude, a stimulus known to augment pulmonary arterial pressure. It is possible that higher prevailing operating pressures within the pulmonary circulation may have altered the neural contribution of the pulmonary arterial baroreflex. Indeed, Simpson and colleagues have previously observed profound increases in the set-point for MSNA in lowlanders following acute exposure to high altitude. Whether the same protocol of reducing pulmonary arterial pressure would produce similar reductions in MSNA at sea level remains to be investigated. The importance of baroreceptor loading conditions is highlighted by work in patients with heart failure with reduced ejection fraction who have altered MSNA responses to selective increases in cardiac filling pressure with lower body positive pressure but similar responses to age-matched healthy controls with lower body negative pressure (Millar et al. 2015). Whether low-pressure pulmonary baroreceptors contribute to the increased resting sympathetic outflow characterizing cardiovascular disease states (e.g. hypertension, heart failure and pulmonary arterial hypertension) is currently unknown and remains a tantalizing future hypothesis. Alternatively, it would be of interest to explore whether chronic exposure to high altitude can influence the pulmonary pressure–MSNA reflex. Work by the same research group has shown that native highlanders have lower MSNA and pulmonary operating pressures when compared to lowlanders following ascent to high altitude, despite similar arterial blood pressure. Arterial baroreflex MSNA set-points in highlanders at altitude are more closely related to lowlanders at sea level. Therefore, it would be worthwhile to investigate the possible sympathoexcitatory role of pulmonary arterial baroreceptors in native highlanders to further our understanding of the existence of a circulatory afferent receptor that functions in a positive feedback manner in humans. One unresolved question pertains to the physiological relevance of a pulmonary arterial baroreflex. Positive feedback mechanisms in the heart, such as the Bainbridge reflex, are physiologically important for matching cardiac output to venous return, although positive feedback control in the circulation is less clear. It is important to note that the current study did not investigate MSNA responses to bidirectional manipulation of pulmonary arterial pressure, owing to the difficulty of experimentally increasing pulmonary arterial pressure independent of the systemic circulation. However, under the assumption that the pulmonary arterial baroreflex is bidirectional (particularly when pulmonary arterial pressure is normalized under non-hypoxic conditions), we speculate that the findings by Simpson and colleagues may provide physiological insight into an additional mechanism involved in resetting the set-point of MSNA during exercise. Catheterization of the pulmonary circulation during semirecumbent exercise has demonstrated that even low-intensity exercise can increase both atrial and pulmonary pressure, and decrease pulmonary compliance (Wright et al. 2016), suggesting exercise can alter the loading patterns of stretch-sensitive pulmonary afferents. It is possible that excitation from exercise-induced pulmonary loading, and subsequent convergence of this excitatory input to central brainstem regions, can contribute to the rightward upward shift of arterial baroreflex control of MSNA during exercise. Future studies should investigate whether the inhalation of nitric oxide can attenuate the MSNA response and alter arterial baroreflex resetting during exercise. Lastly, it remains of interest to determine if pulmonary loading during exercise contributes to the exaggerated sympathetic and blood pressure responses commonly observed in cardiovascular disease states. Although no studies have attempted to delineate this relationship, selectively reducing pulmonary pressure using inhaled nitric oxide improved exercise capacity in patients with heart failure (Koelling et al. 1998), a condition known to have a neurovascular limitation to exercise. Although the mechanisms responsible for the improved exercise capacity are unclear, an interesting speculation may relate to this positive feedback mechanism within the pulmonary circulation. In summary, Simpson and colleagues have performed a challenging and comprehensive assessment of a largely unexplored role of pulmonary arterial baroreceptors in humans. The findings support the concept of a positive feedback mechanism originating from low-pressure mechanosenstive pulmonary arterial baroreceptors capable of altering peripheral sympathetic nerve activity. Noteworthy, this mechanism contrasts with the well-known negative feedback from coronary and arterial baroreceptors. Future studies are required to identify the possible contribution of pulmonary arterial baroreceptors in the baroreflex resetting during exercise and its contribution to sympathetic nerve activation at rest and during exercise in different populations such as native highlanders and patients with cardiovascular diseases. Finally, Simpson and colleagues should be commended on their innovative research that provides a fertile pathway for future investigations to better our understanding of baroreflex regulation in humans. None declared. M.N. was supported by the Ontario Graduate Scholarship. We thank Dr Philip Millar for insightful comments and discussion on the manuscript. Additionally, we apologize for not citing all relevant articles due to reference limitations.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.