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