Pulmonary arterial mechanoreceptors mediate sustained sympathoexcitation during high altitude hypoxia in humans

Sympathetic nervous system activation is a hallmark of high-altitude hypoxia, yet the afferent mechanisms remain incompletely defined. We examined the relative contributions of pulmonary arterial mechanoreceptors and carotid chemoreceptors - two excitatory pathways co-activated by hypoxia - to sustained sympathoexcitation at altitude. Nine healthy lowlanders (27 ± 7 years, three female) were studied after 6-9 days at 3800 m under four conditions: (1) control, (2) inhaled nitric oxide (iNO, 40 ppm) to reduce pulmonary arterial pressure, (3) low-dose dopamine infusion (2 µg kg^- ¹ min^- ¹) to suppress the carotid chemoreflex, and (4) combined iNO and dopamine. End-tidal oxygen and carbon dioxide were kept constant throughout. We assessed muscle sympathetic nerve activity (MSNA), systemic haemodynamics, ventilation and pulmonary arterial systolic pressure. iNO reduced pulmonary arterial pressure and significantly decreased MSNA (condition 1: 25 ± 8 bursts min^-1 vs. condition 2: 21 ± 7 bursts min^-1; P = 0.0415), whereas dopamine infusion reduced ventilation (P < 0.001) without a consistent effect on MSNA (condition 1: 25 ± 8 bursts min^-1 vs. condition 3: 28 ± 13 bursts min^-1; P = 0.112). Combined intervention produced a small reduction in sympathetic nerve activity (condition 3: 28 ± 13 bursts min^-1 vs. condition 4: 26 ± 13 bursts min^-1; P = 0.0643), likely due to baroreflex engagement. These findings confirm that unloading pulmonary arterial pressure attenuates MSNA, reinforcing the role of pulmonary mechanoreceptors in high altitude sympathoexcitation. Attempts to isolate a carotid chemoreflex contribution were likely confounded by dopamine's haemodynamic effect, which introduced variability and limited the specificity of this intervention. Thus, interpretation of this component remains exploratory, highlighting the integrative complexity of reflex control of high altitude sympathoexcitation in humans.