Mechanisms reducing parasympathetic activity in chronic hypoxia

Parasympathetic activity is reduced in chronic hypoxia, but the underlying mechanism(s) are unclear. We investigated whether (i) arterial chemoreflex activation, (ii) increased pulmonary ventilation and/or (iii) pulmonary stretch, (iv) hypocapnia resulting from increased ventilation or (v) hypovolemia due to plasma volume contraction reduce parasympathetic activity in chronic hypoxia. In 13 lowlanders (8M/5F), we administered β-adrenergic blockade (intravenous propranolol) to isolate parasympathetic control of HR and thus use HR as a reciprocal index of parasympathetic activity, first at sea level (SL) and then after 9-12 days of exposure to high altitude (HA, 3800 m). Under β-adrenergic blockade, HR was 9.3 ± 6.5bpm higher at HA than at SL (P < 0.001), supporting parasympathetic withdrawal in chronic hypoxia. This HA-induced HR increase remained unchanged when (i) the arterial chemoreflex was inhibited by pure oxygen breathing (P = 0.083) but decreased when (ii) pulmonary ventilation was matched between SL and HA by paced breathing (P = 0.031). Performing apnoeas abolishing differences in pulmonary stretch (iii) did not reduce the HA-induced HR acceleration (P = 0.275), whereas (iv) increasing end-tidal CO₂ partial pressure to counteract hypocapnia at HA further enhanced it (P = 0.006). Restoring blood volume at HA to SL values by saline infusion (v) also failed to reduce the HA-induced HR acceleration (P = 0.813). Our findings support a contribution of increased ventilation, but not of arterial chemoreflex activation, hypocapnia or hypovolemia, to the parasympathetic withdrawal associated with chronic hypoxia. That performing apnoea failed to reduce the HA-induced elevation in HR furthermore indicates that the increased ventilation reduces parasympathetic activity via mechanisms other than pulmonary stretch. KEY POINTS: Chronic hypoxia reduces parasympathetic activity, but the underlying mechanisms remain unclear. At sea level and after 9-12 days of sojourn at high altitude, we used β-adrenergic blockade to isolate parasympathetic control of the heart, so that heart rate could be used as a reciprocal index for parasympathetic activity. Heart rate under β-adrenergic blockade was higher at high altitude than at sea level, supporting parasympathetic withdrawal in chronic hypoxia. Matching ventilation between sea level and high altitude reduced the high altitude-induced heart rate acceleration, indicating that the increased pulmonary ventilation in chronic hypoxia contributes to parasympathetic withdrawal. Conversely, the high altitude-induced heart rate acceleration was not reduced by inhibition of the arterial chemoreflex, or removal of hypoxia-indued hypocapnia or hypovolemia, thus not supporting these as mechanisms of reduced parasympathetic activity in chronic hypoxia.