Parasympathetic withdrawal increases heart rate after 2 weeks at 3454 m altitude.

KEY POINTS: Heart rate is increased in chronic hypoxia and we tested whether this is the result of increased sympathetic nervous activity, reduced parasympathetic nervous activity, or a non-autonomic mechanism. In seven lowlanders, heart rate was measured at sea level and after 2 weeks at high altitude after individual and combined pharmacological inhibition of sympathetic and/or parasympathetic control of the heart. Inhibition of parasympathetic control of the heart alone or in combination with inhibition of sympathetic control abolished the high altitude-induced increase in heart rate. Inhibition of sympathetic control of the heart alone did not prevent the high altitude-induced increase in heart rate. These results indicate that a reduced parasympathetic nervous activity is the main mechanism underlying the elevated heart rate in chronic hypoxia. ABSTRACT: Chronic hypoxia increases resting heart rate (HR), but the underlying mechanism remains incompletely understood. We investigated the relative contributions of the sympathetic and parasympathetic nervous systems, along with potential non-autonomic mechanisms, by individual and combined pharmacological inhibition of muscarinic and/or ß-adrenergic receptors. In seven healthy lowlanders, resting HR was determined at sea level (SL) and after 15-18 days of exposure to 3454 m high altitude (HA) without drug intervention (control, CONT) as well as after intravenous administration of either propranolol (PROP), or glycopyrrolate (GLYC), or PROP and GLYC in combination (PROP+GLYC). Circulating noradrenaline concentration increased from 0.9 ± 0.4 nmol l-1 at SL to 2.7 ± 1.5 nmol l-1 at HA (P = 0.03). The effect of HA on HR depended on the type of autonomic inhibition (P = 0.006). Specifically, HR was increased at HA from 64 ± 10 to 74 ± 12 beats min-1 during the CONT treatment (P = 0.007) and from 52 ± 4 to 59 ± 5 beats min-1 during the PROP treatment (P < 0.001). In contrast, HR was similar between SL and HA during the GLYC treatment (110 ± 7 and 112 ± 5 beats min-1 , P = 0.28) and PROP+GLYC treatment (83 ± 5 and 85 ± 5 beats min-1 , P = 0.25). Our results identify a reduction in cardiac parasympathetic activity as the primary mechanism underlying the elevated HR associated with 2 weeks of exposure to hypoxia. Unexpectedly, the sympathoactivation at HA that was evidenced by increased circulating noradrenaline concentration had little effect on HR, potentially reflecting down-regulation of cardiac ß-adrenergic receptor function in chronic hypoxia. These effects of chronic hypoxia on autonomic control of the heart may concern not only HA dwellers, but also patients with disorders that are associated with hypoxaemia.

Twenty-eight days at 3454-m altitude diminishes respiratory capacity but enhances efficiency in human skeletal muscle mitochondria.

Modifications of skeletal muscle mitochondria following exposure to high altitude (HA) are generally studied by morphological examinations and biochemical analysis of expression. The aim of this study was to examine tangible measures of mitochondrial function following a prolonged exposure to HA. For this purpose, skeletal muscle biopsies were obtained from 8 lowland natives at sea level (SL) prior to exposure and again after 28 d of exposure to HA at 3454 m. High-resolution respirometry was performed on the muscle samples comparing respiratory capacity and efficiency. Exercise capacity was assessed at SL and HA. Respirometric analysis revealed that mitochondrial respiratory capacity diminished in complex I- and complex II-specific respiration in addition to a loss of maximal state-3 oxidative phosphorylation capacity from SL to HA, all independent from alterations in mitochondrial content. Leak control coupling, respiratory control ratio, and oligomycin-induced leak respiration, all measures of mitochondrial efficiency, improved in response to HA exposure. SL respiratory capacities correlated with measures of exercise capacity near SL, whereas mitochondrial efficiency correlated best with exercise capacity following HA. This data demonstrate that 1 mo of exposure to HA reduces respiratory capacity in human skeletal muscle; however, the efficiency of electron transport improves.

Thermodilution-determined Internal Jugular Venous Flow.

PURPOSE: Cerebral blood flow (CBF) increases ~20% during whole body exercise although a Kety-Schmidt-determined CBF is reported to remain stable; a discrepancy that could reflect evaluation of arterial vs. internal jugular venous (IJV) flow and/or that CBF is influenced by posture. Here we test the hypothesis that IJV flow, as determined by retrograde thermodilution increases during exercise when body position is maintained. METHODS: Introducing retrograde thermodilution, IJV flow was measured in eight healthy humans at supine and upright rest and during exercise in normoxia and hypoxia with results compared with changes in ultrasound-derived IJV flow and middle cerebral artery mean velocity (MCA Vmean). RESULTS: Thermodilution determined IJV flow was in reasonable agreement with values established in a phantom (R = 0.59, P < 0.0001) and correlated to the ultrasound-derived IJV flow (n = 7; Kendall τ, 0.28; P = 0.036). When subjects stood up, IJV blood flow decreased by 9% ± 13% (mean ± SD) (219 ± 57 to 191 ± 73 mL·min; P < 0.0001) and the influence of body position was maintained during exercise (P < 0.0001). Exercise increased both IJV flow and MCA Vmean (P = 0.019 and P = 0.012, respectively) and the two responses were similar (P = 0.50). During hypoxia, however, only MCA Vmean responded with a further increase (P < 0.0001). CONCLUSIONS: As determined by retrograde thermodilution, IJV flow seems little sensitive to hypoxia, but does demonstrate the about 15% reduction in CBF when humans are upright and, provided that body position is maintained, also the increase in CBF during whole body exercise.

Hypovolemia explains the reduced stroke volume at altitude.

During acute altitude exposure tachycardia increases cardiac output (Q) thus preserving systemic O2 delivery. Within days of acclimatization, however, Q normalizes following an unexplained reduction in stroke volume (SV). To investigate whether the altitude-mediated reduction in plasma volume (PV) and hence central blood volume (CBV) is the underlying mechanism we increased/decreased CBV by means of passive whole body head-down (HDT) and head-up (HUT) tilting in seven lowlanders at sea level (SL) and after 25/26 days of residence at 3454 m. Prior to the experiment on day 26, PV was normalized by infusions of a PV expander. Cardiovascular responses to whole body tilting were monitored by pulse contour analysis. After 25/26 days at 3454 m PV and blood volume decreased by 9 ± 4% and 6 ± 2%, respectively (P < 0.001 for both). SV was reduced compared to SL for each HUT angle (P < 0.0005). However, the expected increase in SV from HUT to HDT persisted and ended in the same plateau as at SL, albeit this was shifted 18 ± 20° toward HDT (P = 0.019). PV expansion restored SV to SL during HUT and to an ∼8% higher level during HDT (P = 0.003). The parallel increase in SV from HUT to HDT at altitude and SL to a similar plateau demonstrates an unchanged dependence of SV on CBV, indicating that the reduced SV during HUT was related to an attenuated CBV for a given tilt angle. Restoration of SV by PV expansion rules out a significant contribution of other mechanisms, supporting that resting SV at altitude becomes reduced due to a hypovolemia.