No abstract

Key points In an anaesthetised animal model, independent stimulation of baroreceptors in the pulmonary artery elicits reflex sympathoexcitation. In humans, pulmonary arterial pressure is positively related to basal muscle sympathetic nerve activity (MSNA) under conditions where elevated pulmonary pressure is evident (e.g. high altitude); however, a causal link is not established. Using a novel experimental approach, we demonstrate that reducing pulmonary arterial pressure lowers basal MSNA in healthy humans. This response is distinct from the negative feedback reflex mediated by aortic and carotid sinus baroreceptors when systemic arterial pressure is lowered. Afferent input from pulmonary arterial baroreceptors may contribute to sympathetic neural activation in healthy lowland natives exposed to high altitude. Abstract In animal models, distension of baroreceptors located in the pulmonary artery induces a reflex increase in sympathetic outflow; however, this has not been examined in humans. Therefore, we investigated whether reductions in pulmonary arterial pressure influenced sympathetic outflow and baroreflex control of muscle sympathetic nerve activity (MSNA). Healthy lowlanders (n = 13; 5 females) were studied 4–8 days following arrival at high altitude (4383 m; Cerro de Pasco, Peru), a setting that increases both pulmonary arterial pressure and sympathetic outflow. MSNA (microneurography) and blood pressure (BP; photoplethysmography) were measured continuously during ambient air breathing (Amb) and a 6 min inhalation of the vasodilator nitric oxide (iNO; 40 ppm in 21% O2), to selectively lower pulmonary arterial pressure. A modified Oxford test was performed under both conditions. Pulmonary artery systolic pressure (PASP) was determined using Doppler echocardiography. iNO reduced PASP (24 ± 3 vs. 32 ± 5 mmHg; P < 0.001) compared to Amb, with a similar reduction in MSNA total activity (1369 ± 576 to 994 ± 474 a.u min−1; P = 0.01). iNO also reduced the MSNA operating point (burst incidence; 39 ± 16 to 33 ± 17 bursts·100 Hb−1; P = 0.01) and diastolic operating pressure (82 ± 8 to 80 ± 8 mmHg; P < 0.001) compared to Amb, without changing heart rate (P = 0.6) or vascular–sympathetic baroreflex gain (P = 0.85). In conclusion, unloading of pulmonary arterial baroreceptors reduced basal sympathetic outflow to the skeletal muscle vasculature and reset vascular–sympathetic baroreflex control of MSNA downward and leftward in healthy humans at high altitude. These data suggest the existence of a lesser‐known reflex input involved in sympathetic activation in humans.

Early acclimatization to high-altitude is characterized by various respiratory, hematological, and cardiovascular adaptations that serve to restore oxygen delivery to tissue. However, less is understood about renal function and the role of renal oxygen delivery (RDO2) during high-altitude acclimatization. We hypothesized that: 1) RDO2 would be reduced after 12-hours of high-altitude exposure (high-altitude day1) but restored to sea-level values after one-week (high-altitude day7); and 2) RDO2 would be associated with renal reactivity (RR), an index of acid-base compensation at high-altitude. Twenty-four healthy lowlander participants were tested at sea-level (344m; Kelowna, Canada), on day1 and day7 at high-altitude (4330m; Cerro de Pasco, Peru). Cardiac output, renal blood flow, arterial and venous blood sampling for renin-angiotensin-aldosterone-system hormones and NT pro-B type natriuretic peptides were collected at each time point. RR was calculated as: (Δ arterial bicarbonate)/(Δ partial pressure of arterial carbon dioxide) between sea-level and high-altitude day1, and sea-level and high-altitude day7. The main findings were: 1) RDO2 was initially decreased at high-altitude compared to sea-level (ΔRDO2: -22±17%, P<0.001), but was restored to sea-level values on high-altitude day7 (ΔRDO2: -6±14%, P=0.36). The observed improvements in RDO2 resulted from both changes in renal blood flow (Δ from high-altitude day1: +12±11%; P=0.008), and arterial oxygen content (Δ from high-altitude day1 +44.8±17.7%; P=0.006); and 2) RR was positively correlated with RDO2 on high-altitude day7 (r=0.70; P<0.001), but not high-altitude day1 (r=0.26; P=0.29). These findings characterize the temporal responses of renal function during early high-altitude acclimatization, and the influence of RDO2 in the regulation of acid-base.

The high-altitude maladaptation syndrome chronic mountain sickness (CMS) is characterized by excessive erythrocytosis and frequently accompanied by accentuated arterial hypoxaemia. Whether altered autonomic cardiovascular regulation is apparent in CMS is unclear. Therefore, during the 2018 Global REACH expedition to Cerro de Pasco, Peru (4383 m), we assessed integrative control of blood pressure (BP) and determined basal sympathetic vasomotor outflow and arterial baroreflex function in eight Andean natives with CMS ([Hb] 22.6 ± 0.9 g⋅dL −1) and seven healthy highlanders ([Hb] 19.3 ± 0.8 g⋅dL −1). R-R interval (RRI, electrocardiogram), beat-by-beat BP (photoplethysmography) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded at rest and during pharmacologically induced changes in BP (modified Oxford test). Although [Hb] and blood viscosity (7.8 ± 0.7 vs. 6.6 ± 0.7 cP; d = 1.7, P = 0.01) were elevated in CMS compared to healthy highlanders, cardiac output, total peripheral resistance and mean BP were similar between groups. The vascular sympathetic baroreflex MSNA set-point (i.e. MSNA burst incidence) and reflex gain (i.e. responsiveness) were also similar between groups (MSNA set-point, d = 0.75, P = 0.16; gain, d = 0.2, P = 0.69). In contrast, in CMS the cardiovagal baroreflex operated around a longer RRI (960 ± 159 vs. 817 ± 50 ms; d = 1.4, P = 0.04) with a greater reflex gain (17.2 ± 6.8 vs. 8.8 ± 2.6 ms⋅mmHg −1 ; d = 1.8, P = 0.01) versus healthy highlanders. Basal sympathetic vasomotor activity was also lower compared to healthy highlanders (33 ± 11 vs. 45 ± 13 bursts⋅min −1 ; d = 1.0, P = 0.08). In conclusion, our findings indicate adaptive differences in basal sympathetic vasomotor activity and heart rate This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

High-altitude (>2500m) exposure results in increased muscle sympathetic nervous activity (MSNA) in acclimatizing lowlanders. However, little is known about how altitude affects MSNA in indigenous high-altitude populations. Additionally, the relationship between MSNA and blood pressure regulation (i.e., neurovascular transduction) at high-altitude is unclear. We sought to determine 1) how high-altitude effects neuro-cardiovascular transduction and 2) whether differences exist in neuro-cardiovascular transduction between low and high-altitude populations. Measurements of MSNA (microneurography), mean arterial blood pressure (MAP; finger photoplethysmography), and heart rate (electrocardiogram) were collected in: I) lowlanders (n=14) at low (344m) and high-altitude (5050m), II) Sherpa highlanders (n=8; 5050m), and III) Andean (with and without excessive erythrocytosis) highlanders (n=15; 4300m). Cardiovascular responses to MSNA burst sequences (i.e. singlet, couplet, triplet, and quadruplets) were quantified using custom software (coded in MATLAB, v2015b). Slopes were generated for each individual based on peak responses and normalized total MSNA. High altitude reduced neuro-cardiovascular transduction in lowlanders (MAP slope: high-altitude, 0.0075±0.0060 vs low-altitude, 0.0134±0.080; p=0.03). Transduction was elevated in Sherpa (MAP slope, 0.012±0.007) compared to Andeans (0.003±0.002; p=0.001). MAP transduction was not statistically different between acclimatizing lowlanders and Sherpa (MAP slope, p=0.08) or Andeans (MAP slope, p=0.07). When accounting for resting MSNA (ANCOVA), transduction was inversely related to basal MSNA (bursts/min) independent of population (RRI, r= 0.578 p<0.001; MAP, r= -0.627 p<0.0001). Our results demonstrate transduction is blunted in individuals with higher basal MSNA, suggesting blunted neuro-cardiovascular transduction is a physiological adaptation to elevated MSNA rather than an effect or adaptation specific to chronic hypoxic exposure.