Baker, Sarah E.

Repetitive hypoxic apneas, similar to those observed in sleep apnea, result in resetting of the sympathetic baroreflex to higher blood pressures (BP). This baroreflex resetting is associated with hypertension in preclinical models of sleep apnea (intermittent hypoxia, IH); however, the majority of understanding comes from males. There are data to suggest that female rats exposed to IH do not develop high BP. Clinical data further support sex differences in the development of hypertension in sleep apnea, but mechanistic data are lacking. Here we examined sex-related differences in the effect of IH on sympathetic control of BP in humans. We hypothesized that after acute IH we would observe a rise in muscle sympathetic nerve activity (MSNA) and arterial BP in young men ( n = 30) that would be absent in young women ( n = 19). BP and MSNA were measured during normoxic rest before and after 30 min of IH. Baroreflex sensitivity (modified Oxford) was evaluated before and after IH. A rise in mean BP following IH was observed in men (+2.0 ± 0.7 mmHg, P = 0.03), whereas no change was observed in women (−2.7 ± 1.2 mmHg, P = 0.11). The elevation in MSNA following IH was not different between groups (4.7 ± 1.1 vs. 3.8 ± 1.2 bursts/min, P = 0.65). Sympathetic baroreflex sensitivity did not change after IH in either group ( P > 0.05). Our results support sex-related differences in the effect of IH on neurovascular control of BP and show that any BP-raising effects of IH are absent in young women. These data enhance our understanding of sex-specific mechanisms that may contribute to BP changes in sleep apnea.

Aging increases autonomic support of blood pressure; however, the impact of aerobic fitness on autonomic support of blood pressure has not been addressed in women. As such, we hypothesized that aerobic fitness would be related to the change in blood pressure during ganglionic blockade such that women with greater aerobic fitness would have a blunted fall in blood pressure during ganglionic blockade due to increased vagal tone. Thirteen young premenopausal and 13 older postmenopausal women completed a screening visit where aerobic fitness (maximal oxygen consumption, VO 2max ) was measured. On a separate study day, participants were instrumented for assessment of muscle sympathetic nerve activity, heart rate (electrocardiography), and beat by beat blood pressure (arterial catheter and pressure transducer) and underwent pharmacological blockade of the autonomic ganglia using trimethaphan camyslate. Heart rate, blood pressure, and muscle sympathetic nerve activity were analyzed before and during ganglionic blockade. In young women, there was a significant relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =0.761, P =0.003). In older women, there was no relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =−0.106, P =0.73). Measures of heart rate variability were related to fitness in young women, but not older women (root mean square of successive differences between normal heartbeats, r =0.713, P =0.006 versus r =−0.172, P =0.575). Our data suggest that in young women, autonomic support of blood pressure is attenuated in those that are highly fit; however, this relationship is not significant in older women.

ABSTRACT Although over 100 studies and reviews have examined the ergogenic effects of dietary nitrate (NO 3 − ) supplementation in young, healthy men and women, it is unclear if participant and environmental factors modulate the well-described ergogenic effects—particularly relevant factors include biological sex, aerobic fitness, and fraction of inspired oxygen (F i O 2 ) during exercise. To address this limitation, the literature was systematically reviewed for randomized, crossover, placebo-controlled studies reporting exercise performance outcome metrics with NO 3 − supplementation in young, healthy adults. Of the 2033 articles identified, 80 were eligible for inclusion in the meta-analysis. Random-effects meta-analysis demonstrated that exercise performance improved with NO 3 − supplementation compared with placebo ( d = 0.174; 95% confidence interval (CI), 0.120–0.229; P < 0.001). Subgroup analyses conducted on biological sex, aerobic fitness, and F i O 2 demonstrated that the ergogenic effect of NO 3 − supplementation was as follows: 1) not observed in studies with only women ( n = 6; d = 0.116; 95% CI, −0.126 to 0.358; P = 0.347), 2) not observed in well-trained endurance athletes (≥65 mL·kg −1 ·min −1 ; n = 26; d = 0.021; 95% CI, −0.103 to 0.144; P = 0.745), and 3) not modulated by F i O 2 (hypoxia vs normoxia). Together, the meta-analyses demonstrated a clear ergogenic effect of NO 3 − supplementation in recreationally active, young, healthy men across different exercise paradigms and NO 3 − supplementation parameters; however, the effect size of NO 3 − supplementation was objectively small ( d = 0.174). NO 3 − supplementation has more limited utility as an ergogenic aid in participants with excellent aerobic fitness that have optimized other training parameters. Mechanistic research and studies incorporating a wide variety of subjects (e.g., women) are needed to advance the study of NO 3 − supplementation; however, additional descriptive studies of young, healthy men may have limited utility.

Background In humans, maximal exercise capacity is reduced during hypoxic environmental conditions. In response to hypoxia, the hemoglobin binding affinity is decreased, promoting oxygen off‐loading at the tissue level and causing a right‐shift of the oxyhemoglobin dissociation curve (ODC). However, comparative biology demonstrates many species (e.g. Bar‐headed geese), who are adapted to hypoxia instead have high‐affinity hemoglobin (left‐shifted ODC). Therefore we studied unique human participants with hemoglobinopathies that result in high affinity hemoglobin (HAH) to investigate the role of oxygen affinity in exercise performance and tissue oxygenation during hypoxic conditions. Methods HAH participants (n=5, 1M/4F, Age= 34±11 yr, P 50 =16±1 mmHg) and matched control participants (n=12, 5M/7F, age=39±12 yr, and P 50 =26±1 mmHg) completed two incremental exercise tests to exhaustion on a cycle ergometer under two conditions: 1) room air (F i O 2 = 0.21, NORM), and 2) normobaric hypoxia gas mixture (F i O 2 = 0.15, HYP), separated by a 45 minute break. The vastus lateralis (VL) muscle was studied using frequency‐domain near infrared spectroscopy (NIRS) to measure concentrations of oxygenated ([OxyHb+Mb]), deoxygenated ([DeoxyHb+Mb]) hemoglobin and myoglobin, and tissue saturation (S t O 2 ). Data were analyzed using a three‐way (Inspirate [HYP, NORM], Hb type [Normal, HAH], exercise intensity [Rest, 40, 60, 80, 100% normoxic PPO]) univariate analysis of variance. Results HAH had an attenuated decline in exercise tolerance (peak power output at maximal exertion) in HYP compared to controls (HAH: 2.9±6.4% decline vs CTL: 11.7±5.4% decline, P<0.05). There was a significant effect of Hb type on [DeoxyHb+Mb] (P=0.048) suggesting less O 2 offloading in HAH compared to controls in the VL at rest and throughout graded exercise in both NORM and HYP. There were no significant effects of inspirate or exercise intensity on [DeoxyHb+Mb], and no significant differences in [OxyHb+Mb] between HAH and controls. There was a significant effect of Hb type on S t O 2 in NORM controls (P<0.01) However, during hypoxic exercise S t O 2 was the same in both HAH and controls except at end exercise (HAH 64.1±6.4% vs CTL: 62.1±4.2%, P<0.05). Conclusion HAH individuals have less oxygen off‐loading at rest and during exercise but higher tissue saturation during exercise in NORM compared to controls. Our results suggest that the similar levels of exercise capacity in hypoxia for HAH are due, at least in part, to maintenance of microvascular extraction similar to that during normoxic exercise. Future studies utilizing direct measurements of skeletal muscle blood flow during exercise are needed to understand integrative exercise in HAH patients. Support or Funding Information This work was funded by NIH R‐35‐HL139854 and the Mayo Foundation. Muscle oxygenation during graded exercise tests in normoxia and hypoxia. Data are presented as means ± standard error. Abbreviations: [OxyHb+Mb], concentration of oxygenated hemoglobin+myoglobin; [DeoxyHb+MB], concentration of deoxygenated hemoglobin+ myoglobin; PPO, peak power output. † denotes significant main effect of Hb types across all workloads. * denotes significant difference from CTL at same %PPO. Figure 1

Although over 100 studies and reviews have examined the ergogenic effects of dietary nitrate (NO 3 − ) supplementation ( e.g. beetroot juice) in young, healthy men and women, it is unclear if participant and environmental factors modulate the well‐described ergogenic effects—particularly relevant factors include biological sex, aerobic fitness and fraction of inspired oxygen (F i O 2 ) during exercise. To address this limitation, the literature was systematically reviewed for randomized, cross‐over, placebo‐controlled studies reporting exercise performance outcome metrics with NO 3 − supplementation in young, healthy adults. There were 2,033 articles identified, and 80 articles met inclusion criteria for the meta‐analysis. Random‐effects meta‐analysis demonstrated that exercise performance was improved with NO 3 − supplementation compared to placebo ( d =0.174, 95% CI [0.120–0.229], P <0.001). Subgroup analyses conducted on biological sex, aerobic fitness and F i O 2 demonstrated that the ergogenic effect of NO 3 − supplementation was: 1) not observed in studies with only women ( n =6, d=0.116, 95% CI [−0.126–0.358], P =0.347), 2) not observed in participants with moderate aerobic fitness (less than 45 mL·kg −1 ·min −1 ; n =4, d =0.168, 95% CI [−0.134–0.469], P =0.276) or elite aerobic fitness (65 mL·kg −1 ·min −1 or greater; n =26, d =0.021, 95% CI [−0.103–0.144], P =0.745) and 3) was not modulated by F i O 2 (hypoxia: n =17, d =0.214, 95% CI [0.054–0.375], P =0.009 vs. normoxia n =97, d =0.175, 95% CI [0.114–0.237], P <0.001). Together, the meta‐analyses demonstrated a clear ergogenic effect of NO 3 − supplementation in recreationally‐active, young, healthy men across many different exercise paradigms and NO 3 − supplementation parameters; however, the effect size of NO 3 − supplementation was objectively small . Although NO 3 − supplementation may be effective in moderately fit, healthy men, NO 3 − supplementation has limited utility as an ergogenic aid in participants that have optimized other training parameters. Mechanistic research and studies incorporating a wide variety of subjects ( e.g. women) are needed to advance the study of NO 3 − supplementation; however, additional descriptive studies of young healthy men may have limited utility. Figure 1 Figure 2