Indomethacin markedly blunts cerebral perfusion and reactivity, with little cognitive consequence in healthy young and older adults.

KEY POINTS: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely-reduced cerebral blood flow (CBF) impairs cognition in healthy adults. In the present study, we used a placebo-controlled, single-blinded, randomized cross-over design to test the hypothesis that acutely-reduced CBF (using a pharmacological aid; indomethacin) would impair cognition in young and older healthy adults. At baseline, older adults had lower cognitive performance and CBF, but similar cerebrovascular reactivity to CO2 and dynamic cerebral autoregulation compared to young adults. In both young and older adults, cognitive performance on a mental switching task was slightly (7%) reduced after indomethacin, but not significantly associated with reductions in CBF (∼31%). These results indicate that cognitive performance is broadly resilient against a ∼31% reduction in CBF per se in healthy young and older adults. ABSTRACT: Cognitive function depends on adequate cerebrovascular perfusion and control. However, it is unknown whether acutely-reduced cerebral blood flow (CBF) impairs cognition in healthy adults. Using a placebo-controlled, single-blinded, randomized cross-over design, we tested the hypothesis that acutely-reduced CBF (using indomethacin [1.2 mg kg-1 oral dose]) would impair cognition in young (n = 13; 25 ± 4 years) and older (n = 12; 58 ± 6 years) healthy adults. CBF and cerebrovascular control were measured using middle cerebral artery blood velocity (MCAvmean ) and its reactivity to hypercapnia (CVRHYPER ) and hypocapnia (CVRHYPO ), respectively. Cognitive function was assessed using a computerized battery including response time tasks. Baseline comparisons revealed that older adults had 14% lower MCAvmean and 15% lower cognitive performance (all P ≤ 0.048), but not lower CVRHYPER/HYPO (P ≥ 0.26). Linear and rank-based mixed models revealed that indomethacin decreased MCAvmean by 31% (95% confidence interval = -35 to -26), CVRHYPER by 68% [interquartile range (IQR) = -94 to -44] and CVRHYPO by 50% (IQR = -83 to -33) (treatment-effect; all P < 0.01), regardless of age. Baseline CVRHYPER/HYPO values were strongly associated with their indomethacin-induced reductions (r = 0.70 to 0.89, P < 0.01). Mental switching performance was impaired 7% (IQR = 0-19) after indomethacin (P = 0.04), but not significantly associated with reductions in MCAvmean (Young: rho = -0.31, P = 0.30; Older: rho = 0.06, P = 0.86). In conclusion, indomethacin reduced MCAvmean and impaired cognition slightly; however, no clear association was evident in younger or older adults. Older adults had poorer cognition and lower MCAvmean , but similar CVRHYPER/HYPO .

Advances in the available non-biological pharmacotherapy prevention and treatment of acute mountain sickness and high altitude cerebral and pulmonary oedema.

INTRODUCTION: The physiological responses on exposure to high altitude are relatively well known, but new discoveries are still being made, and novel prevention and treatment strategies may arise. Basic information has changed little since our previous review in this journal 10 years ago, but considerable more detail on standard therapies, and promising new approaches are now available. AREAS COVERED: Herein, the authors review the role of pharmacological agents in preventing and treating high-altitude illnesses. The authors have drawn on their own experience and that of international experts in this field. The literature search was concluded in March 2018. EXPERT OPINION: Slow ascent remains the primary prevention strategy, with rapid descent for the management of serious altitude illnesses. Pharmacological agents are particularly helpful when rapid ascent cannot be avoided or when rapid descent is not possible. Acetazolamide remains the drug of choice for prophylaxis of acute mountain sickness. However, evidence indicates that reduced dosage schemes compared to the current recommendations are warranted. Calcium channel blockers and phosphodiesterase inhibitors remain the drugs of choice for the management of high-altitude pulmonary edema. Dexamethasone should be reserved for the treatment of more severe cases of altitude illnesses such as cerebral edema.

Higher physical fitness levels are associated with less language decline in healthy ageing.

Healthy ageing is associated with decline in cognitive abilities such as language. Aerobic fitness has been shown to ameliorate decline in some cognitive domains, but the potential benefits for language have not been examined. In a cross-sectional sample, we investigated the relationship between aerobic fitness and tip-of-the-tongue states. These are among the most frequent cognitive failures in healthy older adults and occur when a speaker knows a word but is unable to produce it. We found that healthy older adults indeed experience more tip-of-the-tongue states than young adults. Importantly, higher aerobic fitness levels decrease the probability of experiencing tip-of-the-tongue states in healthy older adults. Fitness-related differences in word finding abilities are observed over and above effects of age. This is the first demonstration of a link between aerobic fitness and language functioning in healthy older adults.

Effects of submaximal and supramaximal interval training on determinants of endurance performance in endurance athletes.

We compared the effects of submaximal and supramaximal cycling interval training on determinants of exercise performance in moderately endurance-trained men. Maximal oxygen consumption (VO2max ), peak power output (Ppeak ), and peak and mean anaerobic power were measured before and after 6 weeks (3 sessions/week) of submaximal (85% maximal aerobic power [MP], HIIT85 , n = 8) or supramaximal (115% MP, HIIT115 , n = 9) interval training to exhaustion in moderately endurance-trained men. High-intensity training volume was 47% lower in HIIT115 vs HIIT85 (304 ± 77 vs 571 ± 200 min; P < 0.01). Exercise training was generally associated with increased VO2max (HIIT85 : +3.3 ± 3.1 mL/kg/min; HIIT115 : +3.3 ± 3.6 ml/kg/min; Time effect P = 0.002; Group effect: P = 0.95), Ppeak (HIIT85 : +18 ± 9 W; HIIT115 : +16 ± 27 W; Time effect P = 0.045; Group effect: P = 0.49), and mean anaerobic power (HIIT85 : +0.42 ± 0.69 W/kg; HIIT115 : +0.55 ± 0.65 W/kg; Time effect P = 0.01; Group effect: P = 0.18). Six weeks of submaximal and supramaximal interval training performed to exhaustion seems to equally improve VO2max and anaerobic power in endurance-trained men, despite half the accumulated time spent at the target intensity.

Swimming in warm water is ineffective in heat acclimation and is non-ergogenic for swimmers.

Heat acclimation (HA) in air confers adaptations that improve exercise capabilities in hot and possibly temperate air. Swimmers may benefit from HA, yet immersion may constrain adaptation. Therefore, we examined whether warm-water swimming constitutes effective HA. In a randomized-crossover study, eight male swimmers swam 60 min/day on 7 days in 33 °C (HA) or 28 °C (CON) water. They performed 20-min distance trials before and after each regime: in 33 °C water (Warm); 28 °C water (Temperate); and cycling in 29 °C air (Terrestrial) following standardized exercise. Rectal temperature (Tre ) rose ∼ 1 °C in HA sessions, and sweat loss averaged 1.4 L/h. After accounting for CON, HA did not confer any clear expansion of plasma volume [1.9% (95% CI: 7.7)], reduction in heart rate during standardized cycling exercise [1 b/min (9)], reduction in Tre during rest [+0.1 °C (0.1)] or exercise, or change in sudomotor function. Only perceived temperature and discomfort tended to improve. Performance was clearly not improved for Warm [+0.3% (1.8)] or Temperate [+0.3% (1.9)], was unclear for Terrestrial [+0.4% (17.7)], and was unrelated to changes in resting plasma volume (r < 0.3). In conclusion, short-term HA using swimming in 33 °C water confers little adaptation and is not ergogenic for warm or temperate conditions.

Cerebrovascular responses during rowing: Do circadian rhythms explain morning and afternoon performance differences?

The purpose of this study was to characterize cerebrovascular responses to rowing exercise, investigating whether their diurnal variation might explain performance differences across a day. Twelve male rowers completed incremental rowing exercise and a 2000-m ergometer time trial at 07:00 h and 16:00 h, 1 week apart, while middle cerebral artery velocity (MCAv), cerebral (prefrontal), and muscular (vastus lateralis) tissue oxygenation and hemoglobin volume (via near-infrared spectroscopy), heart rate, and pressure of end-tidal CO2 (PET CO2) were recorded. MCAv was 20-25% above resting levels (68 ± 12 cm/s) during submaximal and maximal exercise intensities, despite PET CO2 being reduced during maximal efforts (down ∼ 0.5-0.8 kPa); thus revealing a different perfusion profile to the inverted-U observed in other exercise modes. The afternoon time trial was 3.4 s faster (95% confidence interval 0.9-5.8 s) and mean power output 3.2% higher (337 vs 347 W; P = 0.04), in conjunction with similar exercise-induced elevations in MCAv (P = 0.60) and reductions in cerebral oxygenation (TOI) (P = 0.12). At the muscle, afternoon trials involved similar oxygen extraction (HHb volume and TOI) albeit from a relatively lower total Hb volume (P < 0.01). In conclusion, rowing performance was better in the afternoon, but not in conjunction with differences in MCAv or exercise-induced differences in cerebral oxygenation.

Influence of high altitude on cerebral blood flow and fuel utilization during exercise and recovery.

We examined the hypotheses that: (1) during incremental exercise and recovery following 4-6 days at high altitude (HA) global cerebral blood flow (gCBF) increases to preserve cerebral oxygen delivery (CDO2) in excess of that required by an increasing cerebral metabolic rate of oxygen ( CM RO2); (2) the trans-cerebral exchange of oxygen vs. carbohydrates (OCI; carbohydrates = glucose + ½lactate) would be similar during exercise and recovery at HA and sea level (SL). Global CBF, intra-cranial arterial blood velocities, extra-cranial blood flows, and arterial-jugular venous substrate differences were measured during progressive steady-state exercise (20, 40, 60, 80, 100% maximum workload (Wmax)) and through 30 min of recovery. Measurements (n = 8) were made at SL and following partial acclimatization to 5050 m. At HA, absolute Wmax was reduced by ∼50%. During submaximal exercise workloads (20-60% Wmax), despite an elevated absolute gCBF (∼20%, P < 0.05) the relative increases in gCBF were not different at HA and SL. In contrast, gCBF was elevated at HA compared with SL during 80 and 100% Wmax and recovery. Notwithstanding a maintained CDO2 and elevated absolute CM RO2 at HA compared with SL, the relative increase in CM RO2 was similar during 20-80% Wmax but half that of the SL response (i.e. 17 vs. 27%; P < 0.05 vs. SL) at 100% Wmax. The OCI was reduced at HA compared with SL during 20, 40, and 60% Wmax but comparable at 80 and 100% Wmax. At HA, OCI returned almost immediately to baseline values during recovery, whereas at SL it remained below baseline. In conclusion, the elevations in gCBF during exercise and recovery at HA serve to maintain CDO2. Despite adequate CDO2 at HA the brain appears to increase non-oxidative metabolism during exercise and recovery.

Influence of sympathoexcitation at high altitude on cerebrovascular function and ventilatory control in humans.

We sought to determine the influence of sympathoexcitation on dynamic cerebral autoregulation (CA), cerebrovascular reactivity, and ventilatory control in humans at high altitude (HA). At sea level (SL) and following 3-10 days at HA (5,050 m), we measured arterial blood gases, ventilation, arterial pressure, and middle cerebral blood velocity (MCAv) before and after combined α- and ß-adrenergic blockade. Dynamic CA was quantified using transfer function analysis. Cerebrovascular reactivity was assessed using hypocapnia and hyperoxic hypercapnia. Ventilatory control was assessed from the hypercapnia and during isocapnic hypoxia. Arterial Pco(2) and ventilation and its control were unaltered following blockade at both SL and HA. At HA, mean arterial pressure (MAP) was elevated (P < 0.01 vs. SL), but MCAv remained unchanged. Blockade reduced MAP more at HA than at SL (26 vs. 15%, P = 0.048). At HA, gain and coherence in the very-low-frequency (VLF) range (0.02-0.07 Hz) increased, and phase lead was reduced (all P < 0.05 vs. SL). Following blockade at SL, coherence was unchanged, whereas VLF phase lead was reduced (-40 ± 23%; P < 0.01). In contrast, blockade at HA reduced low-frequency coherence (-26 ± 20%; P = 0.01 vs. baseline) and elevated VLF phase lead (by 177 ± 238%; P < 0.01 vs. baseline), fully restoring these parameters back to SL values. Irrespective of this elevation in VLF gain at HA (P < 0.01), blockade increased it comparably at SL and HA (∼43-68%; P < 0.01). Despite elevations in MCAv reactivity to hypercapnia at HA, blockade reduced (P < 0.05) it comparably at SL and HA, effects we attributed to the hypotension and/or abolition of the hypercapnic-induced increase in MAP. With the exception of dynamic CA, we provide evidence of a redundant role of sympathetic nerve activity as a direct mechanism underlying changes in cerebrovascular reactivity and ventilatory control following partial acclimatization to HA. These findings have implications for our understanding of CBF function in the context of pathologies associated with sympathoexcitation and hypoxemia.

Exhaled nitric oxide and pulmonary artery pressures during graded ascent to high altitude.

Nitric oxide (NO) is a potent vasodilator that regulates pulmonary vascular tone. During ascent to high altitude, pulmonary vascular tone increases leading to pulmonary hypertension. To explore the mechanisms underpinning this effect, we investigated the relationship between exhaled NO (P(E(NO)); nm Hg) and pulmonary artery systolic pressure (PASP; mm Hg) in 11 healthy adults during hypoxic challenge at sea level [with oxygen saturations (S(P(O(2)))) of 80% and 90%] and at intervals during graded ascent to 5050 m. During normobaric hypoxia, PASP progressively increased from 22.7 mm Hg to 33.5 mm Hg (p=0.006), whilst P(E(NO)) remained unchanged. In contrast, during ascent to high altitude, PASP increased progressively from 22.7 mm Hg to 39.1 mm Hg (p<0.001), but P(E(NO)) decreased from 18.8 nm Hg to 9.0 nm Hg (p<0.001). However, after appropriate adjustments, P(E(NO)) had no significant effect on PASP at altitude (p=0.309). These findings indicate that although exhaled NO decreases with altitude, it does not appear to be a major contributor to hypoxic pulmonary vasoconstriction.

Is there diurnal variation in initial and delayed orthostatic hypotension during standing and head-up tilt?

Moving rapidly from a supine to a standing posture is a common daily activity, yet a significant physiological challenge. Syncope can result from the development of initial orthostatic hypotension (IOH) involving a transient fall in systolic/diastolic blood pressure (BP) of >40/20 mm Hg within the first 15 s, and/or a delayed orthostatic hypotension (DOH) involving a fall in systolic/diastolic BP of >20/10 mm Hg within 15 min of posture change. Although epidemiological data indicate a heightened syncope risk in the morning, little is known about the diurnal variation in the IOH and DOH mechanisms associated with postural change. The authors hypothesized that the onset of IOH and DOH occurs sooner, and the associated cardiorespiratory and cerebrovascular changes are more pronounced, in the early morning. At 06:00 and 16:00 h, 17 normotensive volunteers, aged 26 ± 1 yrs (mean ± SE), completed a protocol involving supine rest, an upright stand, and a 60° head-up tilt (HUT) during which continuous beat-to-beat measurements of middle cerebral artery velocity (MCAv), mean arterial BP (MAP), heart rate, and end-tidal Pco(2) (P(ET)co(2)) were obtained. Mean MCAv was ∼12% lower at baseline in the morning (p ≤ .01) and during the HUT (p < .01), despite a morning elevation in P(ET)co(2) by ∼2.2 mm Hg (p = .01). The decline in MAP during initial standing (morning vs. afternoon: 50% ± 4% vs. 49% ± 3%) and HUT (39% ± 3% vs. 38% ± 3%) did not vary with time-of-day (p > .30). In conclusion, although there is a marked reduction in MCAv in the morning, there is an absence of diurnal variation in the onset of and associated physiological responses associated with IOH and DOH. These responses, at least in this population, are unlikely contributors to the diurnal variation in orthostatic tolerance.

Diurnal variation in time to presyncope and associated circulatory changes during a controlled orthostatic challenge.

Epidemiological data indicate that the risk of neurally mediated syncope is substantially higher in the morning. Syncope is precipitated by cerebral hypoperfusion, yet no chronobiological experiment has been undertaken to examine whether the major circulatory factors, which influence perfusion, show diurnal variation during a controlled orthostatic challenge. Therefore, we examined the diurnal variation in orthostatic tolerance and circulatory function measured at baseline and at presyncope. In a repeated-measures experiment, conducted at 0600 and 1600, 17 normotensive volunteers, aged 26 +/- 4 yr (mean +/- SD), rested supine at baseline and then underwent a 60 degrees head-up tilt with 5-min incremental stages of lower body negative pressure until standardized symptoms of presyncope were apparent. Pretest hydration status was similar at both times of day. Continuous beat-to-beat measurements of cerebral blood flow velocity, blood pressure, heart rate, stroke volume, cardiac output, and end-tidal Pco(2) were obtained. At baseline, mean cerebral blood flow velocity was 9 +/- 2 cm/s (15%) lower in the morning than the afternoon (P < 0.0001). The mean time to presyncope was shorter in the morning than in the afternoon (27.2 +/- 10.5 min vs. 33.1 +/- 7.9 min; 95% CI: 0.4 to 11.4 min, P = 0.01). All measurements made at presyncope did not show diurnal variation (P > 0.05), but the changes over time (from baseline to presyncope time) in arterial blood pressure, estimated peripheral vascular resistance, and alpha-index baroreflex sensitivity were greater during the morning tests (P < 0.05). These data indicate that tolerance to an incremental orthostatic challenge is markedly reduced in the morning due to diurnal variations in the time-based decline in blood pressure and the initial cerebral blood flow velocity "reserve" rather than the circulatory status at eventual presyncope. Such information may be used to help identify individuals who are particularly prone to orthostatic intolerance in the morning.

Respiratory modulation of cardiovagal baroreflex sensitivity.

Emerging evidence has suggested that with minimal prerequisite training, slow deep breathing around 0.10 Hz can acutely enhance cardiovagal baroreflex sensitivity (BRS) in humans. Such reports have led to the speculation that behavioral interventions designed to reduce breathing frequency may serve a therapeutic role in ameliorating depressed baroreflex function in conditions such as chronic heart failure, essential hypertension, and obstructive airway disease. This study sought to test the hypothesis that slow controlled breathing acutely enhances cardiovagal baroreflex function in young healthy volunteers. Distinct from earlier studies, however, baroreflex function was examined (n = 30) using the classical pharmacological modified Oxford method, which enabled the assessment of cardiovagal BRS through experimentally driven baroreceptor stimulation across a wide range of blood pressures. For a comparison against existing evidence, spontaneous cardiovagal BRS was also assessed using the alpha-index and sequence method. Compared with fast breathing (0.25 Hz), slow breathing (0.10 Hz) was associated with an increase in the alpha-index (8.1 +/- 14 ms/mmHg, P < 0.01) and spontaneous up-sequence BRS (10 +/- 11 ms/mmHg, P < 0.01). In contrast, BRS derived from spontaneous down sequences and the modified Oxford method were unaltered by slow breathing. The lack of change in BRS derived from the modified Oxford method challenges the concept that slow breathing acutely augments arterial baroreflex function in otherwise healthy humans. Our results also provide further evidence that spontaneous BRS may not reflect the BRS determined by experimentally driven baroreceptor stimulation.

Increased fat oxidation and regulation of metabolic genes with ultraendurance exercise.

AIM: Regular endurance exercise stimulates muscle metabolic capacity, but effects of very prolonged endurance exercise are largely unknown. This study examined muscle substrate availability and utilization during prolonged endurance exercise, and associated metabolic genes. METHODS: Data were obtained from 11 competitors of a 4- to 5-day, almost continuous ultraendurance race (seven males, four females; age: 36 +/- 11 years; cycling Vo(2peak): males 57.4 +/- 5.9, females 48.1 +/- 4.0 mL kg(-1) min(-1)). Before and after the race muscle biopsies were obtained from vastus lateralis, respiratory gases were sampled during cycling at 25 and 50% peak aerobic power output, venous samples were obtained, and fat mass was estimated by bioimpedance under standardized conditions. RESULTS: After the race fat mass was decreased by 1.6 +/- 0.4 kg (11%; P < 0.01). Respiratory exchange ratio at the 25 and 50% workloads decreased (P < 0.01) from 0.83 +/- 0.06 and 0.93 +/- 0.03 before, to 0.71 +/- 0.01 and 0.85 +/- 0.02, respectively, after the race. Plasma fatty acids were 3.5 times higher (from 298 +/- 74 to 1407 +/- 118 micromol L(-1); P < 0.01). Muscle glycogen content fell 50% (from 554 +/- 28 to 270 +/- 25 nmol kg(-1) d.w.; n = 7, P < 0.01), whereas the decline in muscle triacylglycerol (from 32 +/- 5 to 22 +/- 3 mmol kg(-1) d.w.; P = 0.14) was not statistically significant. After the race, muscle mRNA content of lipoprotein lipase and glycogen synthase increased (P < 0.05) 3.9- and 1.7-fold, respectively, while forkhead homolog in rhabdomyosarcoma, pyruvate dehydrogenase kinase 4 and vascular endothelial growth factor mRNA tended (P < 0.10) to be higher, whereas muscle peroxisome proliferator-activated receptor gamma co-activator-1beta mRNA tended to be lower (P = 0.06). CONCLUSION: Very prolonged exercise markedly increases plasma fatty acid availability and fat utilization during exercise. Exercise-induced regulation of genes encoding proteins involved in fatty acid recruitment and oxidation may contribute to these changes.