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KEY POINTS In vitro evidence has identified that coagulation is activated by increased oxidative stress, though the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial in healthy participants to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise given their synergistic capacity to promote free radical formation. Systemic free radical formation was shown to increase during hypoxia and was further compounded by exercise, responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation at rest in normoxia, and this was normalised only in the face of prevailing oxidation. Collectively, these findings suggest that human free radical formation is an adaptive phenomenon that serves to maintain vascular haemostasis. ABSTRACT In vitro evidence suggests that blood coagulation is activated by increased oxidative stress although the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise. Healthy males were randomly assigned double-blind to either an antioxidant (n = 20) or placebo group (n = 16). The antioxidant group ingested two capsules/day that each contained 500 mg of l-ascorbic acid and 450 international units (IU) of dl-α-tocopherol acetate for 8 weeks. The placebo group ingested capsules of identical external appearance, taste and smell (cellulose). Both groups were subsequently exposed to acute hypoxia and maximal physical exercise with venous blood sampled pre-supplementation (normoxia), post-supplementation at rest (normoxia and hypoxia) and following maximal exercise (hypoxia). Systemic free radical formation (electron paramagnetic resonance spectroscopic detection of the ascorbate radical (A•- )) increased during hypoxia (15,152 ± 1193 AU vs. 14,076 ± 810 AU at rest, P

AimsArterial hypoxaemia stimulates free radical formation. Cellular studies suggest this may be implicated in coagulation activation though human evidence is lacking. To examine this, an observational study was designed to explore relationships between systemic oxidative stress and haemostatic responses in healthy participants exposed to inspiratory hypoxia.ResultsActivated partial thromboplastin time and international normalised ratio were measured as routine clinical biomarkers of coagulation and ascorbate free radical (A•−) as a direct global biomarker of free radical flux. Six hours of hypoxia activated coagulation, and increased formation of A•−, with inverse correlations observed against oxyhaemoglobin saturation.ConclusionsThis is the first study to address the link between free radical formation and coagulation in vivo. This ‘proof-of-concept’ study demonstrated functional associations between hypoxaemia and coagulation that may be subject to redox activation of the intrinsic pathway. Further studies are required to identify precisely which intrinsic factors are subject to redox activation.

BACKGROUND The metabolic vasodilator mediating postexercise hypotension (PEH) is poorly understood. Recent evidence suggests an exercise-induced reliance on pro-oxidant-stimulated vasodilation in normotensive young human subjects, but the role in the prehypertensive state is not known. METHODS Nine prehypertensives (mean arterial pressure (MAP), 106 ± 5 mm Hg; 50 ± 10 years old) performed 30 minutes of cycle exercise and a nonexercise trial. Arterial distensibility was characterized by simultaneously recording upper- and lower-limb pulse wave velocity (PWV) via oscillometry. Systemic vascular resistance and conductance were determined by MAP/Q and Q/MAP, respectively. Venous blood was assayed for indirect markers of oxidative stress (lipid hydroperoxides (LOOH); spectrophotometry), plasma nitric oxide (NO) and S-nitrosothiols (fluorometry), atrial natriuretic peptide (ANP), and angiotensin II (ANG-II) (radioimmunoassay). RESULTS Exercise reduced MAP (6mm Hg) and vascular resistance (15%) at 60 minutes after exercise, whereas conductance was elevated (20%) (P < 0.05). The hypotension resulted in a lower MAP at 60 and 120 minutes after exercise compared with nonexercise (P < 0.05). Upper-limb PWV was also 18% lower after exercise compared with baseline (P < 0.05). Exercise increased LOOH coincident with the nadir in hypotension and vascular resistance but failed to affect plasma NO or S-nitrosothiols. Exercise-induced increases in LOOH were related to ANG-II (r = 0.97; P < 0.01) and complemented by elevated ANP concentrations. CONCLUSIONS These data indicate attenuated vascular resistance after exercise with increased oxidative stress and unchanged NO. Whether free radicals are obligatory for PEH requires further investigation, although it seems that oxidative stress occurs during the hyperemia underlying PEH.

Reactive hyperaemia induces a slowing of pulse wave velocity (PWV) in conduit arteries of healthy subjects (flow-mediated slowing (FMS)). This could be an alternative method for assessing peripheral vasomotor function to the gold standard method of flow-mediated dilatation (FMD) a more expensive and technically demanding technique. We aimed to assess the reproducibility of FMS in healthy participants and to test its ability to detect differences in vasomotor function in patients with familial hypercholesterolaemia (FH) and post-lipoprotein apheresis (LA) treatment.Altogether 25 healthy participants were studied on two occasions to assess reproducibility of FMS. In a case control study of 22 patients with FH and matched healthy controls, FMD and FMS were compared. An intervention study in 12 patients with FH looked at the impact of a single LA treatment on FMS assessed pre and post treatment.FMS demonstrated good reproducibility (coefficient of variation (CoV) 7.3%). Patients with FH had reduced FMS in comparison to matched healthy controls (FMS% FH -15.13 ± 5.04% vs controls -18.41 ± 5.15%, p = 0.023), with no difference in FMD% between the two groups. A single LA treatment significantly improved FMS (pre -18.81 ± 9.84 vs post -24.09 ± 7.61%, p = 0.016).FMS is a reproducible technique, which is able to detect differences in vasomotor function both in a condition associated with endothelial dysfunction and following an acute intervention known to improve endothelial function. This simple technique has potential for accessible assessment of vasomotor function in clinical studies.

Aging is associated with diffuse impairments in vascular endothelial function and traditional aerobic exercise is known to ameliorate these changes. High intensity interval training (HIIT) is effective at improving vascular function in aging men with existing disease, but its effectiveness remains to be demonstrated in otherwise healthy sedentary aging. However, the frequency of commonly used HIIT protocols may be poorly tolerated in older cohorts. Therefore, the present study investigated the effectiveness of lower frequency HIIT (LfHIIT) on vascular function in a cohort of lifelong sedentary (SED; n =22, age 62.7 ± 5.2 years) men compared with a positive control group of lifelong exercisers (LEX; n = 17, age 61.1 ± 5.4 years). The study consisted of three assessment phases; enrolment to the study (Phase A), following 6 weeks of conditioning exercise in SED (Phase B) and following 6 weeks of low frequency HIIT in both SED and LEX (LfHIIT; Phase C). Conditioning exercise improved FMD in SED (3.4 ± 1.5% to 4.9 ± 1.1%; P, The effects of low frequency high intensity interval training (HIIT) on vascular endothelial function in lifelong sedentary men remains currently unknown. The present study examined the impact of low frequency HIIT following conditioning exercise on low determinants of vascular endothelial function and angiogenic biomarkers in aging men compared with a positive control group of similarly aged. The major findings of this study indicate that low frequency HIIT is a well‐tolerated and effective exercise mode for reducing cardiovascular risk and maintaining but not improving endothelial function beyond that achieved by conditioning exercise in aging men, irrespective of fitness level.

Elevated cardiorespiratory fitness improves resting cerebral perfusion, although to what extent this is further amplified during acute exposure to exercise stress and the corresponding implications for cerebral oxygenation remain unknown. To examine this, we recruited 12 moderately active and 12 sedentary healthy males. Middle cerebral artery blood velocity (MCAv) and prefrontal cortical oxyhemoglobin (cO2Hb) concentration were monitored continuously at rest and throughout an incremental cycling test to exhaustion. Despite a subtle elevation in the maximal oxygen uptake (active: 52 ± 9 ml/kg per minute versus sedentary: 33 ± 5 ml/kg per minute, P < 0.05), resting MCAv was not different between groups. However, more marked increases in both MCAv (+28 ± 13% versus +18 ± 6%, P < 0.05) and cO2Hb (+5 ±4% versus −2 ± 3%, P < 0.05) were observed in the active group during the transition from low- to moderate-intensity exercise. Collectively, these findings indicate that the long-term benefits associated with moderate increase in physical activity are not observed in the resting state and only become apparent when the cerebrovasculature is challenged by acute exertional stress. This has important clinical implications when assessing the true extent of cerebrovascular adaptation.

Background and Purpose— Age-related impairments in cerebral blood flow and cerebrovascular reactivity to carbon dioxide (CVR CO2 ) are established risk factors for stroke that respond favorably to aerobic training. The present study examined to what extent cerebral hemodynamics are improved when training is sustained throughout the adult lifespan. Methods— Eighty-one healthy males were prospectively assigned to 1 of 4 groups based on their age (young, ≤30 years versus old, ≥60 years) and lifetime physical activity levels (trained, ≥150 minutes recreational aerobic activity/week versus sedentary, no activity). Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound), mean arterial pressure (MAP, finger photoplethysmography), and end-tidal partial pressure of carbon dioxide (P ETCO 2 , capnography) were recorded during normocapnia and 3 mins of iso-oxic hypercapnea (5% CO 2 ). Cerebrovascular resistance/conductance indices (CVRi/CVCi) were calculated as MAP/MCAv and MCAv/MAP, respectively, and CVR CO2 as the percentage increase in MCAv from baseline per millimeter of mercury (mm Hg) increase in P ETCO 2 . Maximal oxygen consumption ( O 2MAX , online respiratory gas analysis) was determined during cycling ergometry. Results— By design, older participants were active for longer (49±5 versus 6±4 years, P O 2MAX , MCAv, CVCi, and CVR CO2 and increase in CVRi ( P O 2MAX and both MCAv and CVR CO2 ( r =0.58–0.77, P Conclusions— These findings highlight the importance of maintaining aerobic fitness throughout the lifespan given its capacity to improve cerebral hemodynamics in later-life.

The present study examined to what extent professional boxing compromises cerebral haemodynamic function and its association with CTBI (chronic traumatic brain injury). A total of 12 male professional boxers were compared with 12 age-, gender- and physical fitness-matched non-boxing controls. We assessed dCA (dynamic cerebral autoregulation; thigh-cuff technique and transfer function analysis), CVRCO2 (cerebrovascular reactivity to changes in CO2: 5% CO2 and controlled hyperventilation), orthostatic tolerance (supine to standing) and neurocognitive function (psychometric tests). Blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasound), mean arterial blood pressure (finger photoplethysmography), end-tidal CO2 (capnography) and cortical oxyhaemoglobin concentration (near-IR spectroscopy) were continuously measured. Boxers were characterized by fronto-temporal neurocognitive dysfunction and impaired dCA as indicated by a lower rate of regulation and autoregulatory index (P

Evidence clearly points to an enhanced vasodilatation in systemic vessels during hypoxic exercise that serves to defend oxygen delivery to active musculature in the face of a reduced inspired fraction of O2 (Wilkins et al. 2008). Exercise-induced hyperaemia is a complex process with redundant mechanisms that can be called upon when required. During hypoxic exercise there is an additional dilator response in human skeletal muscle attributable to the reduction in arterial oxygen content rather than arterial O2 tension per se. Importantly, prevailing vascular tone results from both neural and metabolic factors acting on the vascular smooth muscle and endothelium. At the vascular endothelium adrenergic and non-adrenergic vasoactive pathways play a regulatory role in normal vascular function. The overall effect on haemodynamics and arterial pressure will be determined by how these various pathways and mechanisms integrate at the level of the vascular smooth muscle cell. Over recent years various research groups, including ours (Bailey et al. 2009), have combined a number of invasive experimental protocols across isolated vascular beds in conjunction with pharmacological blockade of vasoactive metabolite receptors or the actual metabolite itself to elucidate any potential contribution to exercise and/or hypoxic vasodilatation. One of the most intensely studied candidates for both exercise hyperaemia and hypoxic vasodilatation is nitric oxide (NO•). Increases in blood flow, cyclic wall stress due to pulsatile blood flow and catecholamines produce an up-regulation and release of NO• from the vascular endothelium (Busse & Fleming, 2006) via the enzyme endothelial nitric oxide synthase (eNOS). Hypoxia has been associated with additional sources of NO• release from deoxyhaemoglobin, β-adrenergic and adensosine receptor stimulation (Stamler et al. 1997; Bryan & Marshall, 1999; Wilkins et al. 2008). The NO• released toward the vascular lumen is a powerful vasodilator responsible for mediating basal vascular tone (Stamler et al. 1997). However, not all vascular beds respond in a similar manner with the pulmonary vasculature demonstrating a strong hypoxia-induced vasoconstriction whereas the cerebral vasculature responds in a similar fashion to the systemic vessels with a vasodilatation (Bailey et al. 2009). Metabolism of NO• within the vasculature to the more biochemically stable moiety nitrite serves as a means to determine circulating bioavailability of NO•. It appears that whilst this metabolic pathway of NO• was initially considered unidirectional, exogenous nitrite can induce sustained vasodilatation especially when the local vascular environment is hypoxic or ischaemic (Maher et al. 2008). It is within this environment that deoxygenated haemoglobin appears to convert nitrite to NO• (Stamler et al. 1997). Our laboratory, in collaboration with others, recently reported a reduced pulmonary vasoconstriction with systemic infusion of sodium nitrite (Ingram et al. 2010) while others have also reported augmented systemic arterial hypoxic vasodilatation with the same agent (Maher et al. 2008). Thus, with this background it is evident that during hypoxic exercise there is a compensatory vasodilatation that is sustained during increased exercise intensity and a clear contender for mediating the response is NO• either from enhanced endothelial release and/or circulating deoxyhaemoglobin. Casey et al. (2010), in a recent article in the The Journal of Physiology, sought to address this issue by examining the effects of hypoxic forearm exercise whilst simultaneously infusing the NOS inhibitor NG-monomethyl-l-arginine (l-NMMA) to investigate the influence of endothelial-derived NO•. In a parallel branch of the investigation, the authors also attempted to glean further information regarding hypoxic-induced NO• release via adenosine receptor stimulation by exogenous administration of combined l-NMMA and aminophylline, an adenosine receptor antagonist (Casey et al. 2010). Efficacy of eNOS blockade was established via intra-arterial acetylcholine infusion. Casey and colleagues (2010) utilised the isolated forearm exercise model with 22 healthy young adults. Subjects performed rhythmic forearm exercise in the non-dominant arm at 10% and 20% of individual maximal voluntary contraction. Twelve subjects completed protocol 1 (saline or l-NMMA infusion) and ten subjects completed protocol 2 (saline or l-NMMA–aminophylline infusion). Due to the long half-life of l-NMMA, study drugs were administered in the same order. Exercise was performed in normoxia and normocapnic hypoxia. Hypoxic inspiration rendered systemic arterial O2 saturations at ∼80%. Arterial pressure responses were monitored with an indwelling pressure transducer in the brachial artery whilst forearm blood flow was determined in the brachial artery via ultrasound. Forearm vascular conductance was calculated by the quotient of forearm blood flow and arterial pressure (Casey et al. 2010). The paper highlights three key findings of importance regarding the role of NO• in hypoxic vasodilatation.

This study investigated gender differences in upper-body contribution to cycle muscle power in 23 adolescents. All subjects performed two 5-s and one 20-s cycling sprint, using two protocols: with handgrip (WG) and without handgrip (WOG). Maximal handgrip strength was assessed for each individual. Absolute peak and mean cycling power was corrected for total fat-free mass (FFM) and for lean leg volume (LLV). Males showed higher cycling performance than females. Peak power and 20-s mean power (flywheel inertia included), but not optimal velocity, were higher WG than WOG. Especially for peak power, absolute differences between both protocols were higher in males than in females, and were significantly related to handgrip strength. The significant contribution of the upper body suggested that, for standardisation of cycle muscle power, total FFM is a more relevant variable compared with LLV. Furthermore, in adolescents, the higher contribution of the upper body musculature in males partly explained gender differences in peak power.

Objectives: Assessment of pulse wave velocity (PWV) is normally used as a measure of arterial stiffness. However, measurement of change in PWV before and after a period of reactive hyperaemia may enable the technique to be harnessed as a measure of endothelial function as flow-mediated slowing (FMS). The aim of this study was to validate this approach as a novel method of endothelial function assessment. Methods: FMS and flow-mediated dilatation (FMD) of the brachio-radial arterial tract was assessed in 25 young healthy subjects on two separate occasions to assess reproducibility. To assess the ability of the technique to investigate acute vascular dysfunction FMS and FMD was assessed before and after a 20-minute period of ischaemia-reperfusion (IR) in 15 healthy subjects. Finally, 12 Familial Hypercholesterolaemia patients undergoing lipoprotein apheresis had FMS assessed pre and post treatment. Results: Reproducibility -Baseline PWV and FMS% showed good reproducibility (CV 3.3% & 7.2% respectively). There was no correlation between baseline brachial artery diameter and PWV visit 1 r=0.325 p=0.113 visit 2 r=0.335 p=0.192 or FMD and FMS visit 1 r= 0.27 p=0.192 visit 2 r=−0.425 p= 0.053. Ischaemia Reperfusion – There was a significant decrease in FMD following IR (−28.5% p=0.04). The trend to a reduction in FMS post-IR was not significant (−13.2% p=0.112). Following lipoprotein apheresis there was a 28.2% increase in FMS (from 18.8% to 24.1% p=0.006). Conclusions: FMS is a reproducible technique. The ability of the method to detect changes in endothelial function shows considerable promise but requires further investigation.