Nicholas T. Kruse

Influence of passive stretch on muscle blood flow, oxygenation and central cardiovascular responses in healthy young males

The aim of this study was to examine the effect of skeletal muscle stretching on peripheral, central, and autonomic cardiovascular responses in humans. Twelve healthy males completed a controlled passive stretch of the plantar flexors for 4 min at three different intensities. Doppler ultrasound velocimetry and imaging techniques assessed mean leg blood flow (MLBF), antegrade blood flow, and retrograde blood flow of the popliteal artery. Near-infrared spectroscopy assessed the concentration of deoxygenated hemoglobin + myoglobin ([HHb]) and the sum of its deoxygenated and oxygenated forms [i.e., blood volume ([Hbtot])]. Heart rate (HR) and mean arterial pressure were measured simultaneously to peripheral hemodynamic responses. During stretch there was an increase (P < 0.05) in antegrade and retrograde blood flow along with [HHb] and [Hbtot] relative to baseline, whereas MLBF was not altered. HR increased (P < 0.01) in a stretch intensity- and time-dependent manner, suggesting a threshold tension must be met that results in a mechanoreflex-mediated increase in HR. After stretch there was an increase (P < 0.05) in [Hbtot] and MLBF in each condition, suggesting that stretch creates a poststretch hyperemic response. Furthermore, retrograde blood flow was decreased (P < 0.05) after stretch in each stretch condition. Mean arterial pressure was decreased (P < 0.05) after moderate-intensity stretching. Collectively, our data provide novel mechanistic evidence on cardiovascular responses to skeletal muscle stretching in humans. Moreover, the reductions in MAP and retrograde blood flow suggest that stretch transiently reduces myogenic vascular tone in a poststretch resting period.

Cardiovascular Responses to Skeletal Muscle Stretching: “Stretching” the Truth or a New Exercise Paradigm for Cardiovascular Medicine?

Stretching is commonly prescribed with the intended purpose of increasing range of motion, enhancing muscular coordination, and preventing prolonged immobilization induced by aging or a sedentary lifestyle. Emerging evidence suggests that acute or long-term stretching exercise may modulate a variety of cardiovascular responses. Specifically, at the onset of stretch, the mechanical deformation of the vascular bed coupled with stimulation of group III muscle afferent fibers initiates a cascade of events resulting in both peripheral vasodilation and a heart rate-driven increase in cardiac output, blood pressure, and muscle blood flow. This potential to increase shear stress and blood flow without the use of excessive muscle energy expenditure may hold important implications for future therapeutic vascular medicine and cardiac health. However, the idea that a cardiovascular component may be involved in human skeletal muscle stretching is relatively new. Therefore, the primary intent of this review is to highlight topics related to skeletal muscle stretching and cardiovascular regulation and function. The current evidence suggests that acute stretching causes a significant macro- and microcirculatory event that alters blood flow and the relationship between oxygen availability and oxygen utilization. These acute vascular changes if performed chronically may result in improved endothelial function, improved arterial blood vessel stiffness, and/or reduced blood pressure. Although several mechanisms have been postulated, an increased nitric oxide bioavailability has been highlighted as one promising candidate for the improvement in vessel function with stretching. Collectively, the evidence provided in this review suggests that stretching acutely or long term may serve as a novel and alternative low intensity therapeutic intervention capable of improving several parameters of vascular function.

Evidence of a greater functional sympatholysis in habitually aerobic trained postmenopausal women

Habitual aerobic exercise attenuates elevated vasoconstriction during acute exercise (functional sympatholysis) in older men; however, this effect remains unknown in postmenopausal women (PMW). This study tested the hypothesis that PMW who participate in habitual aerobic exercise demonstrate a greater functional sympatholysis compared with their untrained counterparts. Nineteen PMW (untrained n = 9 vs. trained n = 10) performed 5 min of steady-state (SS) forearm exercise at relative [10% and 20% of maximum voluntary contraction (MVC)] and absolute (5 kg) contraction intensities. Lower-body negative pressure (LBNP) was used to increase sympathetic vasoconstriction during rest and forearm exercise. Brachial artery diameter and blood velocities (via Doppler ultrasound) determined forearm blood flow (FBF; ml/min). Forearm muscle oxygen consumption ([Formula: see text]; ml/min) and arteriovenous oxygen difference (a-vO2diff) were estimated during SS-exercise and SS-exercise with LBNP. Forearm vascular conductance (FVC; ml·min-1·100 mmHg-1) was calculated from FBF and mean arterial pressure (MAP; mmHg). Vasoconstrictor responsiveness was determined as the %change in FVC during LBNP. The reduction in FVC (% change FVC) during LBNP was lower in trained compared with untrained PMW at 10% MVC (-7.3 ± 1.2% vs. -13.0 ± 1.1%; P < 0.05), 20% MVC (-4.4 ± 0.8% vs. -8.6 ± 1.4%; P < 0.05), and 5 kg (-5.3 ± 0.8% vs. -8.9 ± 1.4%; P < 0.05) conditions, whereas there were no differences at rest (-32.7 ± 4.4% vs. -33.7 ± 4.0%). Peripheral (FVC, FBF, and [Formula: see text]) and the magnitude change in systemic hemodynamics (heart rate and MAP) did not differ between groups during exercise. Collectively, the findings present the first evidence suggesting that PMW who participate in aerobic exercise demonstrate a greater functional sympatholysis compared with untrained PMW during mild to moderate forearm exercise. NEW & NOTEWORTHY Habitual aerobic exercise attenuates the elevated sympathetic nervous system-induced vasoconstriction during an acute bout of exercise (improved functional sympatholysis) in aging men; however, this effect remains unknown in postmenopausal women (PMW). The novel findings of this study suggest that habitual aerobic exercise results in an enhanced functional sympatholysis in PMW. Conversely, habitual aerobic exercise does not alter blood flow and oxygen utilization during acute forearm exercise compared with PMW who do not habitually exercise.

Eight weeks of nitrate supplementation improves blood flow and reduces the exaggerated pressor response during forearm exercise in peripheral arterial disease

Peripheral artery disease (PAD) is characterized by a reduced blood flow (BF) and an elevated blood pressure (pressor) response during lower extremity exercise. Although PAD is evident in the upper extremities, no studies have determined BF and pressor responses during upper extremity exercise in PAD. Emerging evidence suggests that inorganic nitrate supplementation may serve as an alternative dietary strategy to boost nitric oxide bioavailability, improving exercising BF and pressor responses during exercise. The present study investigated 1) BF and pressor responses to forearm exercise in patients with PAD ( n = 21) relative to healthy age-matched control subjects ( n = 16) and 2) whether 8 wk of NaNO3 supplementation influenced BF and pressor responses to forearm exercise in patients with PAD. Patients with moderate to severe PAD were randomly assigned to a NaNO3 (1 g/day, n = 13)-treated group or a placebo (microcrystalline cellulose, n = 8)-treated group. Brachial artery forearm BF (FBF; via Doppler) and blood pressure (via finger plethysmography) were measured during mild-intensity (~3.5-kg) and moderate-intensity (~7-kg) handgrip exercise. The absolute change (from baseline) in FBF was reduced (except in the 3.5-kg condition) and BP responses were increased in patients with PAD compared with healthy control subjects in 3.5- and 7-kg conditions (all P < 0.05). Plasma nitrate and nitrite were elevated, exercising (7-kg) ΔFBF was improved (from 141 ± 17 to 172 ± 20 ml/min), and mean arterial pressure response was reduced (from 13 ± 1 to 9 ± 1 mmHg, P < 0.05) in patients with PAD that received NaNO3 supplementation for 8 wk relative to those that received placebo. These results suggest that the BF limitation and exaggerated pressor response to moderate-intensity forearm exercise in patients with PAD are improved with 8 wk of NaNO3 supplementation. NEW & NOTEWORTHY Peripheral artery disease (PAD) results in an exaggerated pressor response and reduced blood flow during lower limb exercise; however, the effect of PAD in the upper limbs has remained unknown. These results suggest that 8 wk of inorganic nitrate supplementation improves the blood flow limitation and exaggerated pressor response to moderate-intensity forearm exercise in PAD.

Sympathetic nervous system activation reduces contraction-induced rapid vasodilation in the leg of humans independent of age

Contraction-induced rapid vasodilation is attenuated similarly in the upper and lower limbs of older adults. In the forearm, this attenuation is in part due to a greater sympathetic vasoconstriction. We examined whether the age-related reduction in contraction-induced vasodilation in the leg is also due to a sympathetic vasoconstrictive mechanism. Thirteen young (24 ± 1 yr) and twelve older adults (67 ± 1 yr) performed single-leg knee extension at 20 and 40% of work-rate maximum (WRmax) during control and cold-pressor test (CPT) conditions. Femoral artery diameter and blood velocity were measured using Doppler ultrasound. Vascular conductance (VC; ml·min-1·mmHg-1) was calculated using blood flow (ml/min) and mean arterial pressure (mmHg). Peak (ΔVC from baseline) and total VC were blunted in older adults during control conditions across exercise intensities (P < 0.05). Peak and total VC were reduced during CPT in both age groups across exercise intensities (P < 0.05). The relative change (i.e., %reduction; CPT vs. control) in peak (-25 ± 5 vs. -22 ± 4% at 20% WRmax; and -21 ± 6 vs. -27 ± 5% at 40% WRmax; P = 0.42-0.55) and total VC (-28 ± 5 vs. -36 ± 6% at 20% WRmax; and -22 ± 8 vs. -33 ± 5% at 40% WRmax; P = 0.23-0.34) were similar between young and older adults. When matched for absolute workload (~10 W), age differences persisted in peak VC (P < 0.05) under both conditions, with similar relative changes in peak and total VC during CPT. Our data suggest that 1) sympathetic stimulation reduces contraction-induced rapid vasodilation in the leg of young and older adults similarly; and 2) enhanced sympathetic vasoconstriction does not fully explain age-related differences in contraction-induced vasodilation within the leg.NEW & NOTEWORTHY Aging is associated with attenuated contraction-induced rapid onset vasodilation (ROV). Within the forearm, this attenuation is partially due to enhanced sympathetic vasoconstriction. In the current study, we found that sympathetic vasoconstriction reduces contraction-induced ROV within the leg of both young and older adults, with the magnitude of change being similar between age groups. Our current results suggest that age-related attenuations in contraction-induced ROV within the leg are not fully explained by a sympathetic vasoconstrictor mechanism.

A 'passive' movement into the future of assessing endothelial dysfunction?

Nitric oxide (NO) is a ubiquitous gaseous molecule that plays an important role in many biological processes in the human body, but perhaps none more important than its vasoprotective role within blood vessels. For many years researchers and clinicians have assessed the role of NO on blood vessel health using a variety of invasive and non-invasive techniques. The most popular non-invasive ‘assay’ to assess NO-mediated endothelial vascular function is flow-mediated dilatation (FMD) via reactive hyperaemia. This particular modality has grown in popularity as changes in conduit artery diameter due to reactive hyperaemia have been associated with future cardiovascular risk. While the FMD technique may be considered partially NO mediated, and therefore likely to reflect endothelium-dependent vascular function, this particular model may not be an appropriate method to measure systemic vascular health and, therefore, its efficacy remains limited. Thus, there is a growing interest in examining alternative methods with which to assess cardiovascular health across the lifespan. Recently, studies from the lab of R. S. Richardson have employed the technique of passive leg movement (PLM) as a novel and potentially practical assessment of systemic vascular function via NOdependent mechanisms. In this context, PLM presents a unique modality for investigating vasodilatory mechanisms (e.g. mechanical or endothelial) while confounding factors such as skeletal muscle contractioninduced metabolites are minimized. Ageing is associated with a progressive decline in peripheral blood flow and vasodilatation, largely attributed to reductions in NO bioavailability and/or signalling. Older adults consistently show decrements in FMD compared to young adults. A caveat to previous investigations utilizing FMD or PLM is that these assessments were typically performed while participants were in a supine position. Movement from a supine to an upright position increases femoral perfusion pressure (FPP) (= arterial pressure – venous pressure), and thereby increases the driving force for blood flow and shear rate within the femoral artery, attributed largely to the effect of gravity. This change in blood flow and shear rate is attenuated with N-monomethyl L-arginine (L-NMMA), an inhibitor of nitric oxide synthase (NOS), resulting in reductions in anterograde shear rate. Previously, it has been shown that in response to PLM, older adults exhibit a reduced NO bioavailability or signalling (Trinity et al. 2015). Increasing perfusion pressure (supine-to-upright) elicits a vasodilator reserve in young adults, whereas older adults show no improvement in blood flow or vasodilatation when measured in the upright position (increased FPP). In a recent article published in The Journal of Physiology, Groot et al. (2015) explored whether the contribution of NO to the vasodilator capacity was altered as a result of changes in FPP during PLM in healthy young versus older individuals. To test the hypothesis that inhibition of NOS would ablate the vasodilator reserve observed with increases in FPP, Groot et al. (2015) assessed leg vascular conductance (LVC) during PLM with FPP manipulation. Results revealed that in both the upright and supine position, older adults exhibited attenuated peak LVC and vasodilator reserve when FPP was increased compared to young adults. When L-NMMA was infused, peak LVC was reduced in the young, while no change was observed in older adults. Furthermore, the magnitude of peak change LVC reduction was greater when young subjects were upright compared to supine; however, during L-NMMA infusion in the supine position, there were no age differences in peak LVC. These results suggest that the increase in peak LVC during PLM with concomitant increases in FPP are largely NO dependent, and that the attenuated response in older adults is presumably due to reductions in NO bioavailability or signalling. Groot et al. (2015) further explored the onset of the vasodilator responses to PLM, namely, the rapid vasodilatation seen within the first 7 s of PLM. Older adults exhibited an attenuated rapid vasodilator response compared to young adults across L-NMMA and position trials. Interestingly, and in contrast to previous research utilizing contraction-induced rapid vasodilatation in the forearm (Casey et al. 2013), NOS inhibition had no effect on the rapid vasodilator response in the supine position of either young or older adults. However, NOS inhibition attenuated the rapid dilator response in young adults in the upright position, with no change in older adults. These results suggest that within the PLM model with greater FPP, NO plays a distinct role in the rapid dilator response in young adults only. Contraction-induced rapid onset vasodilatation (ROV) is blunted in both the arm and leg with ageing (Hughes et al. 2015). Mechanistically, reduced NO bioavailability and/or signalling has been implicated in the blunting of ROV within the forearm with age; however, these findings have yet to be extended to the leg (Casey et al. 2013). The ROV response to single contractions versus PLM appears to be similar, yet each modality utilizes different techniques of analysing the rapid hyperaemia and vasodilatation elicited. Given the heterogeneity of vasodilator responses between the arm and leg, evidence from the PLM model suggests that reduced NO bioavailability contributes to impairments in ROV, independent of metabolic influences. Therefore, based on the aforementioned evidence and current findings by Groot et al. (2015), the attenuated ROV in the leg of older adults is most likely due to a reduced NO bioavailability or signalling. Based on the above discussion, the findings from Groot et al. (2015) appreciably improve our understanding of the mechanisms underpinning PLM, NO-mediated vascular function and FPP with age. However, it also raises the question with more insistence of potential experimental considerations that may accompany PLMinduced hyperaemia, which may warrant further research. Indeed, the primary goal of the study by Groot et al. (2015) was to further advance the clinical relevance of

Impaired modulation of postjunctional α1‐ but not α2‐adrenergic vasoconstriction in contracting forearm muscle of postmenopausal women

Contraction‐mediated blunting of postjunctional α‐adrenergic vasoconstriction (functional sympatholysis) is attenuated in skeletal muscle of ageing males, brought on by altered postjunctional α1‐ and α2‐adrenergic receptor sensitivity. The extent to which postjunctional α‐adrenergic vasoconstriction occurs in the forearms at rest and during exercise in postmenopausal women remains unknown. The novel findings indicate that contraction‐mediated blunting of α1‐ (via intra‐arterial infusion of phenylephrine) but not α2‐adrenergic (via intra‐arterial infusion of dexmedetomidine) vasoconstriction was attenuated in postmenopausal women compared to young women. Additional important findings revealed that postjunctional α‐adrenergic vasoconstrictor responsiveness at rest does not appear to be affected by age in women. Collectively, these results contribute to our understanding of local neurovascular control at rest and during exercise with age in women.

Habitual exercise training in older adults offsets the age-related prolongation in leg vasodilator kinetics during single limb lower body exercise

We tested the hypothesis that aging is associated with prolonged leg vasodilator kinetics and habitual exercise training in older adults improves these responses relative to untrained older adults. Additionally, we examined the relationship between contraction-induced rapid onset vasodilation (ROV) and vasodilator kinetics. Young ( n = 10), older untrained ( n = 13), and older trained ( n = 14) adults performed single and rhythmic knee-extension contractions at 20% and 40% work-rate maximum (WRmax). Femoral artery diameter and mean blood velocity were measured by Doppler ultrasound. Vascular conductance (VC; ml·min-1·mmHg-1) was calculated using blood flow (ml/min) and mean arterial pressure (mmHg). The primary outcome was the kinetic response (mean response time; MRT), modeled using an exponential model, expressed as the number of duty cycles to change 63% of the steady-state amplitude. There were no age- or training-related differences in VC MRT between the groups at 20% WRmax. Older untrained adults exhibited prolonged VC MRT at 40% WRmax relative to young (37 ± 16 vs. 24 ± 10 duty-cycles; P < 0.05) and older trained adults (37 ± 16 vs. 23 ± 14 duty-cycles; P < 0.05). There were no differences in VC MRT between young and older trained adults at 40% WRmax ( P = 0.96). There were no associations between peak ROV and VC MRT at 20% or 40% WRmax ( r = -0.08 and 0.22; P = 0.67 and 0.20, respectively) in the group as a whole. Our data suggest 1) advancing age prolongs leg vasodilator kinetics; 2) habitual exercise training in older adults offsets this age-related prolongation; and 3) contraction-induced ROV is not related to vasodilator kinetics within a group of young and older adults. NEW & NOTEWORTHY Aging is associated with reductions in exercise hyperemia and vasodilation at the onset of exercise, as well as during steady-state exercise. Habitual endurance exercise training offsets these age-related reductions. We found that aging prolongs vasodilator kinetics in the leg of older untrained but not older trained adults. Finally, our results demonstrate that contraction-induced rapid vasodilation is not associated with vasodilator kinetics within the leg of young and older adults.

Age‐associated impairments in contraction‐induced rapid onset vasodilatation within the forearm are independent of mechanical factors

What is the central question of this study? We examined whether the mechanical contribution to contraction‐induced rapid‐onset vasodilatation (ROV) differed with age and whether ROV is associated with peripheral artery stiffness. Furthermore, we examined how manipulation of perfusion pressure modulates ROV in young and older adults. What is the main finding and its importance? The mechanical contribution to ROV is similar in young and older adults. Conversely, peripheral arterial stiffness is not associated with ROV. Enhancing perfusion pressure augments ROV to a similar extent in young and older adults. These results suggest that age‐related attenuations in ROV are not attributable to a mechanical component and that ROV responses are independent of peripheral artery stiffness.

We are what we eat? Eating ‘against the grain’ may not be as beneficial to performance and ‘economy’ in endurance athletes

During prolonged, submaximal exercise skeletal muscle uses both carbohydrates (CHO) and lipids as substrates to synthesize adenosine triphosphate (ATP), the fundamental unit of energy. The relative contribution of these substrates to fuel pathways depends upon several factors including mode, intensity and duration of exercise, the athlete’s training status, and both acute and prolonged dietary intake. With regard to the latter, optimal performance by the athlete is greatly influenced by the combination of adequate fuel stores in relation to the demands of his/her event as well as ‘metabolic flexibility’, defined in the context of sports performance as the ability to rapidly and efficiently utilize these pathways to maximize ATP synthesis. Seminal work conducted by Coyle’s lab in the early 1990s showed that CHO-dense diets were more ergogenic than fat-rich diets for aerobic performance (Coggan & Coyle, 1991). These findings are supported by the notion that intramuscular glycogen stores are depleted far in advance of intramuscular adipose tissue; therefore, boosting glycogen depositions improves performance beyond increases in adipose tissue, a paradigm which holds strong amongst athletes and coaches today. However, these effects remain equivocal with some athletes responding well to such nutritional strategies whereas others are less responsive. A growing number of ultra-endurance athletes have reported experimenting with alternative nutritional strategies, such as low-CHO diets, experiencing a spectrum of self-perceived benefits. Such data have led to the concept of ‘training low, but competing high’, whereby selected training sessions are completed in conditions of reduced CHO availability with CHO reserves restored immediately prior to competition. The intent of this strategy, termed the low-CHO high fat diet (LCHF) or the ‘keto-diet’, is to increase the utilization of intramuscular fat as fuel elevating circulating ketone levels (Phinney et al. 1983; Burke, 2015; Volek et al. 2016). Thus, acutely manipulating substrate availability via diet modification (i.e. LCHF) may influence intramuscular substrate stores and patterns of fuel metabolism – a potential consequence of this being an improved ‘economy’ and aerobic performance. Despite the growing interest of LCHF diets, athletes and coaches remain hindered by scarce scientific data and frequently resort to anecdotal evidence as the primary argument for such nutritional-training strategies. Our understanding of nutritional strategies (i.e. the ketogenic diet) and endurance sports performance is developing but remains limited by tightly controlled studies. Although evidence has shown that LCHF allows individuals to metabolize fat more favourably (compared to glycogen) (Volek et al. 2016), the beneficial effects on endurance sport performance remain unknown. Therefore, an article in this issue of The Journal of Physiology by Burke and colleagues (Burke et al. 2017) attempted to address some of these long-awaited issues by investigating whether a low-carbohydrate, ketogenic diet is equal or superior in performance to the popular high-carbohydrate diet in endurance athletes. Burke et al. recruited 21 Olympic-calibre male race walkers to participate in one of three dietary interventions, either: (1) high carbohydrate (HCHO), periodized low/high carbohydrate (PCHO), or low carbohydrate/high fat (LCHF) over 3 weeks, during two separate training camps. Interventions were calorically equivalent and both training camps were of similar structure (i.e. modes and volume of exercise). Assessments occurred during 3 days prior to, and following, both training camps; all assessment days utilized identical protocols. Day 1’s assessment consisted of a fasted, maximal exercise test to determine peak O2 uptake (V̇O2peak). During the second test day, subjects completed a 10 km race walk, and on the final test day, subjects completed a 25 km competitive race walk. All experimental groups experienced improvements in V̇O2peak; however, only the HCHO and PCHO groups improved their 10 km race walk time. Additionally, a reduction in respiratory exchange ratio at maximal exertion was noted in the LCHF group despite an increased V̇O2peak alluding to a dietary-induced shift in substrate metabolism favouring β-oxidation during near-maximal exercise. The LCHF group was also the sole group to increase their V̇O2 values during submaximal stages of the maximal exercise test following training. Collectively, these findings suggest that training-induced improvements in submaximal running economy and endurance performance are compromised with a LCHF diet. Until recently, only anecdotal evidence has supported the contention that the LCHF diet improves aerobic performance. Indeed, the applicability of performance assessment protocols clouds our understanding of these studies in relation to ultra-endurance events. Burke and colleagues utilized a clever design to assess performance by mimicking 10 km and 20 km race walk competition scenarios to which athletes received monetary compensation based on performance. This design allowed the athletes to maximize their effort without the underlying bias/influence of dietary status. To this end, the results provide first-hand evidence to suggest that a LCHF diet blunts performance which is likely derived from a reduced economy at submaximal work rates. The authors are to be applauded for these significant and novel contributions to nutrition and exercise science; however, several notable considerations may warrant attention when interpreting these results as they may provide additional clarity to findings and may stimulate new ideas for future work. It should also be noted that while the population investigated in Burke’s study adds to the study’s novelty, cross-sectional evidence (Volek et al. 2016) suggests that athletes competing in events >50 miles (or >2 h in duration) exhibit greater benefits from LCHF diets compared to athletes competing in events <2 h. Extended endurance races (ultramarathons) occur at