Master of Science / Department of Kinesiology / Thomas J. Barstow / Dietary nitrate supplementation via beetroot juice (BR) has been shown to have positive effects on mitochondrial and muscle efficiency during large muscle mass exercise in humans, and more recently on locomotory muscle blood flow [Q-dot] in rats. To date, an integrated measure of these effects has not been performed in humans. Therefore, we assessed the influence of BR on [Q-dot] and muscle oxygenation characteristics during moderate and severe intensity handgrip exercise. Seven healthy men (age: 25 ± 3 yrs; height: 179 ± 4 cm; weight: 82 ± 9 kg) completed four constant-power exercise tests randomly assigned to condition (BR or placebo (PL)) and intensity (moderate (40% peak) or severe (85% peak)). Resting mean arterial pressure was significantly lower after BR compared to PL (79.3 ± 5.8 vs 86.8 ± 6.7 mmHg; p < 0.01). All subjects were able to sustain 10 min of exercise at moderate intensity in both conditions. BR had no significant effect on exercise tolerance during severe (342 ± 83 vs 382 ± 138 s, p = 0.382). Brachial artery [Q-dot] was not significantly different after BR at rest or any time during exercise in either intensity. Deoxygenated-[hemoglobin + myoglobin] was elevated at min 2 & 3 for moderate (p < 0.05) and throughout severe exercise (p = 0.03) after BR. The estimated metabolic cost ([V-dot]O₂) was not significantly different during either intensity after BR. These findings support the notion that an acute dose of BR may be valuable to reduce blood pressure in young adults, but revealed that it does not augment [Q-dot] or [V-dot]O₂ during small muscle mass handgrip exercise.

Doctor of Philosophy / Department of Kinesiology / Carl Ade / During exercise, muscle blood flow (Q ̇m) increases to match metabolic demand of the active skeletal muscle. In order for this matching to take place, ‘competition’ between local vasodilating metabolites and sympathetically mediated vasoconstriction, termed “functional sympatholysis,” must take place. A key feature of functional sympatholysis is that it is driven largely by metabolic rate (i.e., a higher work rates lead to greater sympatholysis), but may also be largely dependent on nitric oxide bioavailability and oxidative stress in certain disease states (e.g., hypertension). Thus, evaluation of these factors may provide valuable insight into the vascular control mechanisms during exercise in both health and disease. Therefore, the purpose of this dissertation was to 1) determine the role metabolic rate and blood flow on mediating functional sympatholysis, 2) determine the role of nitric oxide bioavailability on functional sympatholysis with high salt intake, a risk factor for primary hypertension, and 3) determine the effect of increases in nitric oxide bioavailability on functional sympatholysis in primary hypertension patients. In the first investigation (Chapter 1), we increased the relaxation phase of the contraction-relaxation cycle to increase active skeletal muscle blood flow (Q ̇m) and see if this would impact vasoconstriction of the active skeletal muscle. We showed that a decreased relaxation time led to greater functional sympatholysis. Interestingly, despite a lower metabolic rate (15% and 20% MVC), we showed that there was no difference in vasoconstriction between the increased relaxation times. These results may show that increases in Q ̇m play a role in functional sympatholysis when mechanical compression is minimized. In the second investigation (Chapter 2), we sought to determine if high dietary sodium (HS) intake would impact functional sympatholysis. We showed that HS intake (15g/day for 7 days) did not impact functional sympatholysis during exercise. Importantly, we show a significant increase in mean arterial pressure (i.e., pressor response) during handgrip exercise. These findings show the deleterious changes in blood pressure, but further work is needed to pinpoint specific mechanisms causing the responses. In the final investigation (Chapter 3), we used an acute nitrate rich (NR) supplement to improve NO bioavailability in hypertensive post-menopausal women (PMW), and observe the impact on functional sympatholysis. We provide novel evidence that functional sympatholysis is improved (~50%) with a NR supplement. The finding that a NR supplement can attenuate vasoconstriction in hypertensive PMW sheds light on the complexities of hypertension, functional sympatholysis and NO bioavailability. The current results indicate that the ‘competition’ between vasodilating metabolites and sympathetically mediated vasoconstriction can be independently modified in health and disease. In individuals with impairment to local vasodilation (e.g., hypertension), the ability to increase functional sympatholysis and muscle blood flow may lead to improvements in cardiovascular health. Taken together, the present results suggest that modifying duty cycle, sodium intake, and NO bioavailability are important factors to be considered with regard to overall cardiovascular health.

Current knowledge indicates that nonthermal muscle metaboreflex activity plays a critical role in the modulation of skin vasodilation and sweating. However, the mechanisms of control have primarily been studied during isometric handgrip exercise in which muscle metaboreceptor activation is induced by a brief post-exercise ischemia of the upper limb. While the reflex increase in mean arterial pressure associated with this period of ischemia is consistent with the activation of muscle metaboreceptors, the change in baroreflex activity may in itself modulate the response. Thus, we sought to understand how these nonthermal stimuli interact in modulating the control of skin perfusion and sweating under conditions of elevated hyperthermia. Furthermore, we examined the mechanisms responsible for the maintenance of arterial blood pressure under varying levels of heat stress during isometric handgrip exercise. Our study findings indicate that the parallel activation of muscle metaboreceptors and baroreceptors during post-exercise ischemia causes divergent influences on the control of skin blood flow and sweating; and these nonthermal stimuli are dependent on the level of hyperthermia. Moreover, we report that heat stress reduces the increase in arterial blood pressure during isometric handgrip exercise and this attenuation is attributed to a blunted increase in peripheral resistance, since cardiac output increased to similar levels for all heat stress conditions. These results provide important insight and understanding into the role of muscle metabo- and baroreflex activity on the control of skin blood flow and sweating; along with further knowledge into the cardiovascular mechanisms responsible for the regulation of arterial blood pressure during hyperthermia.

Current knowledge indicates that nonthermal muscle metaboreflex activity plays a critical role in the modulation of skin vasodilation and sweating. However, the mechanisms of control have primarily been studied during isometric handgrip exercise in which muscle metaboreceptor activation is induced by a brief post-exercise ischemia of the upper limb. While the reflex increase in mean arterial pressure associated with this period of ischemia is consistent with the activation of muscle metaboreceptors, the change in baroreflex activity may in itself modulate the response. Thus, we sought to understand how these nonthermal stimuli interact in modulating the control of skin perfusion and sweating under conditions of elevated hyperthermia. Furthermore, we examined the mechanisms responsible for the maintenance of arterial blood pressure under varying levels of heat stress during isometric handgrip exercise. Our study findings indicate that the parallel activation of muscle metaboreceptors and baroreceptors during post-exercise ischemia causes divergent influences on the control of skin blood flow and sweating; and these nonthermal stimuli are dependent on the level of hyperthermia. Moreover, we report that heat stress reduces the increase in arterial blood pressure during isometric handgrip exercise and this attenuation is attributed to a blunted increase in peripheral resistance, since cardiac output increased to similar levels for all heat stress conditions. These results provide important insight and understanding into the role of muscle metabo- and baroreflex activity on the control of skin blood flow and sweating; along with further knowledge into the cardiovascular mechanisms responsible for the regulation of arterial blood pressure during hyperthermia.

The vascular endothelium is a single layer of cells that lines the interior surface of our blood vessels. The endothelium plays a key role in vasoprotection and vasoregulation and its proper function is therefore essential to the maintenance of vascular health. The endothelial cells respond to the frictional force (shear stress (SS)) that occurs with an increase in blood flow. As a response, vasoactive substances are released, causing the artery to dilate, this is termed flow-mediated dilation (FMD). Endothelial cell function can be assessed by measuring the vasodilatory response to an increase in SS. Currently however, our ability to interpret the results of FMD assessment in order to make accurate judgements regarding arterial health is hindered by an incomplete understanding of the “dose-response” relationship between SS and FMD. The dose-response relationship is characterized by 1) the SS stimulus required to elicit an FMD response (threshold), 2) the magnitude of dilation for a given increase in SS (the slope of the SS-FMD relationship), and 3) the point at which further increases in SS no longer elicit dilation (the ceiling). The primary purpose of the current study was to characterize the magnitude and day-to-day variability of the parameters described above. N=20 males (mean 22-years). Brachial artery diameter (BAD) and blood velocity (BV) were assessed with echo and Doppler ultrasound. SS was estimated as shear rate (SR=BV/BAD). Subjects performed 2 incremental handgrip exercise trials on two separate visits (V1 and V2). CV=co-efficient of variation. The SS-FMD relationship was characterized by a shallow slope followed by an inflection point (threshold (T1)) and a steeper slope (pre vs. post T1 slope p=0.002). There was no difference between V1 vs. V2 in the SR-FMD slope or threshold (p>0.05), but there was considerable within-subject variability in the SR-FMD parameters: pre-T1 slope CV = 47.0 ± 33.1%; post-T1 slope CV = 55.3 ± 40.7%; T1 CV = 25.6 ± 6.3%. In conclusion, %FMD did not plateau with increasing SR, therefore no ceiling was identified. The inflection in slope may indicate the involvement of different or additional vasodilator mechanisms post-threshold. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2011-09-15 20:17:11.582

Current knowledge indicates that nonthermal muscle metaboreflex activity plays a critical role in the modulation of skin vasodilation and sweating. However, the mechanisms of control have primarily been studied during isometric handgrip exercise in which muscle metaboreceptor activation is induced by a brief post-exercise ischemia of the upper limb. While the reflex increase in mean arterial pressure associated with this period of ischemia is consistent with the activation of muscle metaboreceptors, the change in baroreflex activity may in itself modulate the response. Thus, we sought to understand how these nonthermal stimuli interact in modulating the control of skin perfusion and sweating under conditions of elevated hyperthermia. Furthermore, we examined the mechanisms responsible for the maintenance of arterial blood pressure under varying levels of heat stress during isometric handgrip exercise. Our study findings indicate that the parallel activation of muscle metaboreceptors and baroreceptors during post-exercise ischemia causes divergent influences on the control of skin blood flow and sweating; and these nonthermal stimuli are dependent on the level of hyperthermia. Moreover, we report that heat stress reduces the increase in arterial blood pressure during isometric handgrip exercise and this attenuation is attributed to a blunted increase in peripheral resistance, since cardiac output increased to similar levels for all heat stress conditions. These results provide important insight and understanding into the role of muscle metabo- and baroreflex activity on the control of skin blood flow and sweating; along with further knowledge into the cardiovascular mechanisms responsible for the regulation of arterial blood pressure during hyperthermia.

Current knowledge indicates that nonthermal muscle metaboreflex activity plays a critical role in the modulation of skin vasodilation and sweating. However, the mechanisms of control have primarily been studied during isometric handgrip exercise in which muscle metaboreceptor activation is induced by a brief post-exercise ischemia of the upper limb. While the reflex increase in mean arterial pressure associated with this period of ischemia is consistent with the activation of muscle metaboreceptors, the change in baroreflex activity may in itself modulate the response. Thus, we sought to understand how these nonthermal stimuli interact in modulating the control of skin perfusion and sweating under conditions of elevated hyperthermia. Furthermore, we examined the mechanisms responsible for the maintenance of arterial blood pressure under varying levels of heat stress during isometric handgrip exercise. Our study findings indicate that the parallel activation of muscle metaboreceptors and baroreceptors during post-exercise ischemia causes divergent influences on the control of skin blood flow and sweating; and these nonthermal stimuli are dependent on the level of hyperthermia. Moreover, we report that heat stress reduces the increase in arterial blood pressure during isometric handgrip exercise and this attenuation is attributed to a blunted increase in peripheral resistance, since cardiac output increased to similar levels for all heat stress conditions. These results provide important insight and understanding into the role of muscle metabo- and baroreflex activity on the control of skin blood flow and sweating; along with further knowledge into the cardiovascular mechanisms responsible for the regulation of arterial blood pressure during hyperthermia.

Functional magnetic resonance imaging (fMRI) can be used to track neural activation in the brain during functional activities. The purpose of this study was to investigate brain neural responses to blood flow restricted (BFR) versus control handgrip exercise. Using a randomized crossover design, 25 subjects (12 males, 13 females) completed handgrip exercises during two conditions: BFR vs. control. To familiarize participants with the exercise conditions, one week prior to MRI scanning participants completed each exercise condition once on separate days, with 72 hours between days. The following week fMRI scans were performed at the same time of day, separated by 72 hours. The exercise protocol consisted of five 30-second sets of squeezing a nonmetallic handgrip exerciser (a reported 13.6 kg resistance), doing as many repetitions as possible, with 20-second rest intervals between sets. We saw a significant main effect of exercise condition (BFR versus control) between premotor dorsal (PMd)(F = 5.71, p = 0.022), premotor ventral (PMv)(F = 8.21, p = 0.007), and right ventral striatum (VS_R)(F = 7.36, p = 0.01). When considering anatomical regions of interest, we did not find significant differences between exercise conditions in bilateral S1 (p > 0.82), primary motor cortex (M1)(p > 0.33), supplementary motor area (SMA)(p > 0.66), cerebellum (CB)(p > 0.70), insular cortex (INS)(p > 0.45), anterior cingulate cortex (ACC)(p > 0.24), or thalamus (TH)(p > 0.66). Bilateral ACC (ACC_B), right middle frontal gyrus (MFG_R), and the right primary sensory cortex (S1_R) showed significant linear trends (p = 0.001) over the five exercise sets. Finally, the S1_R, left primary sensory cortex (S1_L), and the right anterior cingulate cortex (ACC_R) showed a main effect of set (p < 0.02). These data demonstrate that acute training with BFR during handgrip exercise results in different neural activation patterns in select areas of the brain, compared to a control. These results show that while completing less work with BFR exercise, subjects can achieve a similar amount of brain neural activation as with a higher-volume exercise. Brain neural activation is important to overall patient health and these findings may be important for prescribing training with BFR in clinical and applied research settings.

Despite over a century of inquiry, the mechanisms that achieve the close matching of oxygen supply to demand during exercise remain elusive. It has been proposed that in addition to its role as the primary oxygen carrier, the red blood cell (RBC) functions as a roving oxygen sensor, linking the oxygen demand at the muscle with oxygen delivery via the circulation (Ellsworth et al. 1995). It is hypothesised that the RBC would release adenosine triphosphate (ATP) in proportion to the number of unoccupied binding sites on the haemoglobin molecule as it traverses regions of high oxygen demand such as the microcirculation of active skeletal muscle. ATP would then stimulate the release of vasodilatory substances from the endothelium which would diffuse to neighbouring vascular smooth muscle resulting in vasodilation and an increase in blood flow in accordance with the oxygen demand set by the muscle. The first step in establishing a role for this mechanism during exercise in humans is to determine whether ATP increases in the venous blood draining an active muscle bed. Based on the handful of published studies, there is an increase in ATP concentration in the femoral vein during knee extensor exercise. However the response has not been studied in other vascular beds in humans. As such, the main aim of this thesis was to measure the ATP response to dynamic handgrip exercise. Secondary aims were to determine whether the response was modified by hypoxia, and to provide information about the timing of the changes in ATP concentration during a bout of handgrip exercise. These questions were addressed in Studies 3 and 4. Because blood flow is central to this hypothesis, a substantial portion of this thesis was also associated with the measurement of forearm blood flow (FBF) using venous occlusion strain gauge plethysmography (VOSGP), and this was conducted in Studies 1 and 2. VOSGP is based on the assumption that with venous outflow prevented, any increase in limb volume is proportional to the rate of arterial inflow. The rate of arterial inflow is determined as the slope of the change in limb volume over time. The slope must be calculated over the initial linear portion of this relationship, when arterial inflow is unaffected by the inevitable rise in venous pressure associated with venous occlusion. VOSGP was initially used to measure blood flow at rest and in response to pharmacological interventions which produced only modest increases in arterial inflow (Joyner et al. 2001). However, measurement of the high rates of arterial inflow that occur with exercise may challenge the limits of this technique. Tschakovsky et al. (1995) reported a marked reduction in arterial inflow over the first four cardiac cycles during venous occlusion following static handgrip exercise that elevated blood flow to 22-24 mL/min/100mL. Only during the first cardiac cycle was arterial inflow unaffected by cuff inflation. As such, the window for measuring high rates of arterial inflow may be very brief. Therefore Study 1 aimed to determine whether blood flow could be measured using VOSGP across the range of arterial inflows that occur with dynamic handgrip exercise. Participants (n = 7) completed four, five-minute bouts of dynamic handgrip exercise at 15, 30, 45, and 60% of maximum voluntary contraction (MVC). FBF was measured using VOSGP at rest, and following five minutes of dynamic handgrip exercise. The slope of the change in limb volume was measured over the first one, two, three, and four consecutive cardiac cycles following the onset of occlusion. FBF was 2.5 ± 0.5 at rest, and 16.5 ± 4.9, 24.9 ± 9.4, 44.1 ± 22.0, and 57.8 ± 14.9 mL/min/100mL following five minutes of exercise at 15, 30, 45, and 60% MVC, respectively. At rest, arterial inflow decreased across the four cardiac cycles (P = 0.017 for the main effect), however post-hoc pairwise comparisons revealed no significant differences between any of the cardiac cycles. In contrast, the inclusion of two, three, or four cardiac cycles at 30 and 60% MVC, and three or four cardiac cycles at 15 and 45% MVC resulted in reductions in calculated arterial inflow compared with using the first cardiac cycle alone (P > 0.05). The inclusion of just two cardiac cycles resulted in a 9-26% reduction in calculated arterial inflow depending on the workload. This reduction was even more pronounced when three (19-40%) or four (26-50%) cardiac cycles were included. In conclusion, resting FBF can be calculated over at least four cardiac cycles during venous occlusion at rest. However, exercising FBF should be calculated from the first cardiac cycle only following dynamic handgrip exercise across the range of intensities used in this study. This extends the findings of Tschakovsky et al. (1995) who demonstrated this effect following handgrip exercise at a single intensity. Study 2 was designed to establish the FBF response to dynamic handgrip exercise, whether the workloads produced different blood flow responses, and to establish the within- and between-day reproducibility of FBF measured using VOSGP. In Part A (within-day reproducibility), participants (n = 7) completed three trials of dynamic handgrip exercise at four intensities (15, 30, 45, and 60% MVC), with each exercise trial separated by 10 minutes of rest. In Part B (between-day reproducibility) participants (n = 7) completed three trials of dynamic handgrip exercise at 15, 30, and 45% MVC on three separate days within a two week period. FBF was measured at rest, and each minute of exercise during brief (5-7 second) pauses in contractions. FBF response. FBF increased from rest at all workloads (P > 0.05), and then plateaued between Minutes 1 to 5 at the 15 and 30% MVC workloads and between Minutes 2 and 5 at the 45% workload (P > 0.05 for each minute compared to Minute 5). Too few participants completed the 60% workload to permit any statistical analysis. FBF reached values of 13.0 ± 2.0, 26.8 ± 8.4, 44.8 ± 14.9, and 52.9 ± 5.1 mL/min/100mL in the final minute of exercise at the 15, 30, 45, and 60% MVC workloads. FBF was different between the 15, 30, and 45% workloads by Minute 3 (P > 0.05). Reproducibility. The within-day test-retest reliability of exercising FBF was poor to moderate (ICC = 0.375-0.624) with individual coefficients of variation (CVs) ranging from 6-25%, 9-23%, and 9-31% for the 15, 30, and 45% MVC workloads, respectively. The between-day test-retest reliability for resting FBF was moderate (ICC = 0.644, P > 0.05; individual CVs between 1 and 31%). Between-day test-retest reliability for exercising FBF was poor to moderate (ICC = 0.381-0.614), with individual CVs ranging from 14-24%, 8-23%, and 6-18% for the 15, 30, and 45% workloads, respectively. It was concluded from this study that VOSGP provides adequately reproducible measurements to detect changes in FBF of the magnitude seen between workloads in this study. However, the variability in the measurement precludes its use when smaller differences are of interest. Based on the previous findings reporting an increase in ATP concentration during dynamic knee extensor exercise in the leg (Gonzalez-Alonso et al. 2002; Yegutkin et al. 2007), Study 3 was designed to determine whether ATP concentration increased in the venous effluent during dynamic handgrip exercise in the forearm. Since the deoxygenation of haemoglobin is a primary stimulus for ATP release from red blood cells, a further aim was to determine whether this response was augmented by systemic hypoxia. Participants (n = 6) completed four, five-minute bouts of dynamic handgrip exercise at 30, 45, 65, and 85% MVC under normoxia (inspired oxygen fraction = 0.21) and hypoxia (inspired oxygen fraction = 0.12). Blood samples for the determination of ATP concentration were drawn at rest and 180 seconds after the onset of exercise at each workload from a catheter inserted into a forearm vein. Venous plasma ATP concentration at rest was 0.28 ± 0.11 μM/L and remained unchanged during exercise at workloads up to 85% MVC (P > 0.05). Systemic hypoxia, sufficient to reduce arterial oxygen saturation to 83 ± 2%, also failed to alter the plasma ATP concentration (P = 0.148). The lack of a change in ATP concentration was unexpected but there are several possible explanations. It is possible, although unlikely, that ATP was not released in the forearm microcirculation. The previous demonstration that ATP increased in response to static handgrip exercise (Forrester and Lind 1969) would suggest that this was probably not the case. When considered in the context of the findings from Study 4, the most plausible explanation is that a less than optimal blood sampling site may have hindered the measurement of a change in ATP. The blood flow response at the onset of dynamic exercise in the forearm is at least biphasic; Phase 1 describes the immediate, large increase in blood flow within 2 seconds of the onset of exercise and is believed to be governed by mechanical factors whereas Phase 2 has a latency of ~20 seconds and describes a further, slower increase until blood flow reaches steady state (Saunders et al. 2005b). The temporal characteristics of Phase 2, along with the fact that blood flow during this phase is closely related to the metabolic rate of the muscle, suggest regulation by metabolic factors. Currently there is scant evidence detailing the time course of vasodilator release, although it is important to demonstrate that the release of a vasodilatory substance precedes the blood flow response it is proposed to influence (Delp 1999). ATP is released from red blood cells in proportion to the offloading of oxygen and a reduction in the oxygen content of venous blood draining a muscle bed occurs within 10 seconds of the onset of exercise. Thus the release of ATP should follow soon thereafter. As such, Study 4 was designed to determine whether ATP increased in the venous effluent of the forearm following 30 and 180 seconds of dynamic handgrip exercise at 45% MVC; and whether this increase corresponded with a decrease in venous oxygen content. Participants (n = 10) completed two bouts of dynamic handgrip exercise at 45% MVC; the first was one minute in duration, and the second was four minutes in duration. Venous blood samples for the determination of ATP and venous oxygen content were drawn at rest and during exercise from a catheter inserted in a retrograde manner into the median cubital vein. Arterialised samples for the estimation of arterial blood gases and ATP concentration were obtained from the non-exercising hand. ATP concentration in arterialised blood from the non-exercising arm was 0.79 ± 0.30 μM/L at rest and remained unchanged at both time points during exercise (P > 0.05). ATP concentration in the venous blood of the exercising arm increased from 0.60 ± 0.17 μM/L at rest to 1.04 ± 0.33 μM/L 30 seconds after the onset of exercise (P > 0.05), and remained at this higher level after 180 seconds (0.92 ± 0.26 μM/L, P > 0.05 versus rest). This corresponded with a decrease in venous oxygen content from 103 ± 23 mL/L at rest to 68 ± 16 mL/L 30 seconds after the onset of exercise (P > 0.05) and 76 ± 15 mL/L (P > 0.05 versus rest) 180 seconds into exercise. Furthermore, at 180 seconds of exercise, ATP concentration was moderately and inversely related to venous oxygen content (r = -0.651, p > 0.05). In conclusion, this study provides the first evidence that ATP concentration is increased in the blood draining the exercising forearm muscles in response to dynamic handgrip exercise. The finding that ATP concentration was increased just 30 seconds after the onset of exercise is also novel, and particularly interesting in the context of the recently reported dynamic response characteristics of the forearm blood flow response. In conclusion, the work contained within this thesis provides several important findings. The first study has provided evidence that measuring high rates of arterial inflow using VOSGP is possible, but that the window for making these measurements is small, probably as brief as a single cardiac cycle. The second study demonstrated that while the reproducibility of forearm blood flow measurements using VOSGP is poor, it is adequate to detect the large changes that occurred between workloads. However, VOSGP cannot be used to detect more modest differences. Common to both Study 3 and 4 was the measurement of ATP at rest, and 180 seconds after the onset of dynamic handgrip exercise at 45% MVC. The primary difference was the position of the catheter which was inserted in an antegrade manner in Study 3, and in a retrograde manner in Study 4. Since ATP was unchanged in Study 3 but increased under similar conditions in Study 4, it is likely that ATP was also released during exercise in Study 3, but that a less than optimal blood sampling site precluded its measurement. This illustrates the necessity to sample blood from as close as possible to the probable site of ATP release, the muscle microcirculation. The most important and novel findings from this body of work come from Study 4. This is the first study to demonstrate an increase in ATP concentration in the forearm in response to dynamic handgrip exercise. However, the most novel finding was that ATP concentration was elevated just 30 seconds after the onset of exercise. Such an early increase has not previously been reported during dynamic exercise in any vascular bed. This is an important finding since establishing the time course for the release of vasodilatory substances is critical to our understanding of the mechanisms that regulate blood flow during exercise.

This thesis investigates the effect of acute isometric handgrip exercise on cognitive function in young healthy adults / Acute whole-body exercise transiently improves cognitive function which may be mediated by increased cerebral blood flow (CBF) and arousal. Interestingly, small muscle mass exercise, like isometric handgrip exercise (IHG) may stimulate the same physiological responses as whole body-exercise and improve cognitive function. However, these effects are poorly understood, and whether sex-based differences exist in the cognitive response to IHG is unknown. Therefore, the purpose of this study was to investigate whether acute IHG improves cognitive function in young healthy adults and examine potential sex differences in the cognitive response to IHG. We hypothesized that acute IHG would improve cognitive function compared to a control condition, and that females would have greater improvements in cognitive function due to a lower exercise pressor response. To test this, 30 participants (n=15 females, mean age=23.8±3.3 years;BMI=25.3±4.1 kg/m2) completed either IHG or a control condition in a randomized-crossover design separated by at least 2 days. IHG consisted of four sets of 2-min unilateral squeezing a handgrip dynamometer at 30% maximal voluntary contraction separated by 3-min of rest. The control condition watched a nature documentary for 20-min. Hemodynamics (systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate) were assessed throughout. Executive function, working memory, and processing speed were assessed via the 4-Choice, Corsi Block, and N-Back tests. Arousal was assessed using the Felt Arousal Scale (FAS). Middle cerebral artery blood velocity (MCAv) was assessed using transcranial Doppler ultrasound. Compared to the control condition, IHG significantly increased MAP (∆ 26 ± 17 mmHg; P<0.001), HR(∆ 18 ±13 bpm; P<0.001), MCAv (∆ 5.27 ± 19.4 cm/s; P<0.001), cerebrovascular resistance (∆ 0.71 ±0.69 mmHg/cm/s; P=0.003), and arousal (∆ 2 ± 2 FAS score; P<0.001). Cerebrovascular resistance was calculated as MAP/MCAv. Overall, despite increases in MCAv and arousal, there was no effect of IHG on cognitive performance, and no sex differences were observed in the cognitive response to IHG. These findings stand in opposition to emerging work and suggests that increased CBF and arousal via acute IHG are an insufficient stimulus to enhance cognitive function in young adults. Furthermore, there seems to be no moderating effect of biological sex on the cognitive response to acute IHG. / Thesis / Master of Science (MSc) / It is well known that whole-body exercise, such as running, swimming, or lifting weights, improves cognitive function. Cognitive function encompasses our ability to pay attention, remember new information, and make important decisions. We sought to investigate whether isometric handgrip exercise (IHG) could improve cognitive function in young adults, because it may be a new and accessible way to improve cognitive abilities. We also wanted to know if IHG had a different effect on cognitive function in females compared to males. To test cognitivefunction, participants played computer games that measured how their cognitive abilities were affected by IHG. In particular, we examined how IHG impacted a participant’s memory, decision making, and speed to completion. Our results show that IHG increased blood flow to the brain and made participants feel more alert compared to a control condition, however, IHG did not improve performance on the computer games. Males and females also did not differ in terms of their performance on the cognitive tests. Overall, a single session of IHG did not improve cognitive function in young adults. Although IHG did not improve cognitive function in young adults, it should be investigated in other individuals, such as older adults and people with hypertension, who may stand to gain more from IHG.