Ischemic Handgrip Exercise Research Articles

Aging exaggerates blood pressure response to ischemic rhythmic handgrip exercise in humans.

Ischemic skeletal muscle conditions are known to augment exercise‐induced increases in blood pressure (BP). Aging is also a factor that enhances the pressor response to exercise. However, the effects of aging on the BP response to ischemic exercise remain unclear. We, therefore, tested the hypothesis that aging enhances the BP response to rhythmic handgrip (RHG) exercise during postexercise muscle ischemia (PEMI). We divided the normotensive participants without cardiovascular diseases into three age groups: young (n = 26; age, 18–28 years), middle‐aged (n = 23; age, 35–59 years), and older adults (n = 23; age, 60–80 years). The participants performed RHG exercise with minimal effort for 1 min after rest with and without PEMI, which was induced by inflating a cuff on the upper arm just before the isometric handgrip exercise ended; the intensity was 30% of maximal voluntary contraction force. Under PEMI, the increase in diastolic BP (DBP) from rest to RHG exercise in the older adult group (Δ13 ± 2 mmHg) was significantly higher than that in the young (Δ5 ± 2 mmHg) and middle‐aged groups (Δ6 ± 1 mmHg), despite there being no significant difference between the groups in the DBP response from rest to RHG exercise without PEMI. Importantly, based on multiple regression analysis, age remained a significant independent determinant of both the SBP and DBP responses to RHG exercise during PEMI (p < 0.01). These findings indicate that aging enhances the pressor response to ischemic rhythmic exercise.

The association of elevated blood pressure during ischaemic exercise with sport performance in Master athletes with and without morbidity

BackgroundAn exaggerated exercise blood pressure (BP) is associated with a reduced exercise capacity. However, its connection to physical performance during competition is unknown.AimTo examine BP responses to ischaemic handgrip exercise in Master athletes (MA) with and without underlying morbidities and to assess their association with athletic performance during the World Master Track Cycling Championships 2019.MethodsForty-eight Master cyclists [age 59 ± 13yrs; weekly training volume 10.4 ± 4.1 h/week; handgrip maximum voluntary contraction (MVC) 46.3 ± 11.5 kg] divided into 2 matched groups (24 healthy MA and 24 MA with morbidity) and 10 healthy middle-aged non-athlete controls (age 48.3 ± 8.3 years; MVC 40.4 ± 14.8 kg) performed 5 min of forearm occlusion including 1 min handgrip isometric contraction (40%MVC) followed by 5 min recovery. Continuous beat-by-beat BP was recorded using finger plethysmography. Age-graded performance (AGP) was calculated to compare race performances among MA. Healthy Master cyclists were further grouped into middle-age (age 46.2 ± 6.4 years; N:12) and old-age (age 65.0 ± 7.7 years; N:12) for comparison with middle-aged non-athlete controls.ResultsHealthy and morbidity MA groups showed similar BP responses during forearm occlusion and AGP (90.1 ± 4.3% and 91.0 ± 5.3%, p > 0.05, respectively). Healthy and morbidity MA showed modest correlation between the BP rising slope for 40%MVC ischaemic exercise and AGP (r = 0.5, p < 0.05). MA showed accelerated SBP recovery after cessation of ischaemic handgrip exercise compared to healthy non-athlete controls.ConclusionOur findings associate long-term athletic training with improved BP recovery following ischaemic exercise regardless of age or reported morbidity. Exaggerated BP in Master cyclists during ischaemic exercise was associated with lower AGP during the World Master Cycling Championships.

A New Protocol for Controlling and Targeting Reactive Hyperemia Shear Stress to Assess Endothelial Function

Conduit artery endothelial function is most commonly assessed via measurement of flow mediated dilation (FMD) evoked by a transient post-limb occlusion increase in shear stress [reactive hyperemia (RH)]. A limitation of RH-FMD is the uncontrolled nature of the RH shear stress stimulus which produces RH-FMD response variability that is independent of conduit artery endothelial function. The purpose of this study was to develop a protocol to create a uniform, targeted, and transient (40 second) shear stress stimulus and compare it to the standard RH-FMD approach. We hypothesize that incorporating arterial compression in the controlled targeted RH (CTRH) protocol will allow us to achieve a uniform target shear rate (estimate of shear stress) within and between participants. Young, healthy men and women (females n = 4, age = 22 ± 1 years; males n = 2, age = 25 ± 3 years) underwent one trial of RH-FMD and two trials of CTRH-FMD with duplex ultrasound assessment. The CTRH protocol incorporated three-minutes of ischemic handgrip exercise at 30% of participants’ maximum voluntary contraction during a five-minute occlusion to create a large forearm vasodilation and hyperemic reserve. Upon cuff release, the ensuing hyperemia was controlled with manual brachial artery compression at the antecubital fossa. A live velocity readout permitted compression adjustments to achieve the velocity required to maintain a target shear rate of 120 s-1. The cuff was re-inflated after 40s of cuff release. The RH-FMD trial followed the standard five-minute forearm occlusion protocol. The 40s average shear rate was 116.0 ± 8.8s-1 in the CTRH test and 102.1 ± 15.4 s-1 in the RH test. The CTRH test shear rate was significantly closer to the 120s-1 target; calculated as the absolute distance from target in 3s time bins over the 40s period: CTRH = 19.0 ± 3.9s-1; RH = 36.5 ± 6.7 s-1 p = 0.002. The between participant coefficient of variation (CV) for the RH 40s average shear rate was lower in the CTRH test (CTRH CV = 8.1%; RH CV = 15.1%). The within subject trial to trial CV for the CTRH 40s average shear rate was 3.0 ± 4.6%. FMD responses were similar between tests (CTRH-FMD% = 8.3 ± 1.6%; RH-FMD% = 7.6 ± 4.8%, p=0.717). These preliminary findings demonstrate the capacity for RH stimulus control. CTRH-FMD is minimally impacted by stimulus variability and may provide a clearer reflection of brachial artery endothelial function.

Exercise Training Improves Microvascular Function in Burn Injury Survivors.

Vasodilator function is impaired in individuals with well-healed burn injuries; however, therapeutic interventions that lessen or reverse this maladaptation are lacking. The purpose of this study was to test the hypothesis that a 6-month community-based exercise training program would increase microvascular dilator function in individuals with well-healed burn injuries, irrespective of the magnitude of the injured body surface area. Further, we hypothesize that macrovascular dilator function would remain unchanged posttraining. Microvascular function (forearm reactive hyperemia), macrovascular function (brachial artery flow-mediated dilation), and the maximal vasodilatory response after ischemic handgrip exercise (an estimate of microvascular remodeling) were assessed before and after exercise training in nonburned control subjects (n = 11) and individuals with burn injuries covering a moderate body surface area (26% ± 7%; n = 13) and a high body surface area (59% ± 15%; n = 19). Peak vascular conductance and area under the curve during postocclusive reactive hyperemia increased from pretraining to posttraining in control and burn injury groups (both P < 0.05), the magnitude of which did not differ between groups (both P = 0.6). Likewise, the maximal vasodilatory response after ischemic handgrip exercise increased in all groups after exercise training (P < 0.05). Macrovascular dilator function did not differ across time or between groups (P = 0.8). These data suggest that a community-based exercise training program improves microvascular function in individuals with well-healed burn injuries, which may be due in part to vascular remodeling.

Insulin resistance is associated with an exaggerated blood pressure response to ischemic rhythmic handgrip exercise in nondiabetic older adults

Patients with type 2 diabetes display an exaggerated pressor response to exercise. However, evidence supporting the association between the magnitude of the pressor response to exercise and insulin resistance-related factors including hemoglobin A1c (HbA1c) or homeostatic model assessment of insulin resistance (HOMA-IR) in nondiabetic subjects has remained sparse and inconclusive. Thus we investigated the relationship between cardiovascular responses to exercise and insulin resistance-related factors in nondiabetic healthy men (n = 23) and women (n = 22) above 60 yr old. We measured heart rate (HR) and blood pressure (BP) responses during: isometric handgrip (IHG) exercise of 30% maximal voluntary contraction, a period of skeletal muscle ischemia (SMI) induced by tourniqueting the arm after IHG, and rhythmic dynamic handgrip (DHG) exercise during SMI. Greater diastolic BP (DBP) responses to DHG with SMI was associated with male sex (r = 0.44, P = 0.02) and higher HbA1c (r = 0.33, P = 0.03), heart-ankle pulse wave velocity (haPWV) (r = 0.45, P < 0.01), and resting systolic BP (SBP) (r = 0.36, P = 0.02). HbA1c persisted as a significant determinant explaining the variance in the DBP response to DHG with SMI in multivariate models despite adjustment for sex, haPWV, and resting SBP. It was also determined that the DBP response to DHG with SMI in a group in which HOMA-IR was abnormal (Δ33 ± 3 mmHg) was significantly higher than that of groups in which HOMA-IR was at intermediate (Δ20 ± 4 mmHg) and normal (Δ23 ± 2 mmHg) levels. These data suggest that even in nondiabetic older adults, insulin resistance is related to an exaggerated pressor response to exercise especially when performed under ischemic conditions.NEW & NOTEWORTHY The diastolic blood pressure response to rhythmic dynamic handgrip exercise under ischemic conditions was demonstrated to be correlated with insulin resistance-related factors in nondiabetic older adults. This finding provides important insight to the prescription of exercise in this particular patient population as the blood pressure response to exercise, especially under ischemic conditions, could be exaggerated to nonsafe levels.

GABAA receptors modulate sympathetic vasomotor outflow and the pressor response to skeletal muscle metaboreflex activation in humans.

The activation of the group III/IV skeletal muscle afferents is one of the principal mediators of cardiovascular responses to exercise; however, the neuronal circuitry mechanisms that are involved during the activation of group III/IV muscle afferents in humans remain unknown. Recently, we showed that GABAergic mechanisms are involved in the cardiac vagal withdrawal during the activation of mechanically sensitive (predominantly mediated by group III fibres) skeletal muscle afferents in humans. In the present study, we found that increases in muscle sympathetic nerve activity and mean blood pressure during isometric handgrip exercise and postexercise ischaemia were significantly greater after the oral administration of diazepam, a benzodiazepine that increases GABAA activity, but not after placebo administration in young healthy subjects. These findings indicate for the first time that GABAA receptors modulate sympathetic vasomotor outflow and the pressor responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. Animal studies have indicated that GABAA receptors are involved in the neuronal circuitry of the group III/IV skeletal muscle afferent activation-induced neurocardiovascular responses to exercise. In the present study, we aimed to determine whether GABAA receptors modulate the neurocardiovascular responses to activation of metabolically sensitive (predominantly mediated by group IV fibres) skeletal muscle afferents in humans. In a randomized, double-blinded, placebo-controlled and cross-over design, 17 healthy subjects (eight women) performed 2min of ischaemic isometric handgrip exercise at 30% of the maximal voluntary contraction followed by 2min of postexercise ischaemia (PEI). Muscle sympathetic nerve activity (MSNA), blood pressure (BP) and heart rate (HR) were continuously measured and trials were conducted before and 60min after the oral administration of either placebo or diazepam (10mg), a benzodiazepine that enhances GABAA activity. At rest, MSNA was reduced, whereas HR and BP did not change after diazepam administration. During ischaemic isometric handgrip, greater MSNA (pre: ∆13±9burstsmin-1 vs. post: ∆29±15burstsmin-1 , P<0.001), HR (pre: ∆23±11beatsmin-1 vs. post: ∆31±17beatsmin-1 , P<0.01) and mean BP (pre: ∆33±12mmHg vs. post: ∆37±12mmHg, P<0.01) responses were observed after diazepam. During PEI, MSNA and mean BP remained elevated from baseline before diazepam (∆10±8burstsmin-1 and ∆25±14mmHg, respectively) and these elevations were increased after diazepam (∆17±12burstsmin-1 and ∆28±13mmHg, respectively) (P≤0.05). Importantly, placebo pill had no effect on neural, cardiac and pressor responses. These findings demonstrate for the first time that GABAA receptors modulate MSNA and the pressor responses to skeletal muscle metaboreflex activation in humans.

Sex differences in blood pressure regulation during ischemic isometric exercise: the role of the β-adrenergic receptors.

We sought to investigate whether the β-adrenergic receptors play a pivotal role in sex-related differences in arterial blood pressure (BP) regulation during isometric exercise. Sixteen volunteers (8 women) performed 2 min of ischemic isometric handgrip exercise (IHE) and 2 min of postexercise circulatory occlusion (PECO). Heart rate (HR) and beat-to-beat arterial BP were continuously measured. Beat-to-beat estimates of stroke volume (ModelFlow) were obtained and matched with HR to calculate cardiac output (Q̇) and total peripheral resistance (TPR). Two trials were randomly conducted between placebo and nonselective β-adrenergic blockade (40 mg propranolol). Under the placebo condition, the magnitude of the BP response in IHE was lower in women compared with men. During PECO, the BP remained elevated and the sex differences persisted. The β-blockade attenuated the BP response during IHE in men (∆57 ± 4 vs. ∆45 ± 7 mmHg, P = 0.025) due to a reduction in Q̇ (∆3.7 ± 0.5 vs. ∆1.8 ± 0.2 L/min, P = 0.012) while TPR was not affected. In women, however, the BP response during IHE was unchanged (∆27 ± 3 vs. ∆28 ± 3 mmHg, P = 0.889), despite attenuated Q̇ (∆2.7 ± 0.4 vs. ∆1.3 ± 0.2 L/min, P = 0.012). These responses were mediated by a robust increase in TPR under β-blockade (∆-0.2 ± 0.4 vs. ∆2.2 ± 0.7 mmHg·L-1·min, P = 0.012). These findings demonstrate that the sex differences in arterial BP regulation during ischemic IHE are mediated by β-adrenergic receptors.NEW & NOTEWORTHY We found that the blood pressure response during isometric exercise in women is mediated by increases in cardiac output, whereas in men it is mediated by increases in both cardiac output and total peripheral resistance. In addition, women showed a robust increase in total peripheral resistance under β-blockade during isometric exercise and muscle metaboreflex activation. These findings demonstrate that sex differences in blood pressure regulation during isometric exercise are mediated by β-adrenergic receptors.

Blood pressure predicts endothelial function and the effects of ethinyl estradiol exposure in young women.

Hypertension, obesity, and endothelial function predict cardiovascular disease in women, and these factors are interrelated. We hypothesized that hypertension and obesity are associated with endothelial dysfunction in young women and that short-term ethinyl estradiol exposure mitigates this dysfunction. We examined flow-mediated dilation (FMD) responses before and during 7 days of oral ethinyl estradiol (30 µg/day) in 19 women (25 ± 5, 18-35 yr). We divided our sample into two groups based on two criteria: blood pressure and obesity. Women were divided into normal blood pressure (NBP; mean arterial pressure range: 78-91 mmHg, n = 7) and high blood pressure (HBP; mean arterial pressure range: 95-113 mmHg, n = 9) groups. We also stratified our subjects by body composition (lean: 18-31%, n = 8; obese: 38-59%, n = 9). We evaluated brachial FMD after two distinct shear stress stimuli: occlusion alone and occlusion with ischemic handgrip exercise. Obesity was unrelated to both FMD responses. Before ethinyl estradiol administration, the HBP group had blunted ischemic exercise responses relative to the NBP group (8.0 ± 3.5 vs. 12.3 ± 3.2%, respectively, P = 0.05). However, during ethinyl estradiol administration, ischemic exercise responses increased in the HBP group (12.8 ± 6.1%, P = 0.04) but decreased in the NBP group (5.6 ± 2.4%, P = 0.01). Standard FMD did not reveal differences between groups. In summary, 1) moderate HBP predicted endothelial impairment, 2) ethinyl estradiol administration had divergent effects on FMD in women with NBP versus HBP, and 3) enhanced FMD (ischemic handgrip exercise) revealed differences in endothelial function, whereas standard FMD (occlusion alone) did not. NEW & NOTEWORTHY We are the first to show that mild hypertension is a stronger predictor of endothelial dysfunction than obesity in healthy women without overt cardiovascular dysfunction. Importantly, the standard 5-min flow-mediated vasodilation stimulus did not detect endothelial dysfunction in our healthy population; only an enhanced ischemic handgrip exercise shear stress stimulus detected endothelial impairment. Estradiol administration increased flow-mediated dilation in women with high blood pressure, so it may be a therapeutic intervention to improve endothelial function.

Blood Pressure Predicts Endothelial Function and Effect of Ethinyl Estradiol in Young Obese and Lean Women

Obesity, mild hypertension and endothelial function are all predictors of cardiovascular disease in women, and we propose that these factors are interrelated. We hypothesized that obesity and high blood pressure are associated with endothelial dysfunction in young women. Further, we hypothesized that short‐term low‐dose ethinyl estradiol treatment would mitigate this dysfunction. We examined hyperemic responses before and during 30 μg/day oral ethinyl estradiol (EE) treatment for 7 days in 16 healthy women (mean 26 ± 5, 19–35 yrs) with normal (NBP; n=7, MAP range: 78–91 mmHg) or mildly elevated blood pressure (HBP; n=9, MAP range: 95–113 mmHg). We evaluated brachial vasodilatory responses following two stimuli designed to elicit different levels of shear stress: 5‐min occlusion (RH‐FMD), and 3‐min occlusion with ischemic handgrip exercise (IE‐FMD). Body composition did not impact RH‐FMD or IE‐FMD responses. In contrast, Pre‐EE, HBP had lower IE‐FMD responses relative to NBP (8.0 ± 3.5% vs. 12.3 ± 3.2%, respectively; P=0.05). During EE, IE‐FMD increased in HBP (12.8 ± 6.1%; P=0.02) and decreased in NBP (5.6 ± 2.4%, P&lt;0.01). The increase in shear stress (8659 ± 4964 vs. 14753 ± 8189 AUC, s−1; P=0.04) contributed to the increase in IE‐FMD in HBP subjects during EE, while shear stress did not change with EE in NBP (9740 ± 3222 vs. 10564 ± 2984 AUC, s−1; P=0.76). MAP did not predict RH‐FMD responses or associated shear stress, pre‐or during‐EE. Thus, 1) in young healthy women, moderately elevated blood pressure was a predictor of endothelial function whereas obesity was not; 2) EE mitigated endothelial dysfunction associated with elevated blood pressure; 3) the enhanced shear stress stimulus was able to subtle differences in endothelial function where the standard FMD stimulus did not. Because HBP women had only mildly high blood pressure, these data are of particular significance given the new American Heart Association guidelines for hypertension.Support or Funding InformationSupported by the APS Undergraduate Research Excellence Fellowship; the Paul Titus Fellowship Fund, Dept. Obstetrics Gynecology and Reproductive Sciences, Yale School of Medicine; and the AHA Postdoctoral Fellowship.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sex difference in the influence of central blood volume mobilization on the exercise pressor response.

To determine the sex difference in the impact of central venous pressure (CVP) on the pressor response induced by ischemic handgrip exercise. Twelve young healthy individuals (six males, 25 ± 3 years) performed ischemic handgrip exercise during mild levels of lower body negative pressure (LBNP, -5 mmHg) and during a 10° head-down tilt (HDT) to lower and increase CVP, respectively. The protocol consisted of 3 min of baseline ischemia, followed by 2 min of isometric handgrip exercise at 35 % of maximal voluntary contraction force, and 2 min of post-exercise circulatory occlusion. Mean arterial pressure (MAP) was assessed continuously by finger plethysmography and CVP was estimated from the venous pressure of the non-exercising dependent arm. Baseline CVP was greater during HDT than LBNP (8.4 ± 1.8 vs. 6.5 ± 1.8 mmHg, p < 0.01). MAP was greater during LBNP than HDT throughout the protocol (p = 0.05). During ischemic handgrip exercise, CVP increased in males but not in females (Group × protocol interaction: p = 0.01). A group × condition interaction was also observed for MAP, with males showing a greater MAP during LBNP than HDT (110 ± 2 vs. 103 ± 2 mmHg, p < 0.01). Baseline CVP inversely affected the pressor response to handgrip exercise in all individuals, with a greater MAP response observed during LBNP than HDT. Increase in CVP in males may be due to a greater splanchnic vasoconstrictor response to ischemic handgrip exercise. Therefore, combined baseline CVP and changes in CVP likely contributed to the greater MAP response observed during LBNP in males.

Impaired brachial artery endothelial function in young healthy women following an acute painful stimulus

Impaired endothelial function has been observed during and immediately following an acutely painful stimulus. However, the extent to which this persists following pain dissipation is unclear. To determine whether painful ischemic handgrip exercise (pain task) causes impaired flow-mediated dilation (FMD) after the sensation of pain and hemodynamic responses have abated. A second purpose was to determine whether the response to pain differed with a predisposition to magnify, ruminate, and feel helpless about pain (pain catastrophizing status). Brachial artery FMD stimulated by reactive hyperemia was assessed via ultrasound in 18 (9 high catastrophizing) healthy, women (20 ± 1 years) before and 15 min after a 3 min pain task. The shear stress stimulus for FMD was estimated as shear rate (blood velocity/brachial artery diameter). RESULTS (MEAN ± SD): None of the variables were significantly impacted by pain catastrophizing status and are presented pooled across group. The pain task increased pain ratings [1 ± 1-6 ± 3 (0-10 scale) (p < 0.001)], mean arterial pressure (MAP) (p < 0.001) and heart rate (HR) (p < 0.001), all returning to pre-pain levels ≤2-min post-pain task (pre-pain vs. 2-min post-pain: pain rating p = 1.000; MAP p = 0.142; HR p = 0.992). The shear rate stimulus was not different between pre- and post-pain task FMD tests (p = 0.200). FMD decreased post-pain task (10.8 ± 4.6 vs. 7.0 ± 2.7 %, p < 0.001). These results indicate that, regardless of pain catastrophizing status, painful ischemic handgrip exercise has a deleterious impact on endothelial function that persists after the pain sensation and hemodynamic responses have abated.

Effect of unilateral forearm inactivity on endothelium-dependent vasodilator function in humans

Exercise training is associated with rapid changes in endothelium-dependent vasodilation, which occur within days of training. Whilst long-term physical inactivity has potent effects on vascular structure, little is known about the immediate impact of inactivity on vascular function. Aim of this study was to measure vascular function before, during (day 4) and after 8 days of unilateral forearm inactivity. Thirteen healthy male subjects (22 ± 1 years) were instructed to wear a sling on the non-dominant arm to induce local inactivity. Before, during (at 4 days) and after the 8-day intervention, we used echo Doppler to measure bilateral brachial artery dilator response to 5-min ischaemia [i.e. flow-mediated dilation (FMD)], ischaemic handgrip exercise (iEX) and endothelium-independent dilation to a NO donor [i.e. glyceryl trinitrate (GTN)]. Maximal handgrip strength of the inactive forearm significantly decreased after 8 days (t tests P = 0.03 for Day 0 vs. Day 8), confirming physical deconditioning in the inactive forearm. A significant decrease in peak blood flow was found in the intervention arm (sling: 539 ± 236, 528 ± 184, 384 ± 142 ml/min) relative to the control arm (559 ± 181, 591 ± 219, 613 ± 169 ml/min; 2-way ANOVA interaction: P = 0.05). Analysis revealed no significant change in brachial artery baseline diameter, FMD %, iEX or GTN across the 8 days in either arm (P > 0.05). Eight days of forearm physical inactivity induced a significant decrease in post-ischaemic limb blood flow, suggestive of remodelling of forearm resistance vessels. However, measures of conduit artery endothelium-dependent vasodilation were not altered across an 8-day period of inactivity, suggesting that initial remodelling occurs at distal ends of the vascular tree.

Brachial artery adaptation to lower limb exercise training: role of shear stress

Lower limb exercise increases upper limb conduit artery blood flow and shear stress, and leg exercise training can enhance upper limb vascular function. We therefore examined the contribution of shear stress to changes in vascular function in the nonexercising upper limbs in response to lower limb cycling exercise training. Initially, five male subjects underwent bilateral brachial artery duplex ultrasound to measure blood flow and shear responses to 30-min cycling exercise at 80% of maximal heart rate. Responses in one forearm were significantly (P < 0.05) attenuated via cuff inflation throughout the exercise bout. An additional 11 subjects participated in an 8-wk cycle training study undertaken at a similar intensity, with unilateral cuff inflation around the forearm during each exercise bout. Bilateral brachial artery flow-mediated dilation responses to a 5-min ischemic stimulus (FMD%), an ischemic handgrip exercise stimulus (iEX), and endothelium-independent NO donor administration [glyceryl trinitrate (GTN)] were measured at 2, 4, and 8 wk. Cycle training increased FMD% in the noncuffed limb at week 2, after which time responses returned toward baseline levels (5.8 ± 4.1, 8.6 ± 3.8, 7.4 ± 3.5, 6.0 ± 2.3 at 0, 2, 4 and 8 wk, respectively; ANOVA: P = 0.04). No changes in FMD% were observed in the cuffed arm. No changes were evident in response to iEX or GTN in either the cuffed or noncuffed arms (P > 0.05) across the 8-wk intervention period. Our data suggest that lower limb cycle training induces a transient increase in upper limb vascular function in healthy young humans, which is, at least partly, mediated via shear stress.

Exercise and arterial adaptation in humans: uncoupling localized and systemic effects

Previous studies have established effects of exercise training on arterial wall thickness, remodeling, and function in humans, but the extent to which these changes are locally or systemically mediated is unclear. We examined the brachial arteries of the dominant (D) and nondominant (ND) upper limbs of elite racquet sportsmen and compared them to those of matched healthy inactive controls. Carotid and superficial femoral artery responses were also assessed in both groups. High-resolution duplex ultrasound was used to examine resting diameter, wall thickness, peak diameter, and blood flow. We found larger resting arterial diameter in the preferred arm of the athletes (4.9 ± 0.5 mm) relative to their nonpreferred arm (4.3 ± 0.4 mm, P < 0.05) and both arms of control subjects (D: 4.1 ± 0.4 mm; ND: 4.0 ± 0.4, P < 0.05). Similar limb-specific differences were also evident in brachial artery dilator capacity (5.5 ± 0.5 vs. 4.8 ± 0.4, 4.8 ± 0.6, and 4.8 ± 0.6 mm, respectively; P < 0.05) following glyceryl trinitrate administration and peak blood flow (1,118 ± 326 vs. 732 ± 320, 737 ± 219, and 698 ± 174 ml/min, respectively; P < 0.05) following ischemic handgrip exercise. In contrast, athletes demonstrated consistently lower wall thickness in carotid (509 ± 55 μm), brachial (D: 239 ± 100 μm; ND: 234 ± 133 μm), and femoral (D: 479 ± 38 μm; ND: 479 ± 42 μm) arteries compared with control subjects (carotid: 618 ± 74 μm; brachial D: 516 ± 100 μm; ND: 539 ± 129 μm; femoral D: 634 ± 155 μm; ND: 589 ± 112 μm; all P < 0.05 vs. athletes), with no differences between the limbs of either group. These data suggest that localized effects of exercise are evident in the remodeling of arterial size, whereas arterial wall thickness appears to be affected by systemic factors.

Repeated increases in blood flow, independent of exercise, enhance conduit artery vasodilator function in humans

This study aimed to determine the importance of repeated increases in blood flow to conduit artery adaptation, using an exercise-independent repeated episodic stimulus. Recent studies suggest that exercise training improves vasodilator function of conduit arteries via shear stress-mediated mechanisms. However, exercise is a complex stimulus that may induce shear-independent adaptations. Nine healthy men immersed their forearms in water at 42°C for three 30-min sessions/wk across 8 wk. During each session, a pneumatic pressure cuff was inflated around one forearm to unilaterally modulate heating-induced increases in shear. Forearm heating was associated with an increase in brachial artery blood flow (P<0.001) and shear rate (P<0.001) in the uncuffed forearm; this response was attenuated in the cuffed limb (P<0.005). Repeated episodic exposure to bilateral heating induced an increase in endothelium-dependent vasodilation in response to 5-min ischemic (P<0.05) and ischemic handgrip exercise (P<0.005) stimuli in the uncuffed forearm, whereas the 8-wk heating intervention did not influence dilation to either stimulus in the cuffed limb. Endothelium-independent glyceryl trinitrate responses were not altered in either limb. Repeated heating increases blood flow to levels that enhance endothelium-mediated vasodilator function in humans. These findings reinforce the importance of the direct impacts of shear stress on the vascular endothelium in humans.

Lack of Macro- and Micro-Vascular Dysfunction in Habitually Exercising Systemic Lupus Erythematosus Patients

Individuals with systemic lupus erythematosus (SLE) exhibit chronically elevated inflammatory markers and experience premature cardiovascular disease. Vascular dysfunction is commonly observed in SLE patients and may explain the accelerated risk. Currently it is unknown whether physical activity status influences vascular function in patients with SLE. PURPOSE: To examine macro- and micro-vascular function in sedentary and exercising SLE patients, compared with healthy controls. METHODS: A total of forty-one young and middle-aged adults, including 15 healthy controls, 12 sedentary SLE, and 14 exercising SLE patients, were studied. Macro- and micro-vascular measures included flow-mediated dilation (via ultrasonography before and after 5-min brachial occlusion), skin reactive hyperemia (via Laser Doppler), and minimal vascular resistance (via venous-occlusion plethysmography after 10-min arterial occlusion with 2-min ischemic handgrip exercise). RESULTS: Age, BMI, and metabolic risk factors were not different between the 3 groups. Maximal aerobic capacity and physical activity score were higher in exercising SLE patients compared with sedentary SLE patients. Endothelium-dependent vasodilation was lower (3.6±1.3 vs. 8.1±1.2%) and inflammatory markers (CRP, IL-12, TNF-·) were higher in sedentary SLE patients compared with healthy controls. Importantly, there were no differences in endothelium-dependent vasodilation (p=0.73) or inflammatory markers between exercising SLE patients and healthy controls. There were no differences between groups in minimal vascular resistance (a surrogate measure of resistance artery structure) or skin reactive hyperemia. In the pooled population, endothelium-dependent vasodilation was inversely associated with IL-6 and IL-10 (both p<0.05). Minimal vascular resistance was positively associated with CRP, IL-6, IL-10, and ICAM-1 (all p<0.05), and skin reactive hyperemia was inversely associated with ICAM-1, TNF- ·, and IL-10 (all p<0.05). CONCLUSIONS: Our results indicate that significant SLE-associated macro- and micro-vascular dysfunction was not observed in physically active SLE patients. Additionally, macro- and micro-vascular function was associated with inflammatory markers, suggesting that the favorable influence of physical activity may be mediated by its effect on inflammatory markers.

Muscle metaboreflex and exercise heart rate: insights from studies in subjects with and without heart failure

We read with interest the recent work of Fisher et al. (2010), who demonstrated, in healthy young men, that muscle metaboreflex-induced sympathetic excitation contributes to the heart rate response to ischaemic handgrip exercise in a graded manner. This effect, masked at lower intensity of exercise by parasympathetic reactivation at the cessation of handgrip, was unmasked by glycopyrrolate during post-handgrip ischaemia, which prolongs metaboreflex stimulation of muscle afferents independently of central command and muscle mechanoreflex influences, and abolished by β-blockade. The authors interpret their findings as indicating that heart rate returns to resting values during ischaemia after moderate exercise because of an overwhelming effect of parasympathetic reactivation, which counters metaboreflex increases in cardiac sympathetic activity. However, after more intense handgrip, cardiac sympathetic activity predominates and the impact of parasympathetic restoration is less obvious. Although this concept has been supported by animal work (O’Leary, 1993), it has not been investigated directly in humans as in the present study (Fisher et al. 2010). Fisher et al. (2010) speculate that in the absence of parasympathetic reactivation, increased cardiac sympathetic nerve activity should delay the post-exercise recovery of heart rate and propose heart failure, which is characterized by augmented cardiac sympathetic activation and diminished cardiac vagal heart rate modulation (Floras, 2009), as an important clinical condition where this independent predictor of mortality (Cole et al. 1999) may be particularly evident. Our own studies of post-handgrip ischaemia provide independent validation of the mechanism tested by Fisher which is of potential concern in heart failure. Our principal findings were: first, that in heart failure the muscle metaboreflex elicits a greater increase in muscle sympathetic nerve activity during ischaemic or intense non-ischaemic handgrip exercise than in age-matched healthy controls; second, that this excitatory reflex response occurs at a lower threshold in heart failure than in healthy subjects; and third, that the magnitude of this effect is a function of exercise capacity (Notarius et al. 2001). Importantly, unlike the young men studied by Fisher et al. (2010), in our series all subjects were of middle age. As we commented upon in the Discussion in our paper, in contrast to the lower intensities of dynamic handgrip (10% and 30% MVC), heart rate did not return to baseline in these heart failure patients after ischaemic (30% MVC) and intense non-ischaemic (50% MVC) handgrip exercise. A graded response to ischaemic and non-ischaemic handgrip also was observed in simultaneously acquired microneurographic recordings of sympathetic nerve traffic directed at calf skeletal muscle. Our findings are therefore consistent with Fisher's hypothesis that diminished vagal drive in heart failure may be insufficient to counter the cardiac sympathetic excitatory response to metaboreflex stimulation once exercise ceases. Together, these clinical and experimental studies (O’Leary, 1993; Notarius et al. 2001; Fisher et al. 2010) offer compelling evidence in favour of a role for the muscle metaboreflex in stimulating the accelerated heart rate response to ischaemic handgrip exercise and intense dynamic exercise, and suggest that this mechanism may be of particular clinical relevance in conditions such as heart failure (Floras, 2009) or hypertension (Esler, 2010) that exhibit cardiac sympathetic excitation and blunted parasympathetic tone.

The Influence of Baroreceptor Loading Status on Muscle Metaboreceptor Modulation of Heat Loss Responses

Muscle metaboreceptors have been shown to have a profound effect on the control of the local heat loss responses of sweating (LSR) and skin blood flow (SkBF). Under experimental conditions which employ the ischemic isometric hand-grip exercise (IHG) model, muscle metaboreceptors tend to reduce active vasodilation and attenuate sweating. However, it remains unclear if non-pharmacologically-induced changes in baroreceptor status may mitigate this response. PURPOSE: To evaluate the influence of baroreceptor loading status on LSR and SkBF during postexercise ischemia. METHODS: Seven physically active males (19-24 years) completed two experimental trials under a normothermic (NS) and hyperthermic (whole-body warming, HS) state. Subjects performed 1-min of IHG exercise at 60% of their maximal voluntary contraction followed by 2-min of ischemia under simultaneous lower body positive pressure (LBPP, +40 mm Hg), negative pressure (LBNP, -20 mm Hg) and no pressure (CON). The sequence of these conditions was performed in random order with a 20-min recovery period between conditions to minimize muscular fatigue. RESULTS: No significant differences were observed during baseline rest or at the end of the IHG exercise. Under both NS and HS, mean arterial pressure (MAP) was increased above baseline resting during ischemia. However, the magnitude of increase in MAP was greater during LBPP for both NS (p<0.001) and HS (p<0.002), but lower during LBNP (p<0.028) under HS relative to CON. Despite differences in baroreceptor loading status under NS, no significant difference in LSR or SkBF were observed. In HS, no differences in SkBF were measured between CON and LBPP. However, SkBF response during ischemia was significantly reduced during LBNP as compared to CON (p=0.015) and LBPP (p=0.023). No differences in LSR were observed between CON and LBNP during ischemia. However, a marked reduction in LSR was measured in LBPP relative to CON (p=0.024) but not LBNP (p=0.092). CONCLUSIONS: These results suggest that baroreceptor loading status can mitigate muscle metaboreceptor-induced changes in local heat loss responses. However, this only appears to occur in a hyperthermic state. Funding support from the Natural Sciences and Engineering Research Council of Canada (held by Dr. G. Kenny).

Assessment Of Peak Peripheral Artery Conduit And Resistance Artery Structure In Humans: Does Occluding Cuff Position Matter?

PURPOSE: To determine whether the position of an occluding cuff on the lower and upper limbs modifies conduit artery diameter and blood flow responses to peak vasodilator stimuli. Edge-detection and wall tracking of high resolution B-mode arterial ultrasound images, combined with synchronized Doppler waveform envelope analysis, was used to calculate conduit artery blood flow (BF) and diameter responses continuously across the cardiac cycle. METHODS: Thirty-six healthy subjects (47.4±3 yrs; 42.2±2 ml.kg-1.min-1) underwent assessment of popliteal and brachial artery blood flow and diameter responses to periods of ischemic exercise and glyceryl trinitrate (GTN) administration. Ischemia was induced with occluding cuff placement both proximal and distal to the imaged artery. RESULTS: The peak popliteal artery diameter response (PADpeak) was observed following a 5 minute period of ischemic combined with 3 minutes of exercise, with the occluding cuff placed above the imaged artery (12.8±1.1% vs 9.7±0.9%, thigh vs calf cuff placement, P<0.05). Peak brachial artery diameter response (BADpeak) was observed following a similar ischemic handgrip exercise stimulus with upper arm cuff placement (17.9±1.3% vs 11.2±0.9%, arm vs forearm cuff placement, P<0.0001). No significant effect of cuff placement was evident for either peak brachial (BAFpeak) or popliteal artery flow (PAFpeak) or conductance responses. CONCLUSIONS: These data indicate that cuff position modifies peak diameter responses through both the popliteal and brachial arteries. Future studies should utilize proximal cuff placement if the aim is to determine peak arterial vasodilation responses as an index of conduit arteriogenic adaptation.

Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency?

It is unclear to what extent muscle phosphorylase b kinase (PHK) deficiency is associated with exercise-related symptoms and impaired muscle metabolism, because 1) only four patients have been characterized at the molecular level, 2) reported symptoms have been nonspecific, and 3) lactate responses to ischemic handgrip exercise have been normal. We studied a 50-year-old man with X-linked PHK deficiency using ischemic forearm and cycle ergometry exercise tests to define the derangement of muscle metabolism. We compared our findings with those in patients with McArdle disease and in healthy subjects. Sequencing of PHKA1 showed a novel pathogenic mutation (c.831G>A) in exon 7. There was a normal increase of plasma lactate during forearm ischemic exercise, but lactate did not change during dynamic, submaximal exercise in contrast to the fourfold increase in healthy subjects. Constant workload elicited a second wind in all patients with McArdle disease, but not in the patient with PHK deficiency. IV glucose administration appeared to improve exercise tolerance in the patient with PHK deficiency, but not to the same extent as in the patients with McArdle disease. Lipolysis was higher in the patient with PHK deficiency than in controls. These findings demonstrate that X-linked PHK deficiency causes a mild metabolic myopathy with blunted muscle glycogen breakdown and impaired lactate production during dynamic exercise, which impairs oxidative capacity only marginally. The different response of lactate to submaximal and maximal exercise is likely related to differential activation mechanisms for myophosphorylase.