Leg Vascular Conductance Research Articles

Sympathetic Vasoconstrictor Responsiveness of the Leg Vasculature During Experimental Endotoxemia and Hypoxia in Humans.

Sympathetic vasoconstriction regulates peripheral circulation and controls blood pressure, but sepsis is associated with hypotension. We evaluated whether apparent loss of sympathetic vasoconstrictor responsiveness relates to distended smooth muscles or to endotoxemia and/or hypoxia. Prospective descriptive study. Hospital research laboratory. Ten healthy young men (age [mean ± SD], 31 ± 8 yr; body weight, 83 ± 10 kg) participated in the study. Leg blood flow and mean arterial pressure were determined, whereas leg vascular conductance was calculated during 1) adenosine infusion (vasodilator control), 2) hypoxia (FIO2 = 10%), 3) endotoxemia, and 4) endotoxemia + hypoxia. Leg sympathetic vasoconstrictor responsiveness (reduction in leg vascular conductance) was evaluated by femoral artery tyramine infusion. Endotoxemia increased body temperature from 36.9 ± 0.4°C to 38.6 ± 0.5°C (p < 0.01) and plasma tumor necrosis factor-α from 6 pg/mL (3-8 pg/mL) to 391 pg/mL (128-2258 pg/mL) (p < 0.01; median [range]). Mean arterial pressure decreased similarly during endotoxemia (-11% ± 16%) and endotoxemia + hypoxia (-10% ± 15%; both p < 0.05). Leg blood flow and leg vascular conductance were not affected by endotoxemia, whereas both were elevated by adenosine infusion (leg blood flow, +94% ± 61%; leg vascular conductance, +97% ± 57%), hypoxia (leg blood flow: +93% ± 58%; leg vascular conductance, +100% ± 115%), and endotoxemia + hypoxia (leg blood flow, +67% ± 120%; leg vascular conductance, +65% ± 57%; p < 0.05). Endotoxemia lessened the tyramine-induced reduction in leg vascular conductance (-28% ± 13%) compared with the reduction during adenosine infusion (-47% ± 5%; p < 0.05). Also, endotoxemia + hypoxia (-17% ± 21%) attenuated the tyramine-induced reduction in leg vascular conductance compared with both adenosine infusion and hypoxia (-45% ± 13%; p < 0.05). Both endotoxemia and combined hypoxia and endotoxemia blunted sympathetic vasoconstrictor responsiveness. Furthermore, tyramine normalized the doubled leg vascular conductance during administration of adenosine, suggesting that distension of vascular smooth muscles does not explain blunted sympathetic vasoconstrictor responsiveness during endotoxemia.

The Effects of Intermittent Hypoxia on the Vasculature and Carotid Baroreflex Regulation

Intermittent hypoxia (IH) occurs in association with obstructive sleep apnea and is thought to contribute to the pathogenesis of hypertension through mechanisms that include endothelial dysfunction, arterial stiffness, increased vascular resistance and impaired arterial baroreflex. The purpose of this study was to examine the acute effects of IH on the vasculature and carotid baroreflex to identify the early contributors to IH‐induced hypertension. We hypothesized that six hours of IH would increase mean arterial pressure (MAP), reduce endothelium‐dependent vasodilatation, impair vascular strain, induce oscillatory arterial shear patterns and shift the carotid baroreflex to operate at higher MAP while eliciting impaired control of leg vascular conductance (LVC). Healthy, young (26.3±1.3 years), normotensive (123±2.5 mmHg/65±1.6 mmHg) men (n=10) free of sleep apnea were exposed to two six hour conditions in randomized order: 1) IH [1‐min room air followed by 1‐min hypoxia (mean minimum oxygen saturation=80.7±0.4%; mean±SEM)], and 2) Sham IH (oxygen saturation=96.7±0.4%). Arterial blood pressure was recorded by using 24‐hour ambulatory blood pressure monitoring. Micro‐and macro‐vascular reactivity was measured by using reactive hyperemia flow‐mediated dilation before and immediately after each condition. During each exposure, vascular strain was measured by 2D speckle tracking in the common carotid and femoral artery (CCA and CFA), and hemodynamics were measured in the brachial artery and CFA using duplex ultrasound. Carotid baroreflex control of MAP and LVC was assessed following each condition by using the variable pressure neck chamber technique (target pressures: −80, −60, −40, −20, +20 and +40 mmHg). Intermittent hypoxia elevated 24‐hour MAP (2.6±0.8 mmHg, P=0.008) and tended to increase nocturnal systolic blood pressure (SBP, 3.9±1.8 mmHg, P=0.053). The augmented SBP may be caused by increased arterial stiffness and vascular resistance. Micro‐ and macro‐vascular reactivity were unaffected by IH but decreased by 17.5±5.5% and 14.1±4.7% following each testing day (P&lt;0.001, P=0.025) due to a blunted shear rate response. Vascular strain was reduced in the CCA during IH (P=0.014) and a trend towards IH‐impaired CFA strain was observed (P=0.055). Only the lower limb hemodynamics were affected by IH, exhibiting reduced blood flow (SHAM: 188.3±18.6 ml/min; IH: 158.0±1.6 ml/min, P=0.016) and increased oscillatory shear index by 20.3±5.7% (P=0.036). Intermittent hypoxia displaced the carotid baroreflex control of MAP curve to higher arterial blood pressures (P=0.045) and blunted LVC responses to hypertensive stimuli (−40 mmHg; SHAM: 24.0±2.5%, IH: 18.3±2.2%, P=0.044; −60 mmHg, SHAM: 31.8±3.2%; IH: 22.0±2.3%, P=0.003; −80 mmHg, SHAM: 40.6±3.9%, IH: 32.2±3.9%, P=0.002). In contrast to our hypotheses, we found that IH had no effect on micro‐ and macro‐vascular endothelial function. However, the differential impact of IH on upper and lower limb oscillatory shear patterns suggest endothelial function in the lower limb may be impaired before the upper limb. Impairments in vascular strain, lower limb hemodynamic shear patterns and carotid baroreflex control precede changes in upper arm endothelial function following six‐hours of IH and may be important in the early pathogenesis of IH‐induced hypertension.Support or Funding InformationNatural Sciences and Engineering Research Council of Canada, Canada Foundation for Innovation

Rescuing Age‐Related Vascular Dysfunction: The Impact of Tetrahydrobiopterin and Antioxidants

PURPOSEAging is associated with an increase in oxidant production that negatively impacts vascular function. This vascular dysfunction is, in part, mediated by a decrease in endothelial nitric oxide synthase (eNOS) activity. Tetrahydrobiopterin (BH4), an important co‐factor involved in eNOS coupling, is highly susceptible to oxidation and therefore less available in the vasculature of aged individuals. Therefore, this study sought to rescue vascular dysfunction in older adults with the acute oral supplementation of both BH4 and an antioxidant cocktail (AOC).METHODSEight healthy older subjects (O: 70±3 yrs) completed four testing sessions, each separated by at least 72 hours in a randomized, double‐blind cross‐over design. Prior to each visit, the older subjects ingested either placebo (PL), an AOC (600 IU α‐tocopherol, 1000 milligrams ascorbic acid, and 600 milligrams α‐lipoic acid), BH4 (10 mg/kg), or BH4+AOC. Vascular function was assessed by supine passive leg movement (PLM)‐induced vasodilation (leg vascular conductance, LVC). Central (heart rate, stroke volume, cardiac output, and mean arterial pressure, MAP) and peripheral hemodynamics (leg blood flow) were measured for 1 minute prior to PLM and then during 2 minutes of PLM with finger photoplethysmography and Doppler ultrasound, respectively. Twelve healthy young subjects (Y: 23±1 yrs) also completed the supine PLM protocol without supplementation, providing young reference data.RESULTSResting central hemodynamics were not different between the young and old with the exception of MAP that was significantly elevated in the old (O: 107±6; Y: 86±2 mmHg; p &lt; 0.01). Compared to the young subjects, the old exhibited significantly lower PLM‐induced peak changes in LVC (O: 2.4±0.3; Y: 6.8±0.7; p &lt; 0.01). Although not significantly lower than the PL condition, BH4 supplementation in the old lowered resting MAP such that there was no longer an age‐related difference (O: 93±6; Y: 86±2 mmHg; p = 0.29). There were no significant effects on resting MAP in the AOC (99±2 mmHg) or BH4+AOC (101±4 mmHg) conditions. The PLM‐induced peak change in LVC was augmented with BH4 (4.8±0.6) compared to all other conditions (PL: 2.4±0.3; AOC: 2.9±0.2; BH4+AOC: 1.8±0.4) in the old, such that the peak change in LVC in the BH4 condition was not different from that in the young (O: 4.8±0.6; Y: 6.8±0.7 ml·min−1·mmHg−1; p = 0.06). Surprisingly, the AOC alone and BH4+AOC conditions did not impact the peak change in LVC compared to PL condition in the older subjects.CONCLUSIONSThis study reveals that acute oral BH4 supplementation significantly improves leg vascular function in older adults when compared to PL, an AOC, or the combination of BH4 and an AOC. Furthermore, the substantial improvement in LVC in the older adults supplemented with BH4 meant that their vascular function was comparable to their younger counterparts and highlights the importance of BH4 in rescuing vascular function with advancing age.

Impaired skeletal muscle vasodilation during exercise in heart failure with preserved ejection fraction

BackgroundExercise intolerance is a hallmark symptom of heart failure patients with preserved ejection fraction (HFpEF), which may be related to an impaired ability to appropriately increase blood flow to the exercising muscle. MethodsWe evaluated leg blood flow (LBF, ultrasound Doppler), heart rate (HR), stroke volume (SV), cardiac output (CO), and mean arterial blood pressure (MAP, photoplethysmography) during dynamic, single leg knee-extensor (KE) exercise in HFpEF patients (n=21; 68±2yrs) and healthy controls (n=20; 71±2yrs). ResultsHFpEF patients exhibited a marked attrition during KE exercise, with only 60% able to complete the exercise protocol. In participants who completed all exercise intensities (0–5–10–15W; HFpEF, n=13; Controls, n=16), LBF was not different at 0W and 5W, but was 15–25% lower in HFpEF compared to controls at 10W and 15W (P<0.001). Likewise, leg vascular conductance (LVC), an index of vasodilation, was not different at 0W and 5W, but was 15–20% lower in HFpEF compared to controls at 10W and 15W (P<0.05). In contrast to these peripheral deficits, exercise-induced changes in central variables (HR, SV, CO), as well as MAP, were similar between groups. ConclusionsThese data reveal a marked reduction in LBF and LVC in HFpEF patients during exercise that cannot be attributed to a disease-related alteration in central hemodynamics, suggesting that impaired vasodilation in the exercising skeletal muscle vasculature may play a key role in the exercise intolerance associated with this patient population.

Mechanical compression during repeated sustained isometric muscle contractions and hyperemic recovery in healthy young males.

BackgroundAn elevated intramuscular pressure during a single forearm isometric muscle contraction may restrict muscle hyperemia. However, during repeated isometric exercise, it is unclear to what extent mechanical compression and muscle vasodilatation contribute to the magnitude and time course of beat-to-beat limb hemodynamics, due to alterations in leg vascular conductance (LVC).MethodsIn eight healthy male subjects, the time course of both beat-to-beat leg blood flow (LBF) and LVC in the femoral artery was determined between repeated 10-s isometric thigh muscle contractions and 10-s muscle relaxation (a duty cycle of 20 s) for steady-state 120 s at five target workloads (10, 30, 50, 70, and 90 % of maximum voluntary contraction (MVC)). The ratio of restricted LBF due to mechanical compression across workloads was determined by the formula (relaxation LBF − contraction LBF)/relaxation LBF (%).ResultsThe exercise protocol was performed completely by all subjects (≤50 % MVC), seven subjects (≤70 % MVC), and two subjects (≤90 % MVC). During a 10-s isometric muscle contraction, the time course in both beat-to-beat LBF and LVC displayed a fitting curve with an exponential increase (P < 0.001, r2 ≥ 0.956) at each workload but no significant difference in mean LBF across workloads and pre-exercise. During a 10-s muscle relaxation, the time course in both beat-to-beat LBF and LVC increased as a function of workload, followed by a linear decline (P < 0.001, r2 ≥ 0.889), that was workload-dependent, resulting in mean LBF increasing linearly across workloads (P < 0.01, r2 = 0.984). The ratio of restricted LBF can be described as a single exponential decay with an increase in workload, which has inflection point distinctions between 30 and 50 % MVC.ConclusionsIn a 20-s duty cycle of steady-state repeated isometric muscle contractions, the post-contraction hyperemia (magnitude of both LBF and LVC) during muscle relaxation was in proportion to the workload, which is in agreement with previous findings. Furthermore, time-dependent beat-to-beat muscle vasodilatation was seen, but not restricted, during isometric muscle contractions through all target workloads. Additionally, the relative contribution of mechanical obstruction and vasodilatation to the hyperemia observed in the repeated isometric exercise protocol was non-linear with regard to workload. In combination with repeated isometric exercise, the findings could potentially prove to be useful indicators of circulatory adjustment by mechanical compression for muscle-related disease.

Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans

We investigated the influence of aging on the group III/IV muscle afferents in the exercise pressor reflex-mediated cardiovascular response to rhythmic exercise. Nine old (OLD; 68 ± 2 yr) and nine young (YNG; 24 ± 2 yr) males performed single-leg knee extensor exercise (15 W, 30 W, 80% max) under control conditions and with lumbar intrathecal fentanyl impairing feedback from group III/IV leg muscle afferents. Mean arterial pressure (MAP), cardiac output, leg blood flow (QL), systemic (SVC) and leg vascular conductance (LVC) were continuously determined. With no hemodynamic effect at rest, fentanyl blockade during exercise attenuated both cardiac output and QL ∼17% in YNG, while the decrease in cardiac output in OLD (∼5%) was significantly smaller with no impact on QL (P = 0.8). Therefore, in the face of similar significant ∼7% reduction in MAP during exercise with fentanyl blockade in both groups, LVC significantly increased ∼11% in OLD, but decreased ∼8% in YNG. The opposing direction of change was reflected in SVC with a significant ∼5% increase in OLD and a ∼12% decrease in YNG. Thus while cardiac output seems to account for the majority of group III/IV-mediated MAP responses in YNG, the impact of neural feedback on the heart may decrease with age and alterations in SVC become more prominent in mediating the similar exercise pressor reflex in OLD. Interestingly, in terms of peripheral hemodynamics, while group III/IV-mediated feedback plays a clear role in increasing LVC during exercise in the YNG, these afferents seem to actually reduce LVC in OLD. These peripheral findings may help explain the limited exercise-induced peripheral vasodilation often associated with aging.

Passive leg movement-induced vasodilation in women: the impact of age

Passive leg movement (PLM), an assessment of predominantly nitric oxide-dependent vasodilation, is decreased with age and cannot be augmented by posture-induced increases in femoral perfusion pressure in older men. However, this novel method of assessing vascular function has yet to be used to evaluate alterations in nitric oxide-dependent vasodilation with age in females. PLM was performed in 10 young (20 ± 1 yr) and 10 old (73 ± 2 yr) women in both the supine and upright-seated postures, whereas central and peripheral hemodynamic measurements were acquired second by second using noninvasive techniques (finger photoplethysmography and Doppler ultrasound, respectively). The heart rate response to PLM was attenuated in the old compared with the young in both the supine (young, 10 ± 1; and old, 5 ± 1 beats/min; P < 0.05) and upright-seated posture (young, 10 ± 2; and old, 5 ± 1 beats/min; P < 0.05), leading to a blunted cardiac output response in the old in the upright-seated posture (young, 1.0 ± 0.2; and old, 0.3 ± 0.1 l/min; P < 0.05). The PLM-induced peak change in leg vascular conductance was lower in the old compared with the young in both postures (young supine, 5.7 ± 0.5; old supine, 2.6 ± 0.3; young upright, 9.2 ± 0.7; and old upright, 2.2 ± 0.4 ml·min(-1)·mmHg(-1); P < 0.05) and was significantly augmented by the upright-seated posture in the young only, revealing a vasodilatory reserve capacity in the young (3.5 ± 0.6 ml·min(-1)·mmHg(-1), P < 0.05) that was absent in the old (-0.5 ± 0.3 ml·min(-1)·mmHg(-1), P = 0.18). These data support previous literature demonstrating attenuated PLM-induced vasodilation with age and extend these findings to include the female population, thus bolstering the utility of PLM as a novel assessment of vascular function across the life span in humans.

Group III/IV Mediated Muscle Reflexes Restrain Vascular Conductance During Exercise In Patients With Hypertension

PURPOSE: We investigated the role of group III/IV-mediated muscle reflexes (i.e. the exercise pressor reflex) in determining the circulatory response to physical activity in patients with essential hypertension. METHODS: Five patients with stage 1–2 hypertension (HT; systolic: 155 ± 5 mmHg; diastolic: 90 ± 2 mmHg; 64 ± 3 years) and eight age-matched normotensive control subjects (NT; systolic: 120 ± 6 mmHg; diastolic: 80 ± 6 mmHg) performed single-leg knee extensor exercise (7, 15, 20 and 30 W) under control conditions and with lumbar intrathecal fentanyl impairing feedback from μ-opioid receptor-sensitive lower limb muscle afferents. Cardiac output (Q; photoplethysmography), leg perfusion pressure (PP = arterial pressure - venous pressure; femoral arterial and venous catheters), and femoral blood flow (QL; Doppler ultrasound) were measured continuously during exercise. Leg vascular conductance (LVC) was calculated as QL/PP. RESULTS: Hypertension had a significant main effect on PP (∼22% higher in HT vs. NT), LVC (∼30% lower in HT vs. NT), and QL (∼13% lower in HT vs. NT) during exercise in control conditions (P < 0.05). Following fentanyl blockade, which had no measurable effects at rest, Q during exercise in HT was, secondary to a small reduction in heart rate (P = 0.08) and a significant decrease in stroke volume, about ∼20% lower compared to control conditions (P < 0.05). In contrast, fentanyl blockade had no effect on Q during exercise in NT (P = 0.4). Additionally, in the face of a similar 8-10% reduction in PP during exercise with fentanyl blockade in NT and HT, there was ∼20% increase in QL during exercise with fentanyl blockade in patients with HT (P < 0.05), contrasting with the unaltered QL response in NT individuals. The net outcome of these changes was a significantly elevated LVC in both groups, but the increase was nearly three-fold greater in HT compared to NT (26 ± 3% vs. 10 ± 2%; P < 0.05). CONCLUSION: Although the exercise pressor reflex plays a critical role in facilitating central hemodynamics (i.e. Q) in HT, it also impairs QL and LVC in these patients. The excessive muscle reflex-mediated sympatho-excitation in HT contributed to the deficit in QL and LVC during exercise under normal conditions and might therefore be a substantial contributor to the exercise intolerance which characterizes this population.

Physical Activity And Passive Leg Movement-Induced Vasodilation

The vasodilatory response to passive leg movement (PLM) is predominantly nitric oxide (NO) mediated. Due to reduced NO bioavailability with advancing age, PLM-induced vasodilation is attenuated in older sedentary subjects. PURPOSE: We sought to determine the impact of varying levels of physical activity on PLM-induced vasodilation, and therefore NO bioavailability, in older subjects. METHODS: PLM was performed on four subject groups (young sedentary (YS), 23 ± 1 yrs, n = 12; old sedentary (OS), 73 ± 2 yrs, n = 12; old active (OA), 71 ± 2 yrs, n = 10; old endurance trained (OT), 72 ± 1 yrs, n = 10) in the upright-seated posture. Central and peripheral hemodynamic responses were determined second-by-second with finger photoplethysmography and Doppler ultrasound, respectively. RESULTS: Peak VO2 was significantly different between all subject groups (YS = 42 ± 3, OS = 26 ± 2, OA = 34 ± 2, OT = 52 ± 2 ml/kg/min; P < 0.05). PLM-induced peak change in leg vascular conductance (ΔLVCpeak) was significantly attenuated in OS compared to YS (OS: 4.4 ± 0.8, YS: 11.8 ± 1.3 ml/min/mmHg; P < 0.05). Both OA and OT groups demonstrated augmented ΔLVCpeak compared to OS (OA: 7.3 ± 0.8, OT: 7.6 ± 0.9 ml/min/mmHg; P < 0.05). However, OA and OT groups were not different (P = 0.82), and remained attenuated compared to YS (P < 0.05). The rapid vasodilatory response (slope of LVC over time; ml/min/mmHg/s), also thought to be partially NO-dependent, was not different between YS, OA, and OT (YS: 1.08 ± 0.14, OA: 0.75 ± 0.10, OT: 0.79 ± 0.14 ml/min/mmHg/s; P < 0.05), but was decreased in OS compared to the other three groups (0.42 ± 0.06 ml/min/mmHg/s; P < 0.05). CONCLUSIONS: These data suggest that remaining physically active during aging likely augments NO-mediated vascular function. However, physical activity, even at levels achieved by highly trained older individuals, failed to fully restore vasodilatory responses to that of the young.

Muscle Reflex Effects on the Autonomic Hemodynamic Response to Passive Leg Movement in Older Individuals

Utilizing passive leg movement (PLM), it has recently been documented that leg afferent‐mediated muscle reflexes (predominantly group III) play a critical role in central (cardiac output, Q; stroke volume, SV; heart rate, HR) and peripheral (leg blood flow, LBF) hemodynamic responses in young individuals. The purpose of this study was to examine the impact of age on the role of the muscle reflex in PLM‐induced hemodynamics. Eight men (67 ± 9 yrs) underwent 2 min of passive knee‐extension before (CON) and after partial blockade of lower limb muscle afferents via lumbar intrathecal fentanyl (FENT). Q (plethysmography), leg perfusion pressure (PP), and LBF (Doppler ultrasound) were measured continuously. Leg vascular conductance (LVC) was calculated as LBF/PP. All variables, assessed at baseline, were significantly affected by PLM. The changes in peak values were similar between CON and FENT for Q (~20% increase; P = 0.11), HR (~15% increase; P = 0.42), SV (~18% increase; P = 0.15), and PP (~7% decrease; P = 0.68). However, as FENT resulted in a greater increase in LBF (266 ± 51% vs. 139 ± 21%; P &lt; 0.05), LVC was also greater (288 ± 51% vs. 155 ± 18%; P &lt; 0.05). These findings are in contrast to prior observations in young individuals in whom, compared to CON, FENT during PLM caused a significant decrease in Q (34% vs. 22%), LBF (295% vs. 210%), and LVC (322% vs. 231%). These findings imply an age‐related shift in the role of the mechanoreceptor‐mediated muscle reflex in regulating central and peripheral hemodynamics. Specifically, group III afferents transition from a facilitating effect on central and peripheral hemodynamics during PLM in the young to having no influence on Q and evidence of restraining LBF and LVC in the old.

Limb Specific Vascular Adjustments at Exercise Onset

ObjectiveTo compare the rate of vascular adjustment at the onset of arm vs. leg exercise using the same exercise modality and hydrostatic conditions.Methods10 healthy recreationally active males (21.9±1.9 yrs) completed step increase dynamic exercise protocols (1s contract/2s relax) at 40%, 80% and 100% of peak vascular conductance response. Forearm handgrip and knee extension was performed in supine position with the exercising muscles at heart level. Continuous measures of brachial (forearm) and femoral (leg) artery blood flow (FBF, LBF; Doppler and Echo ultrasound) and arterial blood pressure (MAP; Finometer) were used to calculate forearm (FVC) and leg (LVC) vascular conductance.ResultsFor all exercise intensities, LVC was (p&lt;0.001) but FVC was not (P=0.705) characterized by a subsequent vasoconstriction at ~10 s (Phase IB) following the rapid initial vasodilation (Phase IA). Phase IA LVC amplitude was greater than steady state in the leg at 40% and no different at 80% (P&lt;0.05), but for FVC it was lower than steady state at all exercise intensities (P&lt;0.05). Phase IA had a greater contribution to the total response amplitude in the leg vs. forearm at all exercise intensities (P&lt;0.05) representing an overshoot compared to the Phase II plateau at 40% and 80% (P&lt;0.05). There was a main effect of limb for the Phase II time constant (leg faster than forearm, P&lt;0.05).ConclusionWhen contraction/relaxation modality and hydrostatic environment are controlled for, rapid vasodilatory mechanisms are more sensitive to the onset of exercise in lower vs. upper limbs and can overshoot steady state. Transient vasoconstriction between the initial rapid and secondary slower adjustment is specific to the lower limb. Funding: NSERC 250367‐06.

Is nitric oxide mediated sympatholysis improved with exercise? Yes or nNO?

Exercise causes marked elevations in sympathetic activity to skeletal muscle beds, the magnitude of which is largely dependent on exercise mode, intensity and the amount of active muscle mass. This sympathetic outflow results in vasoconstriction within inactive muscle beds, whilst in active muscle beds exercise induces the release of sympatholytic factors (i.e. ATP, prostaglandins (PGs), and nitric oxide (NO)). These factors act to attenuate or abolish sympathetic vasoconstriction during exercise. Functional sympatholysis reflects this ability of active muscle beds to release sympatholytic factors to locally attenuate the sympathetic vasoconstrictor response associated with exercise. Combined constrictive and sympatholytic processes allow for cardiac output redistribution, which facilitates adequate perfusion and O2 delivery to metabolically active muscle, and ultimately homeostasis. If a large amount of muscle mass were active (e.g. during whole body exercise), a mismatch between these two processes would lead to either under-perfusion (greater vasoconstriction) or hypotension (greater sympatholysis). While the relevance of functional sympatholysis in clinical/disease populations is unclear, numerous pathophysiological conditions are characterized by elevated sympathetic outflow and impaired sympatholysis contributes to elevated vascular resistance and malperfusion of skeletal muscle during exercise (Saltin & Mortensen, 2012). For example, leg vascular conductance appears to be lower during exercise in hypertensive compared to normotensive adults (Mortensen et al. 2014). Moreover, impaired sympatholysis has been linked to reduced muscle perfusion in elderly versus young individuals during exercise (reviewed in Saltin & Mortensen, 2012). Overall, a complex interplay between blood pressure-regulating reflexes (i.e. baroreflex, muscle metaboreflex, central command, etc.), their consequent sympathetic outflow, and the production of local sympat-holytic factors determine cardiac output distribution to contracting skeletal muscle. However, the integration of these processes is poorly understood.

Characterizing rapid-onset vasodilation to single muscle contractions in the human leg.

Rapid-onset vasodilation (ROV) following single muscle contractions has been examined in the forearm of humans, but has not yet been characterized in the leg. Given known vascular differences between the arm and leg, we sought to characterize ROV following single muscle contractions in the leg. Sixteen healthy men performed random ordered single contractions at 5, 10, 20, 40, and 60% of their maximum voluntary contraction (MVC) using isometric knee extension made with the leg above and below heart level, and these were compared with single isometric contractions of the forearm (handgrip). Single thigh cuff compressions (300 mmHg) were utilized to estimate the mechanical contribution to leg ROV. Continuous blood flow was determined by duplex-Doppler ultrasound and blood pressure via finger photoplethysmography (Finometer). Single isometric knee extensor contractions produced intensity-dependent increases in peak leg vascular conductance that were significantly greater than the forearm in both the above- and below-heart level positions (e.g., above heart level: leg 20% MVC, +138 ± 28% vs. arm 20% MVC, +89 ± 17%; P < 0.05). Thigh cuff compressions also produced a significant hyperemic response, but these were brief and smaller in magnitude compared with single isometric contractions in the leg. Collectively, these data demonstrate the presence of a rapid and robust vasodilation to single muscle contractions in the leg that is largely independent of mechanical factors, thus establishing the leg as a viable model to study ROV in humans.

Interactive effect of acute sympathetic activation and exercise intensity on the dynamic response characteristics of vascular conductance in the human calf muscle

The effect of acute activation of the sympathetic nervous system on the dynamic response of muscle hyperaemia during exercise at different intensities is not clear. To explore this, six men performed 16, 5-min bouts of intermittent calf contractions at two intensities (25 and 50 % MVC) and two levels of sympathetic activation (CPT cold pressor test, CON control). Mean arterial pressure (MAP) and leg vascular conductance (LVC leg blood flow/MAP) were measured during rest and contractions (3 s intervals), and dynamic response characteristics of LVC were estimated using curve-fitting and empirical modeling. MAP was ~20 % greater (P ≤ 0.05) during CPT than CON before and during initial contractions at both intensities. At 25 % MVC, CPT reduced the exercise-induced change in LVC (0.109 vs 0.125 ml 100 ml(-1 )min(-1 )mmHg(-1); P < 0.05), an effect attributed to the reduction in the amplitude of the fast growth phase (0.091 vs 0.128 1 ml 100 ml(-1 )min(-1 )mmHg(-1); P < 0.05). At 50 % MVC, CPT also blunted the fast growth phase (0.147 vs 0.189 ml 100 ml(-1 )min(-1 )mmHg(-1); P < 0.05), but the total change in LVC during exercise was unaffected because of a significant reduction in the amplitude of the rapid decay phase and tendency (P = 0.1) for a lower amplitude of the slow decay phase. Increased sympathetic constraint of vasodilation persists during initial contractions but is overcome at the high intensity by a mechanism apparently related to hyperaemic decay.

Heart failure and movement-induced hemodynamics: Partitioning the impact of central and peripheral dysfunction

BackgroundThe complex pathophysiology of heart failure (HF) creates a challenging paradigm to differentiate the role of central and peripheral hemodynamic dysfunction during conventional exercise. Adopting a novel reductionist approach with potential clinical relevance, we studied the central and peripheral contributors to both continuous and single passive leg movement (PLM)-induced hyperemia in 14 HF patients with reduced ejection fraction (HFrEF) and 13 controls. MethodsHeart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), and femoral artery blood flow (FBF) were recorded during PLM. ResultsThe FBF response (area under the curve; AUC) to 60s of continuous PLM was attenuated in the HFrEF (25±15ml AUC) compared to controls (199±34ml AUC) as were peak changes from baseline for FBF, leg vascular conductance (LVC), CO, and HR. During single PLM, increases in CO and HR were smaller and no longer different between groups, supporting the use of this modality to assess groups with disparate central hemodynamics. Interestingly, single PLM-induced hyperemia, likely predominantly driven by flow-mediated vasodilation due to minimal vessel deformation, was essentially nonexistent in the HFrEF (−9±10ml AUC) in contrast to the controls (43±25ml AUC). ConclusionsThese data fail to support a HFrEF-associated exaggeration in the mechanoreceptor driven component of the exercise pressor response. In fact, by exhibiting limited central hemodynamic responses compared to the controls, the observed attenuation in movement-induced FBF in HFrEF appears largely due to peripheral vascular dysfunction, particularly flow-mediated vasodilation.

Hemodynamic responses during graded and constant-load plantar flexion exercise in middle-aged men and women with type 2 diabetes.

We tested the hypotheses that type 2 diabetes (T2D) impairs the 1) leg hemodynamic responses to an incremental intermittent plantar-flexion exercise and 2) dynamic responses of leg vascular conductance (LVC) during low-intensity (30% maximal voluntary contraction, MVC) and high-intensity (70% MVC) constant-load plantar-flexion exercise in the supine posture. Forty-four middle-aged individuals with T2D (14 women), and 35 healthy nondiabetic (ND) individuals (18 women) were tested. Leg blood flow (LBF) was measured between each contraction using venous occlusion plethysmography. During the incremental test peak force (Fpeak) relative to MVC was significantly reduced (P < 0.05) in men and women with T2D compared with their respective nondiabetic counterparts. Peak LBF and the slope of LBF relative to percentage Fpeak were also reduced (P < 0.05) in women with T2D compared with healthy women (peak blood flow, 460.6 ± 126.8 vs. 628.3 ± 347.7 ml/min; slope, 3.78 ± 1.74 vs. 5.85 ± 3.14 ml·min(-1)·%Fpeak (-1)) and in men with T2D compared with nondiabetic men (peak blood flow, 621.7 ± 241.3 vs. 721.2 ± 359.7 ml/min; slope, 5.75 ± 2.66 vs. 6.33 ± 3.63 ml·min(-1)·%Fpeak (-1)). During constant-load contractions at 30% MVC T2D did not affect the dynamic responses of LVC (LBF/MAP). However, at 70% MVC [completed by a subgroup of participants (20 with T2D, 6 women; 13 ND, 6 women)] the time constant of the second growth phase of LVC was longer and the amplitude of the first growth phase was lower (P < 0.05 for both) in men and women with T2D. The results suggest that the T2D-induced impairments in performance of the leg muscles are related to reductions in blood flow in both men and women.

Chronic hypoxia increases arterial blood pressure and reduces adenosine and ATP induced vasodilatation in skeletal muscle in healthy humans.

To determine the role played by adenosine, ATP and chemoreflex activation on the regulation of vascular conductance in chronic hypoxia. The vascular conductance response to low and high doses of adenosine and ATP was assessed in ten healthy men. Vasodilators were infused into the femoral artery at sea level and then after 8-12 days of residence at 4559 m above sea level. At sea level, the infusions were carried out while the subjects breathed room air, acute hypoxia (FI O2 = 0.11) and hyperoxia (FI O2 = 1); and at altitude (FI O2 = 0.21 and 1). Skeletal muscle P2Y2 receptor protein expression was determined in muscle biopsies after 4 weeks at 3454 m by Western blot. At altitude, mean arterial blood pressure was 13% higher (91 ± 2 vs. 102 ± 3 mmHg, P < 0.05) than at sea level and was unaltered by hyperoxic breathing. Baseline leg vascular conductance was 25% lower at altitude than at sea level (P < 0.05). At altitude, the high doses of adenosine and ATP reduced mean arterial blood pressure by 9-12%, independently of FI O2 . The change in vascular conductance in response to ATP was lower at altitude than at sea level by 24 and 38%, during the low and high ATP doses respectively (P < 0.05), and by 22% during the infusion with high adenosine doses. Hyperoxic breathing did not modify the response to vasodilators at sea level or at altitude. P2Y2 receptor expression remained unchanged with altitude residence. Short-term residence at altitude increases arterial blood pressure and reduces the vasodilatory responses to adenosine and ATP.

Group III/IV muscle afferents impair limb blood in patients with chronic heart failure

ObjectiveTo better understand the hemodynamic and autonomic reflex abnormalities in heart-failure patients (HF), we investigated the influence of group III/IV muscle afferents on their cardiovascular response to rhythmic exercise. MethodsNine HF-patients (NYHA class-II, mean left ventricular ejection-fraction: 27±3%) performed single leg knee-extensor exercise (25/50/80% peak-workload) under control conditions and with lumbar intrathecal fentanyl impairing μ-opioid receptor-sensitive muscle afferents. ResultsCardiac-output (Q) and femoral blood-flow (QL) were determined, and arterial/venous blood samples collected at each workload. Exercise-induced fatigue was estimated via pre/post-exercise changes in quadriceps strength. There were no hemodynamic differences between conditions at rest. During exercise, Q was 8–13% lower with Fentanyl-blockade, secondary to significant reductions in stroke volume and heart rate. Lower norepinephrine spillover during exercise with Fentanyl revealed an attenuated sympathetic outflow that likely contributed to the 25% increase in leg vascular conductance (p<0.05). Despite a concomitant 4% reduction in blood pressure, QL was 10–14% higher and end-exercise fatigue attenuated by 30% with Fentanyl-blockade (p<0.05). Conclusion/practice/implicationsAlthough group III/IV muscle afferents play a critical role for central hemodynamics in HF-patients, it also appears that these sensory neurons cause excessive sympatho-excitation impairing QL which likely contributes to the exercise intolerance in this population.

Rapid vasodilation in response to passive leg movement with age: the role of nitric oxide and the impact of perfusion pressure (546.6)

We sought to elucidate the contribution of NO, with and without posture‐induced increases in femoral perfusion pressure (FPP), on the rapid (first 7 sec) vasodilatory response to passive leg movement (PLM) with age. PLM was performed in 8 young (24±1 yrs) and 7 old (75±3 yrs) healthy males, with (blk) and without (ctrl) NO synthase (NOS) inhibition, in both the supine and upright‐seated posture. Peripheral hemodynamic responses were determined with Doppler ultrasound. In the supine posture, NOS inhibition had no effect on the rapid vasodilation (leg vascular conductance slope/time) in either the young (ctrl: 0.78 ± 0.10; blk: 0.71 ± 0.16 ml/min/mmHg/sec; p&gt;0.05) or on the already attenuated response in the old (ctrl: 0.25 ± 0.06; blk: 0.33 ± 0.07 ml/min/mmHg/sec; p&gt;0.05). However, in the upright‐seated posture, which similarly increased FPP in both groups (~7mmHg), NOS inhibition significantly attenuated the posture‐induced augmentation of rapid vasodilation in the young (ctrl: 1.25 ± 0.23; blk: 0.74 ± 0.11 ml/min/mmHg/sec; p&lt;0.05), with no effect in the old (ctrl: 0.38 ± 0.05; blk: 0.26 ± 0.05 ml/min/mmHg/sec; p&gt;0.05). PLM‐induced rapid vasodilation in the supine posture is NO‐independent and this response is attenuated with age. In the young, elevated FPP increases the role of NO in this rapid vasodilatory response, but has no effect in the old, likely due to decreased NO bioavailability in this population.Grant Funding Source: VA Merit Grant E6910R and PPG Grant

Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans (1165.8)

We investigated the influence of aging on the role of group III/IV muscle afferents in determining circulatory responses to physical activity. Six old (OLD; 70 ± 2 years) and 8 young (YNG; 24 ± 2 years) males performed single‐leg knee extensor exercise (14 W / 30 W / 80% max) under control conditions and with lumbar intrathecal fentanyl impairing feedback from µ‐opioid receptor‐sensitive lower limb muscle afferents. Cardiac output (Q), leg perfusion pressure (PP), leg vascular conductance (LVC), and femoral blood flow (QL) were collected continuously. There were no hemodynamic differences between conditions at rest. Fentanyl blockade during exercise did not affect Q in OLD (P=0.2); however, secondary to significant decreases in heart rate and stroke volume, Q was attenuated by ~20% in YNG (P&lt;0.05). Furthermore, in the face of a similar 5‐7% reduction in PP (P&lt;0.05) during exercise with fentanyl blockade in both groups, LVC increased ~13% in OLD, but decreased ~10% in YNG (both P&lt;0.05). The net effect of these blockade‐induced changes was an unaltered QL response to exercise in OLD, contrasting the significant 15‐17% decrease in YNG. In conclusion, healthy aging alters muscle reflex control of autonomic circulatory responses to exercise. While muscle afferent feedback remains critical in regulating PP, their contribution to central (Q) and peripheral (QL) hemodynamic responses might diminish with age.Grant Funding Source: HL_103786; HL‐116579