Limb Vascular Conductance Research Articles

Elevated sympathetic-mediated vasoconstriction at rest but intact functional sympatholysis during exercise in heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) have exaggerated sympathoexcitation and impaired peripheral vascular conductance. Evidence demonstrating consequent impaired functional sympatholysis is limited in HFrEF. This study aimed to determine the magnitude of reduced limb vascular conductance during sympathoexcitation and whether functional sympatholysis would abolish such reductions in HFrEF. Twenty patients with HFrEF and 22 age-matched controls performed the cold pressor test (CPT) [left foot 2-min in -0.5 (1)°C water] alone and with right handgrip exercise (EX + CPT). Right forearm vascular conductance (FVC), forearm blood flow (FBF), and mean arterial pressure (MAP) were measured. Patients with HFrEF had greater decreases in %ΔFVC and %ΔFBF during CPT (both P < 0.0001) but not EX + CPT (P = 0.449, P = 0.199) compared with controls, respectively. %ΔFVC and %ΔFBF decreased from CPT to EX + CPT in patients with HFrEF (both P < 0.0001) and controls (P = 0.018, P = 0.015), respectively. MAP increased during CPT and EX + CPT in both groups (all P < 0.0001). MAP was greater in controls than in patients with HFrEF during EX + CPT (P = 0.025) but not CPT (P = 0.209). In conclusion, acute sympathoexcitation caused exaggerated peripheral vasoconstriction and reduced peripheral blood flow in patients with HFrEF. Handgrip exercise abolished sympathoexcitatory-mediated peripheral vasoconstriction and normalized peripheral blood flow in patients with HFrEF. These novel data reveal intact functional sympatholysis in the upper limb and suggest that exercise-mediated, local control of blood flow is preserved when cardiac limitations that are cardinal to HFrEF are evaded with dynamic handgrip exercise.NEW & NOTEWORTHY Patients with HFrEF demonstrate impaired peripheral blood flow regulation, evidenced by heightened peripheral vasoconstriction that reduces limb blood flow in response to physiological sympathoexcitation (cold pressor test). Despite evidence of exaggerated sympathetic vasoconstriction, patients with HFrEF demonstrate a normal hyperemic response to moderate-intensity handgrip exercise. Most importantly, acute, simultaneous handgrip exercise restores normal limb vasomotor control and vascular conductance during acute sympathoexcitation (cold pressor test), suggesting intact functional sympatholysis in patients with HFrEF.

Dietary nitrate supplementation and small muscle mass exercise hemodynamics in patients with essential hypertension.

Exaggerated blood pressure and diminished limb hemodynamics during exercise in patients with hypertension often are not resolved by antihypertensive medications. We hypothesized that, independent of antihypertensive medication status, dietary nitrate supplementation would increase limb blood flow, decrease mean arterial pressure (MAP), and increase limb vascular conductance during exercise in patients with hypertension. Patients with hypertension either abstained from (n = 14, Off-Meds) or continued (n = 12, On-Meds) antihypertensive medications. Within each group, patients consumed (crossover design) nitrate-rich or nitrate-depleted (placebo) beetroot juice for 3 days before performing handgrip (HG) and knee-extensor exercise (KE). Blood flow and MAP were measured using Doppler ultrasound and an automated monitor, respectively. Dietary nitrate increased plasma-[nitrite] Off-Meds and On-Meds. There were no significant effects of dietary nitrate on blood flow, MAP, or vascular conductance during HG in Off-Meds or On-Meds. For KE, dietary nitrate decreased MAP (means ± SD across all 3 exercise intensities, 118 ± 14 vs. 122 ± 14 mmHg, P = 0.024) and increased vascular conductance (26.2 ± 6.1 vs. 24.7 ± 7.0 mL/min/mmHg, P = 0.024), but did not affect blood flow for Off-Meds, with no effects On-Meds. Dietary nitrate-induced changes in blood flow (r = -0.67, P < 0.001), MAP (r = -0.43, P = 0.009), and vascular conductance (r = -0.64, P < 0.001) during KE, but only vascular conductance (r = -0.35, P = 0.039) during HG, were significantly related to the magnitude of placebo values, with no differentiation between groups. Thus, the effects of dietary nitrate on limb hemodynamics and MAP during exercise in patients with hypertension are dependent on the values at baseline, independent of antihypertensive medication status, and dependent on whether exercise was performed by the forearm or quadriceps.NEW & NOTEWORTHY Adverse hemodynamic responses to exercise in patients with hypertension, despite antihypertensive medication, indicate a sustained cardiovascular risk. The efficacy of dietary nitrate to improve limb vascular conductance during exercise was inversely dependent on the magnitude of exercising limb vascular conductance at baseline, rather than antihypertensive medication status. The effects of dietary nitrate on hemodynamics during exercise in patients with hypertension are dependent on the values at baseline and independent of antihypertensive medication status.

Cardiac Adjustments During a Very Hot and Dry Heatwave Simulation in Older Adults

Heatwaves are the leading cause of death among natural disasters in the United States and are predicted to increase in frequency, duration, and severity. During heatwaves, older adults (over 65 years old) have disproportionally greater morbidity and mortality, primarily from cardiovascular complications. However, it is unknown whether a very hot and dry heat wave simulation would impair cardiac function in older adults.PurposeWe tested the hypothesis that three hours of exposure to a very hot and dry heat wave simulation would increase left‐ventricular contractility (s’) in older adults.MethodsWe assessed internal body temperature (ingestible telemetric pill and/or rectal thermistor), mean skin temperature (thermocouples), cardiac function (echocardiography), limb blood flow (brachial artery sonography) in eight healthy older adults (5 Female/3 Male; 70 ± 4 years; 26 ± 3 kg•m‐2) while they were exposed to a simulation of the 2018 Los Angeles heatwave for three hours. We measured hemodynamics in a temperate environment (~23 ºC) before repeating these measures after three hours of heat exposure in an environmental chamber (46 ± 1 ºC, 17 ± 1 % relative humidity). For ecological validity, participants performed seven bouts of exercise (3 METS for 5 minutes) dispersed across the three‐hour‐long heat exposure to simulate activities of daily living. Additionally, participants consumed 9 mL of 15 ºC (tap‐temperature) water per kilogram of body mass dispersed throughout the trial. We compared values before (BASE) or at the start (START) of heating with values obtained at the end of heating (END) using a Wilcoxon test for propagation velocity, limb blood flow and vascular conductance, and paired, two‐tailed t‐tests for all other variables.ResultsInternal body temperature (START: 36.8 ± 0.4, END: 38.2 ± 0.5 ºC, p&lt;0.01) and mean skin temperature (START: 35.5 ± 1.3, END: 37.3 ± 0.7 ºC, p=0.02) increased during heating. Heart rate increased (BASE: 73 ± 19, END: 99 ± 40 bpm, p=0.04) and mean arterial pressure decreased (BASE: 90 ± 14, END: 77 ± 11 mmHg, p=0.03) during heating. Combined [septal &amp; lateral] s’ (BASE: 8.2 ± 1.4, END: 11.3 ± 1.5 cm/s, p&lt;0.01) increased during heating, for which changes from BASE to END were moderately, but non‐significantly, related to Δ internal body temperature (R2= 0.25, p= 0.21). Indices of left ventricular diastolic function did not change during heating (p&gt;0.24 for E, A, E/A, combined e’, E/combined e’, propagation velocity, &amp; iso‐volumetric relaxation time). Limb blood flow and vascular conductance increased ~four‐fold during heating (p&lt;0.02 for both).ConclusionThese preliminary data suggest that older adults increase left‐ventricular contractility to maintain stroke volume, potentially to compensate for increased limb vascular conductance, during three hours of exposure to a very hot and dry heatwave simulation.

Influence of muscular contraction on vascular conductance during exercise above versus below critical power

We tested the hypothesis that limb vascular conductance (LVC) would increase during the immediate recovery phase of dynamic exercise above, but not below, critical power (CP) indicating a threshold for muscular contraction-induced impedance of limb blood flow (LBF). CP (115 ± 26 W) was determined in 7 men and 7 women who subsequently performed ∼5 min of near-supine cycling exercise both below and above CP. LVC demonstrated a greater increase during immediate recovery and remained significantly higher following exercise above, compared to below, CP (all p < 0.001). Power output was associated with the immediate increases in LVC following exercise above, but not below, CP (p < 0.001; r = 0.85). Additionally, variance in percent LBF impedance was significantly lower above (CV: 10.7 %), compared to below (CV: 53.2 %), CP (p < 0.01). CP appears to represent a threshold above which the characteristics of LBF impedance by muscular contraction become intensity-dependent. These data suggest a critical level of LBF impedance relative to contraction intensity exists and, once attained, may promote the progressive metabolic and neuromuscular responses known to occur above CP.

Racial Differences In Exercising Limb Blood Flow During Elevated Sympathetic Activity

PURPOSE: Young, healthy African Americans (AA) exhibit lower vascular conductance during an exercise bout compared to Caucasian Americans (CA). This disparity may be due to greater sympathetic vasoconstriction and an impairment in functional sympatholysis during exercise in AA. Thus, the purpose of this study is to examine racial differences in vascular conductance during lower limb exercise in the presence of elevated sympathetic activity administered via cold pressor test (CPT). METHODS: A total of 5 African American (AA) and 4 Caucasian (CA) young (24 ± 2 yrs), healthy males were recruited. Subjects then underwent 6 minutes of rhythmic plantar flexion (PF) exercise at 30% of their previously determine maximum voluntary contraction (MVC). Doppler ultrasonography was utilized to measure superficial femoral artery blood flow on the exercising leg while simultaneous measures of mean arterial pressure (MAP) were obtained via finger plethysmography. Subjects underwent the CPT (minutes 4-6) during which the hand was placed in cold water (4 °C) during PF exercise. Measures were obtained during steady state exercise blood flow (measured at minutes 3-4) and during the CPT (measured at minute 5-6) to determine differences in vascular conductance with and without the presence of elevated sympathetic activity. RESULTS: The CPT resulted in similar increases in MAP in both AA (+24.8 ± 3 mmHg) and CA (+25.56 ± 13 mmHg) (p = 0.95) when compared to PF exercise alone. Exercising leg blood flow [AA (-38.89 ± 62 mL/min); CA (+137.97 ± 62 mL/min) (p = .09)] or leg vascular conductance [AA (-1.00 ± .6 mL/min/mmHg); CA (-0.28 ± .4 ml/min/mmHg) (p = .35)] was not different between groups when evaluated during the CPT and expressed as change from PF exercise alone. CONCLUSIONS: This study suggests that during lower limb exercise, young AA males, when compared to CA, are similarly resistant to reductions in lower limb vascular conductance in response to elevated sympathetic activity.

Endothelial Dysfunction following Prolonged Sitting is Mediated by a Reduction in Shear Stress

We and others recently reported that prolonged sitting impairs endothelial function in the leg vasculature; however, the mechanisms remain unknown. Herein, we tested the hypothesis that a sustained reduction in flow induced shear stress is the underlying mechanism by which sitting induces leg endothelial dysfunction. Specifically, we examined whether preventing the reduction in shear stress during sitting would abolish the detrimental effects of sitting on popliteal artery endothelial function. In 9 young healthy men, bilateral measurements of popliteal artery flow‐mediated dilation (FMD) were performed before and after a 3‐hour sitting period during which one foot was submerged in 42°C water (i.e. WETFOOT), while the contralateral leg remained dry and served as internal control (i.e., DRYFOOT). Local heating is an effective stimulus for dilating the skin circulation and increasing limb vascular conductance and thus, shear stress without producing systemic cardiovascular effects. During sitting, popliteal artery mean shear rate was significantly (P&lt;0.05) reduced in the leg of the DRYFOOT (pre sit: 44.1±4.9s−1, post sit: 25.4±3.8s−1) and sustained in the leg of the WETFOOT (pre sit: 39.6±3.7s−1, post sit: 40.7±5.5s−1). Popliteal artery FMD was impaired after 3 hours of sitting in the leg of the DRYFOOT (pre sit: 5.9±0.9% vs. post sit: 2.9±1.0%) but not WETFOOT (pre sit: 7.3±1.7% vs. post sit: 10.6±2.0%). Collectively, these data demonstrate that preventing the reduction of flow induced shear stress during sitting with local heating abolishes the impairment in popliteal artery endothelial function. Thus, a reduction in shear stress mediates sitting‐induced leg endothelial dysfunction.Support or Funding InformationSupport: NIH K01 HL‐125503 and R21 DK‐105368 (JP)

Rapid onset vasodilation with single muscle contractions in the leg: influence of age.

The influence of aging on contraction-induced rapid vasodilation has been well characterized in the forearm. We sought to examine the impact of aging on contraction-induced rapid vasodilation in the leg following single muscle contractions and determine whether potential age-related impairments were similar between limbs (leg vs. arm). Fourteen young (23 ± 1 years) and 16 older (66 ± 1 years) adults performed single leg knee extensions at 20%, 40%, and 60% of work rate maximum. Femoral artery diameter and blood velocity were measured using Doppler ultrasound. Limb vascular conductance (VC) was calculated using blood flow (mL·min−1) and mean arterial pressure (mmHg). Peak and total vasodilator responses in the leg (change [Δ] in VC from baseline) were blunted in older adults by 44–50% across exercise intensities (P < 0.05 for all). When normalized for muscle mass, age-related differences were still evident (P < 0.05). Comparing the rapid vasodilator responses between the arm and the leg of the same individuals at similar relative intensities (20% and 40%) reveals that aging influences peak and total vasodilation equally between the limbs (no significant age × limb interaction at either intensity, P = 0.28–0.80). Our data demonstrate that (1) older adults exhibit an attenuated rapid hyperemic and vasodilator response in the leg; and (2) the age-related reductions in rapid vasodilation are similar between the arm and the leg. The mechanisms contributing to the age-related differences in contraction-induced rapid vasodilation are perhaps similar to those seen with the forearm model, but have not been confirmed.

Rapid Onset Vasodilation is Blunted with Aging: Evidence for Limb Specificity?

We aimed to examine the impact of aging on rapid onset vasodilation (ROV) in the leg following single muscle contractions. Young (n=14; 23±1yr; 9M/5F) and older (n=14; 66±1yr; 10M/4F) adults performed single muscle contractions at 20%, 40%, and 60% work rate maximum for knee extension. Diameter and blood velocity were measured in the femoral artery using Doppler ultrasound. Limb vascular conductance (VC) was calculated using blood flow (mL/min), mean arterial pressure (mmHg) and normalized for muscle mass (kg). Older adults demonstrated lower peak and total contraction‐induced vasodilation in the leg across exercise intensities compared to young adults (P &lt; 0.001). To explore limb specific differences, leg responses at 20% and 40% were compared to single contractions of the forearm (handgrip) within each subject. At 20%, both older and young adults had a higher ΔVC in the arm vs leg (Older: 90±7 vs. 49±4 mL/kg/min/100mmHg, P &lt; 0.01; Young: 123±7 vs. 94±10 mL/kg/min/100mmHg, P &lt; 0.05). Similarly, a higher ΔVC in the arm vs. leg was also observed at 40% in older and young adults (Older: 126 ± 9 vs. 62±5 mL/kg/min/100mmHg, P &lt; 0.01; Young: 168±11 vs. 109±10 mL/kg/min/100mmHg, P &lt; 0.05). Our data demonstrate that 1) aging blunts skeletal muscle contraction‐induced ROV in the leg and 2) when normalized for muscle mass, both young and older adults demonstrate a greater ROV in the arm compared to the leg.

Respiratory influences on muscle sympathetic nerve activity and limb vascular conductance in the steady‐state

BackgroundIn patients with hypertension, volitional slowing of the respiratory rate has been purported to reduce arterial pressure via withdrawal of sympathetic tone.MethodsWe examined the effects of paced breathing at 7, 14, and 21 breaths per minute with reciprocal changes in tidal volume, on blood pressure, muscle sympathetic nerve activity, forearm blood flow, and forearm vascular conductance in 21 adults (8 F/13 M, 36±14 years).ResultsAlterations in breathing frequency and tidal volume did not affect steady‐state levels of blood pressure, sympathetic activity, blood flow, or vascular conductance (all p&gt;;0.05) despite a frequency‐dependent alteration in within‐breath modulation of sympathetic outflow (i.e. increased modulation during low frequency/high volume breathing) (p=0.000). These findings were consistent across wide ranges of: 1) resting blood pressure, 2) baseline sympathetic activity, 3) cardiovascular disease risk factors.ConclusionResults from the current study challenge the notion that slow, deep breathing lowers arterial pressure by suppressing average sympathetic outflow and calls into question the concept that changes in sympathetic activity via volitional slowing of the respiratory rate is potentially beneficial in the treatment of hypertension. Support: AHA 10PRE3870000(JKL), NIH R01HL105820(WGS), NIH R01HL15469(JAD)

Repeatability of popliteal blood flow and lower limb vascular conductance at rest and exercise during body tilt using Doppler ultrasound

We tested the data repeatability for popliteal blood flow velocity (PBV), popliteal arterial diameter (ADpop), popliteal blood flow (PBF) and lower limb vascular conductance (VC) at rest and exercise in three body positions, two work rates and two inspired oxygen fractions. Fifteen, eleven and ten healthy volunteers participated in the three phases of the studies. Resting protocols were performed in horizontal (HOR), 35° head-down tilt (HDT) and 45° head-up tilt (HUT) for 5 min in each body position. Participants also exercised at lower and higher power outputs (repeated plantar flexion contractions at 20% and 30% maximal voluntary contraction, respectively) in HOR, HDT and HUT and in normoxia (21%O2) and hypoxia (14%O2) with the same work rates and body positions. PBV and ADpop were measured by ultrasound to determine PBF, and VC was estimated by dividing PBF by muscle perfusion pressure (MPP). PBV, ADpop, PBF and VC were not different, demonstrated good agreement and consistency between the two days of testing during both rest and exercise conditions regardless of body position. Therefore, these data support the utilization of Doppler and echo Doppler ultrasound as a reproducible method to measure PBV and ADpop and consequently estimate PBF and VC responses in such conditions.

Lower limb vascular conductance and resting popliteal blood flow during head‐up and head‐down postural challenges

This study hypothesized that central and local reflex mechanisms affecting vascular conductance (VC) through the popliteal artery compensated for the reduction in muscle perfusion pressure (MPP) to maintain popliteal blood flow (PBF) during head-down tilt (35˚ HDT), but not in head-up tilt (45˚ HUT). Resting measurements were made on 15 healthy men in prone position to facilitate the access to the popliteal artery, on two separate days in random order during horizontal (HOR), HDT or HUT. In each body position, the body was supported, and the ankles were maintained in relaxed state so that there was no muscle tension, as with normal standing. Popliteal blood flow velocity and popliteal arterial diameter were measured by ultrasound, and PBF was calculated. MPP was corrected to mid-calf from measured finger cuff pressure, and VC was estimated by dividing PBF by MPP. The MPP in HDT (48±2mmHg) was ~100mmHg less than in HUT (145±2mmHg). PBF was similar between HOR (51±18ml() min(-1) ) and HDT (47±13mlmin(-1) ), but was lower in HUT (30±9mlmin(-1) ). VC was different between HDT (1·0±0·3mlmin(-1) mmHg(-1) ), HOR (0·6±0·2ml min(-1) mmHg(-1) ) and HUT (0·2±0·1mlmin(-1) mmHg(-1) ). In conclusion, the interactions of central and local regulatory mechanisms resulted in a disproportionate reduction of VC during HUT lowering PBF even though MPP was higher, while in HDT, increased VC contributed to maintain PBF at the same level as the HOR control condition.

New perspectives concerning feedback influences on cardiorespiratory control during rhythmic exercise and on exercise performance

The cardioaccelerator and ventilatory responses to rhythmic exercise in the human are commonly viewed as being mediated predominantly via feedforward 'central command' mechanisms, with contributions from locomotor muscle afferents to the sympathetically mediated pressor response. We have assessed the relative contributions of three types of feedback afferents on the cardiorespiratory response to voluntary, rhythmic exercise by inhibiting their normal 'tonic' activity in healthy animals and humans and in chronic heart failure. Transient inhibition of the carotid chemoreceptors during moderate intensity exercise reduced muscle sympathetic nerve activity (MSNA) and increased limb vascular conductance and blood flow; and reducing the normal level of respiratory muscle work during heavier intensity exercise increased limb vascular conductance and blood flow. These cardiorespiratory effects were prevented via ganglionic blockade and were enhanced in chronic heart failure and in hypoxia. Blockade of μ opioid sensitive locomotor muscle afferents, with preservation of central motor output via intrathecal fentanyl: (a) reduced the mean arterial blood pressure (MAP), heart rate and ventilatory responses to all steady state exercise intensities; and (b) during sustained high intensity exercise, reduced O(2) transport, increased central motor output and end-exercise muscle fatigue and reduced endurance performance. We propose that these three afferent reflexes - probably acting in concert with feedforward central command - contribute significantly to preserving O(2) transport to locomotor and to respiratory muscles during exercise. Locomotor muscle afferents also appear to provide feedback concerning the metabolic state of the muscle to influence central motor output, thereby limiting peripheral fatigue development.

Nitric oxide and passive limb movement: a new approach to assess vascular function

Passive limb movement elicits a robust increase in limb blood flow (LBF) and limb vascular conductance (LVC), but the peripheral vascular mechanisms associated with this increase in LBF and LVC are unknown. This study sought to determine the contribution of nitric oxide (NO) to movement-induced LBF and LVC and document the potential for passive-limb movement to assess NO-mediated vasodilatation and therefore NO bioavailability. Six subjects underwent passive knee extension with and without nitric oxide synthase (NOS) inhibition via intra-arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA). LBF was determined second-by-second by Doppler ultrasound, and central haemodynamics were measured by finger photoplethysmography. Although L-NMMA did not alter the immediate increase (initial ∼9 s) in LBF and LVC, NOS blockade attenuated the peak increase in LBF (control: 653 ± 81; L-NMMA: 399 ± 112 ml(−1) min(−1), P = 0.03) and LVC (control: 7.5 ± 0.8; L-NMMA: 4.1 ± 1.1 ml min(−1) mmHg(−1), P = 0.02) and dramatically reduced the overall vasodilatory and hyperaemic response (area under the curve) by nearly 80% (LBF: control: 270 ± 51; L-NMMA: 75 ± 32 ml, P = 0.001; LVC: control: 2.9 ± 0.5; L-NMMA: 0.8 ± 0.3 ml mmHg(−1), P < 0.001). Passive movement in control and L-NMMA trials evoked similar increases in heart rate, stroke volume, cardiac output and a reduction in mean arterial pressure. As movement-induced increases in LBF and LVC are predominantly NO dependent, passive limb movement appears to have significant promise as a new approach to assess NO-mediated vascular function, an important predictor of cardiovascular disease risk.

Is tonic sympathetic vasoconstriction increased in the skeletal muscle vasculature of aged canines?

We tested the hypothesis that tonic adrenergic and nonadrenergic receptor-mediated sympathetic vasoconstriction would increase at rest and during exercise with advancing age. Young (n = 6; 22 ± 1 mo; means ± SE) and old (n = 6; 118 ± 9 mo) beagles were studied. Selective antagonists for alpha-1, alpha-2, neuropeptide Y (NPY), and purinergic (P(2x)) receptors were infused at rest and during treadmill running at 2.5 mph and 4 mph with 2.5% grade. Prazosin produced similar increases in vascular conductance in young and old beagles at rest (Young: 158 ± 34%; Old: 98 ± 19%) and during exercise at 2.5 mph (Young: 80 ± 10%; Old: 58 ± 12%) and 4 mph and 2.5% grade (Young: 57 ± 5%; Old: 26 ± 4%). Rauwolscine caused similar (P > 0.05) increases in vascular conductance in old compared with young dogs at rest (Young: 119 ± 25%; Old: 64 ± 22%) and at 2.5 mph (Young: 86 ± 13%; Old: 60 ± 7%) and 4 mph with 2.5% grade (Young: 61 ± 5%; Old: 43 ± 7%). N2-(diphenylacetyl)-N-[4-hydroxyphenyl)methyl]-d-arginine amide (BIBP) caused a smaller increase (P < 0.05) in vascular conductance in old compared with young dogs at rest (Young: 179 ± 44%; Old: 91 ± 22%), whereas similar increases (P > 0.05) of experimental limb vascular conductance in young and old dogs occurred following BIBP during exercise at 2.5 mph (Young: 56 ± 16%; Old: 50 ± 12%) and 4 mph and 2.5% grade (Young: 45 ± 10%; Old: 25 ± 7%). Pyridoxal-phosphate-6-azophenyl-2'-4'-disulfonic acid infusion produced a larger increase in vascular conductance in old compared with young beagles at rest (Young: 88 ± 14%; Old: 191 ± 58%), whereas similar increases were observed at 2.5 mph (Young: 47 ± 18%; Old: 31 ± 11%) and 4 mph with 2.5% grade (Young: 26 ± 13%; Old: -18 ± 8%). At rest, NPY receptor-mediated restraint of skeletal muscle blood flow was reduced with advancing age, whereas P(2x) receptor-mediated restraint of skeletal muscle blood flow was increased. During exercise, the magnitude of adrenergic and nonadrenergic sympathetic vasoconstriction was not different between young and old dogs. Overall, these data demonstrate that adrenergic receptor-mediated vasoconstriction was not elevated at rest, but nonadrenergic sympathetic vasoconstriction was altered under basal conditions in aged beagles.

Cardiorespiratory responses to exercise in CHF: a conspiracy of maladaptation

Chronic heart failure (CHF) patients have markedly impaired exercise performance in the face of reduced cardiac output, augmented sympathetically mediated systemic vasoconstriction and an excessive hyperventilation secondary to inefficient pulmonary gas exchange and excessive drive to breathe. Olson et al. in a recent article in The Journal of Physiology (Olson et al. 2010) have now shed light on this complex, maladaptive response in CHF by demonstrating that these patients experienced marked increases in stroke volume and cardiac output, and in limb vascular conductance and blood flow, during submaximal exercise when their work of breathing (WOB) was reduced via a mechanical ventilator (MV). There is much to be admired in their experimental design, including use of thermal dilution measures of limb blood flow and oesophageal pressures to quantify WOB. Furthermore, the use of MV to unload the respiratory muscles served to unmask the cardiovascular effects of the normally occurring excessive WOB in these difficult-to-study patients. The increased limb vascular conductance with respiratory muscle unloading is similar in direction (but smaller in magnitude) to that reported in healthy athletes; however, in the CHF patients this effect occurred at only 60% maximum exercise, whereas in health, near-maximum exercise was required to produce sufficient WOB to elicit any cardiovascular effects of respiratory muscle unloading (Dempsey et al. 2006). The augmented stroke volume (SV) and cardiac output observed with reduced inspiratory negative pleural pressure in CHF is opposite in direction to that reported in healthy humans and animals, apparently reflecting a critical dependency of SV on ventricular preload in health and on after-load in CHF. If the observed increase in limb blood flow with unloading does indeed imply a ‘steal’ of flow from the limbs by the diaphragm (which to date has been reported only in a rodent model of CHF), then this shift would probably require (a) activation of respiratory muscle metaboreflexes acting via type III–IV phrenic afferents (Dempsey et al. 2006) for feedback regulation of sympathetic vasoconstrictor outflow, plus (b) a marked difference in vasoconstrictor sensitivity of phrenic arterioles vs. those in limb musculature in response to noradrenaline (norepinephrine) (Aaker & Laughlin, 2002). However, we should not presume that the diaphragm is receiving all of the blood flow it requires during whole body exercise; to the contrary, the diaphragm fatigues during high intensity endurance exercise, but does not fatigue when the same high WOB is sustained voluntarily in a resting subject (Dempsey et al. 2006). These data imply that a strong competition for blood flow between respiratory and limb skeletal muscles does indeed prevail during exercise of heavy intensity. Studies are now required to provide more direct evidence of how alterations in the work of breathing alter this flow distribution between locomotor muscles and those of the chest and abdominal wall during exercise. We also need to determine the mechanisms responsible for activation of respiratory muscle metaboreflexes and, in turn, selective sympathetically mediated vasoconstriction. There are several potential sources of the augmented drive to breathe in CHF. Recent findings in animal models of CHF report upregulation at the level of the carotid chemoreceptor as a key source of both augmented ventilatory and sympathetic drives both at rest (Ding et al. 2008) and especially during exercise (Stickland et al. 2007). One of the links of WOB to limb blood flow and in turn, to exercise performance may be found in the reduced exercise-induced quadriceps fatigue obtained when WOB was reduced via MV during near-maximum exercise in health and during sub-maximum exercise in hypoxia or in patients with chronic obstructive pulmonary disease (COPD) (Amann et al. 2010). In turn, a clinical implication of Olson et al.'s findings would be the use of respiratory muscle unloading together with supplemental O2 in rehabilitation of exercising CHF patients, in order to reduce sympathetic vasoconstriction and effort perception, thereby promoting increased work rates and allowing a greater locomotor muscle training effect to be achieved. Finally it is common clinical practice to contrast an exercising patient's specific perceptions of dyspnoea vs. those of limb muscle discomfort to identify the source of exercise performance limitation (i.e. respiratory vs. limb muscle). However, given the dependence of limb blood flow and O2 transport, fatigue and effort perception on the work of breathing as shown by Olson et al. and in related studies (Dempsey et al. 2006; Amann et al. 2010), this practice is likely to be highly misleading.

The oxygen delivery response to acute hypoxia during incremental knee extension exercise differs in active and trained males

BackgroundIt is well known that hypoxic exercise in healthy individuals increases limb blood flow, leg oxygen extraction and limb vascular conductance during knee extension exercise. However, the effect of hypoxia on cardiac output, and total vascular conductance is less clear. Furthermore, the oxygen delivery response to hypoxic exercise in well trained individuals is not well known. Therefore our aim was to determine the cardiac output (Doppler echocardiography), vascular conductance, limb blood flow (Doppler echocardiography) and muscle oxygenation response during hypoxic knee extension in normally active and endurance-trained males.MethodsTen normally active and nine endurance-trained males (VO2max = 46.1 and 65.5 mL/kg/min, respectively) performed 2 leg knee extension at 25, 50, 75 and 100% of their maximum intensity in both normoxic and hypoxic conditions (FIO2 = 15%; randomized order). Results were analyzed with a 2-way mixed model ANOVA (group × intensity).ResultsThe main finding was that in normally active individuals hypoxic sub-maximal exercise (25 – 75% of maximum intensity) brought about a 3 fold increase in limb blood flow but decreased stroke volume compared to normoxia. In the trained group there were no significant changes in stroke volume, cardiac output and limb blood flow at sub-maximal intensities (compared to normoxia). During maximal intensity hypoxic exercise limb blood flow increased approximately 300 mL/min compared to maximal intensity normoxic exercise.ConclusionCardiorespiratory fitness likely influences the oxygen delivery response to hypoxic exercise both at a systemic and limb level. The increase in limb blood flow during maximal exercise in hypoxia (both active and trained individuals) suggests a hypoxic stimulus that is not present in normoxic conditions.

Restrictions in systemic and locomotor skeletal muscle perfusion, oxygen supply andVO2during high‐intensity whole‐body exercise in humans

Perfusion to exercising skeletal muscle is regulated to match O(2) delivery to the O(2) demand, but this regulation might be compromised during or approaching maximal whole-body exercise as muscle blood flow for a given work rate is blunted. Whether muscle perfusion is restricted when there is an extreme metabolic stimulus to vasodilate during supramaximal exercise remains unknown. To examine the regulatory limits of systemic and muscle perfusion in exercising humans, we measured systemic and leg haemodynamics, O(2) transport, and , and estimated non-locomotor tissue perfusion during constant load supramaximal cycling (498 +/- 16 W; 110% of peak power; mean +/- S.E.M.) in addition to both incremental cycling and knee-extensor exercise to exhaustion in 13 trained males. During supramaximal cycling, cardiac output (Q), leg blood flow (LBF), and systemic and leg O(2) delivery and reached peak values after 60-90 s and thereafter levelled off at values similar to or approximately 6% (P < 0.05) below maximal cycling, while upper body blood flow remained unchanged (approximately 5.5 l min(-1)). In contrast, Q and LBF increased linearly until exhaustion during one-legged knee-extensor exercise accompanying increases in non-locomotor tissue blood flow to approximately 12 l min(-1). At exhaustion during cycling compared to knee-extensor exercise, Q, LBF, leg vascular conductance, leg O(2) delivery and leg for a given power were reduced by 32-47% (P < 0.05). In conclusion, locomotor skeletal muscle perfusion is restricted during maximal and supramaximal whole-body exercise in association with a plateau in Q and limb vascular conductance. These observations suggest that limits of cardiac function and muscle vasoconstriction underlie the inability of the circulatory system to meet the increasing metabolic demand of skeletal muscles and other tissues during whole-body exercise.

Sex differences in leg vasodilation during graded knee extensor exercise in young adults

Limb vascular conductance responses to pharmacological and nonexercise vasodilator stimuli are generally augmented in women compared with men. In the present investigation, we tested the hypothesis that exercise-induced vasodilator responses are also greater in women than men. Sixteen women and 15 men (20-30 yr) with similar fitness and activity levels performed graded quadriceps exercise (supine, single-leg knee extensions, 40 contractions/min) to maximal exertion. Active limb hemodynamics (left common femoral artery diameter and volumetric blood flow), heart rate (ECG), and beat-to-beat mean arterial blood pressure (MAP; radial artery tonometry) were measured during each 3-min workload (4.8 and 8 W/stage for women and men, respectively). The hyperemic response to exercise (slope of femoral blood flow vs. workload) was greater (P < 0.01) in women as was femoral blood flow at workloads >15 W. The leg vasodilatory response to exercise (slope of calculated femoral vascular conductance vs. absolute workload) was also greater in women than in men (P < 0.01) because of the sex difference in hyperemia and the women's lower MAP ( approximately 10-15 mmHg) at all workloads (P < 0.05). The femoral artery dilated to a significantly greater extent in the women ( approximately 0.5 mm) than in the men ( approximately 0.1 mm) across all submaximal workloads. At maximal exertion, femoral vascular conductance was lower in the men (men, 18.0 +/- 0.6 ml.min(-1)xmmHg(-1); women, 22.6 +/- 1.4 mlxmin(-1)xmmHg(-1); P < 0.01). Collectively, these findings suggest that the vasodilatory response to dynamic leg exercise is greater in young women vs. men.

Age and regional specificity of peak limb vascular conductance in women

The influence of age on limb vasodilator capacity in women is unclear. The objectives of this study were to characterize and compare age-associated changes in forearm and calf peak vascular conductance (VC(peak); a functional index of arterial structure) in women and to identify physiological characteristics predictive of variation in limb-specific VC(peak). Peak conductance (plethysmographic flow/mean arterial pressure), VC(peak) of the forearm (forearm VC(peak)), and calf (calf VC(peak)) after 10 min of arterial occlusion were measured in 58 healthy, normally active women aged 21-79 yr. Aerobic capacity (cycle peak oxygen uptake), arterial health (pulse-wave velocity, ankle-brachial index), total cholesterol, limb-specific tissue composition (dual-energy X-ray absorptiometry), and isometric strength (handgrip, plantar flexion) were also assessed. The relative decline in calf VC(peak) with age (-6.8% per decade, P < 0.001) was greater than the forearm (-4.4% per decade, P = 0.004), in contrast to results previously reported for men (forearm decline > calf decline). Limb VC(peak) per kilogram muscle declined with age in the calf (-6.0% per decade; P = 0.002), but not the forearm (P = 0.12). Age, cholesterol, and regional tissue composition were significant predictors of peak conductance in both limbs; however, age was a stronger predictor of peak conductance in the calf. These results suggest that healthy aging is associated with a linear decline in limb vasodilator capacity in women, but the magnitude of this effect is region specific. Further research will be required to determine whether the decline in lower extremity vasodilator capacity with age explains diminished exercising leg vasodilation in older women.

The time course and direction of lower limb vascular conductance changes during voluntary and electrically evoked isometric exercise of the contralateral calf muscle in man.

This study aimed to clarify the direction and timing of the change of non-active lower limb vascular conductance at the onset of contralateral limb isometric exercise and to examine the mechanisms controlling this change. Fifteen human subjects performed 2 min of electrically evoked (Stim) or voluntary (Vol) ischaemic isometric calf plantar flexor exercise at 30 % maximum voluntary contraction (MVC). Blood pressure (BP) and heart rate were continuously recorded and blood flow in the non-active contralateral lower limb was recorded at 15 s intervals. In subsets of subjects the presence of inadvertent muscle contraction was monitored by calf muscle EMG and the effects of the sensation of electrical stimulation without muscle contraction (sham) were investigated. After 10-15 s conductance had increased significantly (P < 0.05) in Vol and Stim by a mean of 15 and 12 %, respectively, whilst BP was unchanged. Following this initial increase conductance decreased progressively during Stim and Vol whilst blood pressure rose. No EMG activity was seen during either protocol. In the sham stimulation experiments where no contraction was evoked the conductance change at the onset of stimulation replicated that seen during Stim exercise. Increases in conductance were independent of central command and muscle force generation, were not activated in anticipation of exercise but could be activated secondarily to peripheral sensations associated with expected exercise. The explanation for our results might involve sympathetic withdrawal related to mental stress; however, a central pathway, which directly activates a vasodilator mechanism in passive calf muscle, remains a possibility.