Blood flow to exercising limbs varies with age, gender, and training status.

Understanding the effects of physiological aging on blood flow to active skeletal muscle and its regulation during exercise has important functional, hemodynamic, and metabolic implications for our rapidly expanding elderly population. During peak exercise involving a large muscle mass, blood flow to the legs is lower in healthy older compared to younger persons; this results from central (reduced cardiac output) and peripheral (reduced leg vascular conductance) limitations. There is considerable variability in the literature concerning age-related changes in leg blood flow during submaximal exercise, with reports of similar or reduced leg blood flow and vascular conductance in older vs. younger subjects depending on the exercise intensity and the gender and training status of the subjects. However, all the studies involving non-endurance-trained subjects are consistent in that older subjects achieve the requisite leg blood flow at higher arterial perfusion pressures than young subjects, suggesting altered local vasoregulatory mechanisms with aging. Although the nature of these age-related alterations is poorly understood, we have preliminary evidence for augmented sympathetic vasoconstrictor responsiveness in the legs of older men during exercise, and blunted leg vasodilator responsiveness in older women. Systematic research will be needed in order to define the central and local mechanisms underlying these age- and gender-specific differences in muscle vascular responsiveness. Such information will be important for designing future interventions aimed at improving muscle blood supply and functional capacity in older persons.     

Carotid baroreflex control of leg vasculature in exercising and non-exercising skeletal muscle in humans

Carotid baroreflex (CBR) function was examined in five men and three women (25 ± 1 years) using the variable-pressure neck collar technique at rest and during dynamic, one-legged knee extension exercise at 7 W and 25 W. The CBR exhibited control of leg vascular conductance (LVC) at rest and during exercise in both an exercising leg (EL) and a non-exercising leg (NEL) across a wide range of pressures from +40 Torr neck pressure (NP) to −80 Torr neck suction (NS). Specifically, increases in LVC (% change) in response to NS were no different across −20 to −80 Torr in either EL or NEL compared to rest, P > 0.05. However, CBR-mediated decreases in percentage LVC in response to NP were attenuated in EL at both 7 W (16 ± 1%) and 25 W (12 ± 1%) compared to rest (40 ± 3%; P < 0.05) as well as compared to responses in the NEL (36 ± 6% at 7 W and 36 ± 7% at 25 W; P < 0.05). This decrease in vascular responsiveness in EL was associated with a reduction in the gain of the percentage muscle sympathetic nerve activity (%MSNA)–%LVC relationship compared to rest ( P < 0.05). Collectively, these data indicate that, despite a clear attenuation of the vascular response to MSNA in the exercising leg, CBR-mediated changes in mean arterial pressure were no different between rest and exercise.     

Inhibition of KATP channel activity augments baroreflex-mediated vasoconstriction in exercising human skeletal muscle

In the present investigation we examined the role of ATP-sensitive potassium (K_ATP) channel activity in modulating carotid baroreflex (CBR)-induced vasoconstriction in the vasculature of the leg. The CBR control of mean arterial pressure (MAP) and leg vascular conductance (LVC) was determined in seven subjects (25 ± 1 years, mean ± s.e.m. ) using the variable-pressure neck collar technique at rest and during one-legged knee extension exercise. The oral ingestion of glyburide (5 mg) did not change mean arterial pressure (MAP) at rest (86 versus 89 mmHg, P > 0.05), but did appear to increase MAP during exercise (87 versus 92 mmHg, P = 0.053). However, the CBR–MAP function curves were similar at rest before and after glyburide ingestion. The CBR-mediated decrease in LVC observed at rest (∼39%) was attenuated during exercise in the exercising leg (∼15%, P < 0.05). Oral glyburide ingestion partially restored CBR-mediated vasoconstriction in the exercising leg (∼40% restoration, P < 0.05) compared to control exercise. These findings indicate that K_ATP channel activity modulates sympathetic vasoconstriction in humans and may prove to be an important mechanism by which functional sympatholysis operates in humans during exercise.     

Augmented sympathetic vasoconstriction in exercising forearms of postmenopausal women is reversed by oestrogen therapy

Sympathetic vasoconstriction is normally attenuated in exercising muscles of young men and women. Recent evidence indicates that such modulation, termed functional sympatholysis, may be impaired in older men. Whether a similar impairment occurs in older women, and what role oestrogen deficiency might play in this impairment, are not known. Based on the strong positive correlation between circulating oestrogen levels and functional sympatholysis previously reported in female rats, we hypothesized that sympatholysis would be impaired in oestrogen-deficient postmenopausal women, and that this impairment would be reversed by oestrogen replacement. To test these hypotheses, we measured vasoconstrictor responses in the forearms of pre- and postmenopausal women using near infrared spectroscopy to detect decreases in muscle oxygenation in response to reflex activation of sympathetic nerves evoked by lower body negative pressure (LBNP). In eight premenopausal women, LBNP decreased muscle oxygenation by 20 ± 1% in resting forearm, but only by 3 ± 2% in exercising forearm  ( P < 0.05)  . In contrast, in eight postmenopausal women, LBNP decreased muscle oxygenation by 15 ± 3% in resting forearm, and by 12 ± 4% in exercising forearm  ( P > 0.05)  . After 1 month of transdermal oestradiol replacement in these women, the normal effect of exercise to blunt sympathetic vasoconstriction was restored (rest, −19 ± 3%; exercise, −2 ± 3%;   P < 0.05  ). These data indicate that functional sympatholysis is impaired in oestrogen-deficient postmenopausal women. The effect of short-term unopposed oestrogen replacement to correct this impairment implicates a role for oestrogen in the sympathetic neural control of muscle haemodynamics during exercise.     

Exercise-induced inhibition of angiotensin II vasoconstriction in human thigh muscle

It is well established that metabolic inhibition of adrenergic vasoconstriction contributes to the maintenance of adequate perfusion to exercising skeletal muscle. However, little is known regarding nonadrenergic vasoconstriction during exercise. We tested the hypothesis that a non-adrenergic vasoconstrictor, angiotensin II (AngII), would be less sensitive to metabolic inhibition than an α₁-agonist, phenylephrine (PE), in the exercising human thigh. In 11 healthy men, femoral blood flow (FBF, ultrasound Doppler and thermodilution) and blood pressure were evaluated during wide-ranging doses of intra-arterial (femoral) infusions of PE and AngII at rest and during two workloads of steady-state knee-extensor exercise (7 W and 27 W). At rest, the maximal decrease in femoral artery diameter (FAD) during AngII (9.0 ± 0.2 to 8.4 ± 0.4 mm) was markedly less than during PE (9.0 ± 0.3 to 5.7 ± 0.5 mm), whereas maximal reductions in FBF and femoral vascular conductance (FVC) were similar during AngII (FBF: −65 ± 6 and FVC: −66 ± 6%) and PE (−57 ± 5 and −59 ± 4%). During exercise, FAD was not changed by AngII, but moderately decreased by PE. The maximal reductions in FBF and FVC were blunted during exercise compared to rest for both AngII (7 W: −28 ± 5 and −40 ± 5%; 27 W: −15 ± 4% and −29 ± 5%) and PE (7 W: −30 ± 4 and −37 ± 6%; 27 W: −15 ± 2 and −24 ± 6%), with no significant differences between drugs. The major new findings are (1) an exercise-induced intensity-dependent metabolic attenuation of non-adrenergic vasoconstriction in the human leg; and (2) functional evidence that AngII-vasoconstriction is predominantly distal, whereas α₁-vasoconstriction is proximal and distal within the muscle vascular bed of the human thigh.     

Noradrenaline spillover during exercise in active versus resting skeletal muscle in man

Increases in plasma noradrenaline (NA) concentration occur during moderate to heavy exercise in man. This study was undertaken to examine the spillover of NA from both resting and contracting skeletal muscle during exercise. Six male subjects performed one-legged knee-extension so that all measurements could be made both in the exercising and in the resting leg. Subjects exercised for 10 min at each of 50% and 100% of the peak performance capacity of the leg. Leg blood flow was measured by thermodilution and blood samples were drawn for the determination of plasma NA and adrenaline, first in the resting leg and then in the exercising leg. To calculate NA spillover, the extraction of NA (NAe) or of adrenalin (Ae) is required: NAe was measured by repeating the experiment under constant [3H]NA infusion following a 40-min rest period. During exercise, NA spillover was significantly larger in the exercising leg than in the resting leg both during 50% and 100% leg exercise. These results suggest that contracting skeletal muscle may contribute to a larger extent than resting skeletal muscle to increasing the level of plasma NA during exercise. Contractile activity may influence the NA spillover from skeletal muscle by a presynaptic and/or postsynaptic influence on the sympathetic nervous activity to this tissue.     

Arm Blood Flow and Oxygenation on the Transition from Arm to Combined Arm and Leg Exercise in Humans

The cardiovascular response to exercise with several groups of skeletal muscle implies that work with the legs may reduce arm blood flow. This study followed arm blood flow ( _arm) and oxygenation on the transition from arm cranking (A) to combined arm and leg exercise (A+L). Seven healthy male subjects performed A at ∼80 % of maximum work rate ( W _max) and A at ∼80 % W _max combined with L at ∼60 % W _max. A transition trial to volitional exhaustion was performed where L was added after 2 min of A. The _arm was determined by constant infusion thermodilution in the axillary vein and changes in biceps muscle oxygenation were measured with near-infrared spectroscopy. During A+L _arm was lowered by 0.38 ± 0.06 l min⁻¹ (10.4 ± 3.3 %,   P < 0.05  ) from 2.96 ± 1.54 l min⁻¹ during A. Total (HbT) and oxygenated haemoglobin (HbO₂) concentrations were also lower. During the transition from A to A+L _arm decreased by 0.22 ± 0.03 l min⁻¹ (7.9 ± 1.8 %,   P < 0.05  ) within 9.6 ± 0.2 s, while HbT and HbO₂ decreased similarly within 30 ± 2 s. At the same time mean arterial pressure and arm vascular conductance also decreased. The data demonstrate reduction in blood flow to active skeletal muscle during maximal whole body exercise to a degree that arm oxygen uptake and muscle tissue oxygenation are compromised.     

Protective role of sympathetic nerve activity to exercising skeletal muscle in the regulation of capillary pressure and fluid filtration

This study describes the integrated sympathetic/metabolic control of capillary pressure (Pc) and filtration in cat skeletal muscle as studied during graded exercise and superimposed graded (2, 6 and 16 Hz) vasoconstrictor nerve excitation. The applied technique permitted simultaneous analysis of the underlying changes of resistance in the whole vascular bed (RT) and in its large-bore arterial resistance vessels (greater than 25 microns), small arterioles (less than 25 microns) and veins. Graded exercise per se caused graded increases in capillary pressure, which at heavy work exceeded the resting control value by 12.2 mmHg, in turn leading to marked loss of plasma fluid by filtration. Sympathetic nerve stimulation was much more efficient in lowering capillary pressure during exercise than at rest, in spite of an exercise-induced marked attenuation of the vasoconstrictor response (RT). The sympathetically evoked capillary pressure fall per unit resistance increase was larger the greater the degree of exercise vasodilation, implying a highly nonlinear relation between capillary pressure and RT and also between the more direct determinant of capillary pressure the post- to precapillary resistance ratio, and RT. Strenuous exercise in vivo is known to be associated with a markedly increased reflex sympathetic discharge to exercising muscle which has been a puzzling feature in view of its untoward restriction of the exercise hyperaemia response. To the extent the present results are representative for this in vivo situation, they suggest that sympathetic discharge to exercising muscle, in spite of some flow restricting effect, might serve a highly beneficial function, causing effective protection against excessive work-induced rise of capillary pressure and harmful plasma fluid loss into the extravascular space of working muscle.     

Onset exercise hyperaemia in humans: partitioning the contributors

Using a step-wise, reductionist approach we characterized the time course and degree to which mechanical, vasodilatory and cardiac mechanisms contribute to the increase in leg blood flow (LBF) at the onset of dynamic knee-extensor exercise. Heart rate (HR) and LBF (ultrasound Doppler) were evaluated during (1) voluntary and (2) passive exercise in the seated position, (3) passive exercise in the supine position with the leg above the heart, and (4) passive exercise with measurements made in the non-moving leg. In trials 2 and 3, the degree of change and time course of peak ΔHR (8.7 ± 2 bpm, seated; 10 ± 1 bpm, supine) and peak ΔLBF (518 ± 135 ml min⁻¹, seated; 448 ± 179 ml min⁻¹, supine) were similar, supporting the concept that the skeletal muscle pump was minimized. Even with the reduction of skeletal muscle pump and metabolic influences (trials 2, 3 and 4) a significant cardio-acceleration and hyperaemia was seen. In the first 5 s of seated passive exercise, the retrograde component of the blood velocity profile was significantly greater than rest or the 5–20 s interval, which may suggest an arterial inflow that initially exceeded leg vasodilatation. Steady-state LBF (minutes 2 and 3) remained elevated during voluntary exercise, but returned to near baseline during passive movement. Taken together, these data suggest that cardio-acceleration (i.e. tachycardia) and mechanical forces other than the skeletal muscle pump play a role in reducing vascular resistance and ultimately increasing LBF at the onset of exercise, followed by steady-state LBF which matches muscle metabolic demand.     

Interaction between sympathetic nerve activation and muscle fibre contraction in resistance vessels of hamster retractor muscle

The interaction between skeletal muscle contraction and sympathetic nerve activation (SNA) on blood flow during exercise has remained ambiguous due to indirect estimates of vasomotor control. In the hamster retractor muscle (   n = 54  ), interactions between three levels of SNA (∼3, 6 and 12 Hz) and of contractile activity (2.5, 10 and 20 % duty cycle) were studied in feed arteries (FA) and first- (1A), second- (2A), and third-order (3A) arterioles using intravital microscopy. During functional dilatation with rhythmic muscle contractions, sympathetic vasoconstriction was sustained in FA and 1A but impaired in 2A and 3A (   P < 0.05  ), where vessels 'escaped' from responding to SNA. To account for changes in baseline diameter and blood flow during contractions, vasodilatation was induced passively (2–3 levels) in resting muscles with papaverine or sodium nitroprusside. Compared to functional dilatation, the range of passive dilatation was similar in 3A and progressively greater in 2A, 1A and FA. With passive dilatation, SNA responses were sustained in 2A and increased with baseline diameter in 3A. Blood flow through FA (rest, ∼20 nl s⁻¹) increased ∼5-fold during contractile activity and ∼10-fold during passive dilatation. Absolute flow reductions (nl s⁻¹) with SNA increased during contractile activity and during passive dilatation; relative flow reductions were impaired during functional dilatation (   P < 0.05  ) and remained constant during passive dilatation. Thus, SNA can restrict blood flow to exercising muscle by constricting FA and 1A while dilatation prevails in 2A and 3A. Such concerted interaction will promote oxygen extraction when blood flow is restricted to maintain arterial pressure.     

Effect of high intensity training on capillarization and presence of angiogenic factors in human skeletal muscle

The effect of intense training on endothelial proliferation, capillary growth and distribution of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was examined in human skeletal muscle. Two intermittent knee extensor training protocols (at ∼150% (Study 1) versus ∼90% (Study 2) of leg ̇ _O2 max) were conducted. Muscle biopsies were obtained throughout the training periods for immunohistochemical assessment of capillarization, cell proliferation (Ki-67-positive cells), VEGF and bFGF. In Study 1, microdialysis samples were collected from the trained and untrained leg at rest and during exercise and added to endothelial cells to measure the proliferative effect. After 4 weeks of training there was a higher ( P < 0.05) capillary-to-fibre ratio (Study 1: 2.4 ± 0.1 versus 1.7 ± 0.1) and number of Ki-67-positive cells (Study 1: 0.18 ± 0.05 versus 0.00 ± 0.01) than before training. Neither the location of proliferating endothelial cells nor capillarization was related to muscle fibre type. The endothelial cell proliferative effect of the muscle microdialysate increased from rest to exercise in both the untrained leg (from 262 ± 60 to 573 ± 87% of control perfusate) and the trained leg (from 303 ± 75 to 415 ± 108% of perfusate). VEGF and bFGF were localized in endothelial and skeletal muscle cells and training induced no changes in distribution. The results demonstrate that intense intermittent endurance training induces capillary growth and a transient proliferation of endothelial cells within 4 weeks, with a similar growth occurring around type I versus type II muscle fibres.     

Carotid chemoreceptor modulation of sympathetic vasoconstrictor outflow during exercise in healthy humans

Recently, we have shown that specific, transient carotid chemoreceptor (CC) inhibition in exercising dogs causes vasodilatation in limb muscle. The purpose of the present investigation was to determine if CC suppression reduces muscle sympathetic nerve activity (MSNA) in exercising humans. Healthy subjects ( N = 7) breathed hyperoxic gas ( F _IO2∼1.0) for 60 s at rest and during rhythmic handgrip exercise (50% maximal voluntary contraction, 20 r.p.m.). Microneurography was used to record MSNA in the peroneal nerve. End-tidal P _CO2 was maintained at resting eupnoeic levels throughout and breathing rate was voluntarily fixed. Exercise increased heart rate (67 versus 77 beats min⁻¹), mean blood pressure (81 versus 97 mmHg), MSNA burst frequency (28 versus 37 bursts min⁻¹) and MSNA total minute activity (5.7 versus 9.3 units), but did not change blood lactate (0.7 versus 0.7 m m ). Transient hyperoxia had no significant effect on MSNA at rest. In contrast, during exercise both MSNA burst frequency and total minute activity were significantly reduced with hyperoxia. MSNA burst frequency was reduced within 9–23 s of end-tidal P _O2 exceeding 250 mmHg. The average nadir in MSNA burst frequency and total minute activity was −28 ± 2% and −39 ± 7%, respectively, below steady state normoxic values. Blood pressure was unchanged with hyperoxia at rest or during exercise. CC stimulation with transient hypoxia increased MSNA with a similar time delay to that obtained with CC inhibition via hyperoxia. Consistent with previous animal work, these data indicate that the CC contributes to exercise-induced increases in sympathetic vasoconstrictor outflow.     

Attenuated vascular responsiveness to noradrenaline release during dynamic exercise in dogs

During dynamic exercise, there is reduced responsiveness to α₁- and α₂-adrenergic receptor agonists in skeletal muscle vasculature. However, it is desirable to examine the sympathetic responsiveness to endogenous release of neurotransmitter, since exogenous sympathomimetic agents are dependent upon their ability to reach the abluminal receptor. Therefore, to further our understanding of sympathetic control of vasomotor tone during exercise, we employed a technique that would elicit the release of endogenous noradrenaline (norepinephrine) during dynamic exercise. Mongrel dogs ( n = 8, 19-24 kg) were instrumented chronically with transit time ultrasound flow probes on both external iliac arteries. A catheter was placed in a side branch of the femoral artery for intra-arterial administration of tyramine, an agent which displaces noradrenaline from the nerve terminal. Doses of 0.5, 1.0 and 3.0 μg ml⁻¹ min⁻¹ of iliac blood flow were infused for 1 min at rest and during graded intensities of exercise. Dose-related decreases in iliac vascular conductance were achieved with these concentrations of tyramine. The reductions in iliac vascular conductance (means ± s.e.m .) were 45 ± 6 %, 30 ± 4 %, 26 ± 3 % and 17 ± 2 %, for the 1.0 μg ml⁻¹ min⁻¹ dose at rest, 3.0 miles h⁻¹, 6.0 miles h⁻¹ and 6.0 miles h⁻¹, 10 % gradient, respectively. At all doses, the magnitude of vasoconstriction caused by administration of tyramine was inversely related to workload. We conclude that there is a reduced vascular responsiveness to sympathoactivation in dynamically exercising skeletal muscle.     

Limb neurovascular control during altered otolithic input in humans

Head-down rotation (HDR), which activates the vestibulosympathetic reflex, increases leg muscle sympathetic nerve activity (MSNA) and produces calf vasoconstriction with no change in either cardiac output or arterial blood pressure. Based on animal studies, it was hypothesized that differential control of arm and leg MSNA explains why HDR does not alter arterial blood pressure. Fifteen healthy subjects were studied. Heart rate, arterial blood pressure, forearm and calf blood flow, and leg MSNA responses were measured during HDR in these subjects. Simultaneous recordings of arm and leg MSNA were obtained from five of the subjects. Forearm and calf blood flow, vascular conductances, and vascular resistances were similar before HDR, as were arm and leg MSNA. HDR elicited similar significant increases in leg (Δ6 ± 1 bursts min⁻¹; 59 ± 16 % from baseline) and arm MSNA (Δ5 ± 1 bursts min⁻¹; 80 ± 28 % from baseline). HDR significantly decreased calf (−19 ± 2 %) and forearm vascular conductance (−12 ± 2 %) and significantly increased calf (25 ± 4 %) and forearm vascular resistance (15 ± 2 %), with ∼60 % greater vasoconstriction in the calf than in the forearm. Arterial blood pressure and heart rate were not altered by HDR. These results indicate that there is no differential control of MSNA in the arm and leg during altered feedback from the otolith organs in humans, but that greater vasoconstriction occurs in the calf than in the forearm. These findings indicate that vasodilatation occurs in other vascular bed(s) to account for the lack of increase in arterial blood pressure during HDR.     

Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance

Brief, intense exercise training may induce metabolic and performance adaptations comparable to traditional endurance training. However, no study has directly compared these diverse training strategies in a standardized manner. We therefore examined changes in exercise capacity and molecular and cellular adaptations in skeletal muscle after low volume sprint-interval training (SIT) and high volume endurance training (ET). Sixteen active men (21 ± 1 years,     ) were assigned to a SIT or ET group ( n = 8 each) and performed six training sessions over 14 days. Each session consisted of either four to six repeats of 30 s 'all out' cycling at ∼250%     with 4 min recovery (SIT) or 90–120 min continuous cycling at ∼65%     (ET). Training time commitment over 2 weeks was ∼2.5 h for SIT and ∼10.5 h for ET, and total training volume was ∼90% lower for SIT versus ET (∼630 versus ∼6500 kJ). Training decreased the time required to complete 50 and 750 kJ cycling time trials, with no difference between groups (main effects, P ≤ 0.05). Biopsy samples obtained before and after training revealed similar increases in muscle oxidative capacity, as reflected by the maximal activity of cytochrome c oxidase (COX) and COX subunits II and IV protein content (main effects, P ≤ 0.05), but COX II and IV mRNAs were unchanged. Training-induced increases in muscle buffering capacity and glycogen content were also similar between groups (main effects, P ≤ 0.05). Given the large difference in training volume, these data demonstrate that SIT is a time-efficient strategy to induce rapid adaptations in skeletal muscle and exercise performance that are comparable to ET in young active men.     

Reflex activation of postganglionic vasoconstrictor neurones supplying skeletal muscle by stimulation of arterial chemoreceptors via non-nicotinic synaptic mechanisms in sympathetic ganglia

Postganglionic sympathetic neurones supplying skeletal muscle and skin can be activated from the preganglionic site via cholinergic nicotinic, muscarinic and noncholinergic synaptic mechanisms. The experiments described in this paper were designed in order to show that postganglionic vasoconstrictor neurones supplying skeletal muscle can be activated by the naturally occurring discharge pattern in preganglionic axons when the nicotinic transmission is blocked. For this purpose, the activity was recorded simultaneously from postganglionic vasoconstrictor axons supplying skeletal muscle and vasoconstrictor axons supplying hairy skin. The preganglionic neurones were driven reflexly by stimulation of the arterial chemoreceptors. 1) During blockade of nicotinic transmission muscle vasoconstrictor neurones were activated via the CNS during stimulation of arterial chemoreceptors. This activation is either generated by muscarinic action of released acetylcholine or by a noncholinergic synaptic mechanism. 2) Postganglionic cutaneous vasoconstrictor neurones were inhibited during stimulation of arterial chemoreceptors. During blockade of cholinergic nicotinic transmission these neurones were not activated reflexly by stimulation of arterial chemoreceptors although they received inputs via cholinergic muscarinic and noncholinergic synaptic mechanisms. 3) The results illustrate that postganglionic vasoconstrictor neurones supplying skeletal muscle can not only be activated via non-nicotinic synaptic mechanisms through synchronous repetitive electrical stimulation of preganglionic axons but also by the discharge pattern produced in preganglionic neurones during stimulation of arterial chemoreceptors.     

Altered neurotransmitter control of reflex vasoconstriction in aged human skin

Cutaneous vasoconstriction (VC) in response to cooling is attenuated in older humans; however, mechanisms underlying this functional decline remain unclear. The present study tested the hypothesis that the contributions of noradrenaline (NA) and sympathetic cotransmitters to reflex-mediated cutaneous VC are altered with age. In 11 young (18–26 years) and 11 older (61–77 years) men and women, forearm skin blood flow was monitored at three sites using laser Doppler flowmetry (LDF) while mean skin temperature was lowered from 34 to 30.5°C using a water-perfused suit. Cutaneous vascular conductance (CVC; LDF/mean arterial pressure) was expressed as percentage change from baseline (%ΔCVC_base). Solutions of yohimbine + propranolol (Y + P), bretylium tosylate (BT), and lactated Ringer solution were infused via intradermal microdialysis at each LDF site to antagonize α- and β-adrenoceptors, block sympathetic release of NA and cotransmitters, and act as control, respectively. During cooling, VC was attenuated at the control site in older subjects compared to young subjects (−16 ± 3 versus −34 ± 4%ΔCVC_base, P < 0.001). Y + P attenuated VC in young subjects (−13 ± 8%ΔCVC_base, P < 0.001 versus control) and abolished VC in older subjects (0 ± 3%ΔCVC_base, P > 0.9 versus baseline). BT completely blocked VC in both age groups. Cutaneous VC in young subjects is mediated by both NA and sympathetic cotransmitter(s); however, reflex VC in aged skin is attenuated compared to young and appears to be mediated solely by NA.     

Blunted Sympathetic Vasoconstriction in Contracting Skeletal Muscle of Healthy Humans: is Nitric Oxide Obligatory?

We tested the hypothesis that nitric oxide (NO) is responsible for blunting sympathetic α-adrenergic vasoconstriction in the active muscles of humans (functional sympatholysis). We measured forearm blood flow (Doppler ultrasound) and calculated the reductions in forearm vascular conductance (FVC) in response to α-adrenergic receptor stimulation during rhythmic handgrip exercise and during a control non-exercise vasodilator condition (intra-arterial adenosine), before and after local NO synthase (NOS) inhibition in healthy men. The forearm vasoconstrictor responses to endogenous noradrenaline release (intra-arterial tyramine) were significantly blunted during moderate exercise compared with adenosine, and these vasoconstrictor responses were not restored by NOS inhibition with N ^G-monomethyl- l -arginine ( l -NMMA;   n = 6  ) or N ^G-nitro- l -arginine methyl ester ( l -NAME;   n = 8  ). Similarly, l -NAME did not restore the vasoconstrictor responses to tyramine in contracting muscle during heavy rhythmic handgrip exercise (   n = 4  ). In four additional subjects, we also found that the vasoconstrictor responses evoked by tyramine during exercise or adenosine were repeatable in the absence of NOS inhibition (i.e. time control). Finally, in five subjects the forearm vasoconstrictor responses to direct α₁-adrenergic (phenylephrine) and α₂-adrenergic (clonidine) receptor stimulation were blunted during moderate exercise compared with adenosine; these responses were also unaffected by l -NAME. Taken together, our results demonstrate that NO is not obligatory for functional sympatholysis in contracting skeletal muscles of healthy men.     

Effect of gastric distension on cardiovascular parameters: gastrovascular reflex is attenuated in the elderly

Stretching the stomach wall in young healthy subjects causes an increase in muscle sympathetic nerve activity and in blood pressure, the gastrovascular reflex. We compared healthy elderly subjects with healthy young subjects to find out whether the gastrovascular reflex attenuates in normal ageing and we studied whether there was a difference in autonomic function or gastric compliance that could explain this possible attenuation. Muscle sympathetic nerve activity, finger blood pressure and heart rate were continuously recorded during stepwise isobaric gastric distension using a barostat in eight healthy young (6 men and 2 women, 27 ± 3.2 years, mean ± s.e.m. ) and eight healthy elderly subjects (7 men and 1 woman, 76 ± 1.5 years). Changes in cardiac output and total peripheral arterial resistance were calculated from the blood pressure signal. The baseline mean arterial pressure and muscle sympathetic nerve activity were higher in the elderly group (both P < 0.05) and muscle sympathetic nerve activity increase during the cold pressor test was lower in the elderly group ( P = 0.005). During stepwise gastric distension, the elderly subjects showed an attenuated increase in muscle sympathetic nerve activity compared to the young subjects ( P < 0.01). The older group tended to show a higher increase in mean arterial pressure ( P = 0.08), heart rate ( P = 0.06) and total peripheral arterial resistance ( P = 0.09) The cardiac output rose slightly in both groups without significant difference between groups. The fundic compliance did not differ between groups. We conclude that stepwise gastric distension caused an increase in muscle sympathetic nerve activity in both groups, but the increase in the elderly was attenuated.     

Preserved contribution of nitric oxide to baseline vascular tone in deconditioned human skeletal muscle

Deconditioning is a risk factor for cardiovascular disease. Exercise reduces this risk, possibly by improving the vascular endothelial nitric oxide (NO) pathway. The effect of deconditioning on the NO pathway is largely unknown. This study was designed to assess baseline NO availability in the leg vascular bed after extreme, long-term deconditioning (spinal cord-injured individuals, SCI) as well as after moderate, short-term deconditioning (4 weeks of unilateral lower limb suspension, ULLS). For this purpose, seven SCI were compared with seven matched controls. Additionally, seven healthy subjects were studied pre- and post-ULLS. Leg blood flow was measured by venous occlusion plethysmography at baseline and during infusion of 5 incremental dosages of N ^G-monomethyl- l -arginine ( l -NMMA) into the femoral artery. Sodium nitroprusside (SNP) was infused to test vascular responsiveness to NO. Baseline leg vascular resistance tended to be higher in SCI compared with controls (37 ± 4 versus 31 ± 2 arbitrary units (AU), P = 0.06). Deconditioning altered neither the vasoconstrictor response to l -NMMA (increase in resistance in SCI versus controls: 102 ± 33% versus 69 ± 9%; pre- versus post-ULLS: 95 ± 18% versus 119 ± 15%), nor the vascular responsiveness to NO. In conclusion, two human in vivo models of deconditioning show a preserved baseline NO availability in the leg skeletal muscle vascular bed.