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1 Noll Physiological Research Center and Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania 16802; and 2 Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center and Presbyterian Hospital of Dallas, Dallas, Texas 75231
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Unlike quadrupeds, the
legs of humans are regularly exposed to elevated pressures relative to
the arms. We hypothesized that this "dependent
hypertension" would be associated with altered adrenergic
responsiveness. Isoproterenol (0.75-24 ng · 100 ml limb
volume
1 · min1) and phenylephrine
(0.025-0.8 µg · 100 ml limb
volume1 · min1) were infused
incrementally in the brachial and femoral arteries of 12 normal
volunteers; changes in limb blood flow were quantified by using
strain-gauge plethysmography. Compared with the forearm, baseline calf
vascular resistance was greater (38.8 ± 2.5 vs. 26.9 ± 2.0 mmHg · 100 ml · min · ml1;
P < 0.001) and maximal conductance was lower
(46.1 ± 11.9 vs. 59.4 ± 13.4 ml · ml1 · min1 · mmHg1;
P < 0.03). Vascular conductance did not differ between
the two limbs during isoproterenol infusions, whereas decreases in
vascular conductance were greater in the calf than the forearm during
phenylephrine infusions (P < 0.001). With responses
normalized to maximal conductance, the half-maximal response for
phenylephrine was significantly less for the calf than the forearm
(P < 0.001), whereas the half-maximal response for
isoproterenol did not differ between limbs. We conclude that
1- but not 
-adrenergic-receptor responsiveness in
human limbs is nonuniform. The relatively greater response to
1-adrenergic-receptor stimulation in the calf may
represent an adaptive mechanism that limits blood pooling and capillary
filtration in the legs during standing.
vasoconstriction; -adrenergic receptor; -adrenergic receptor
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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AT REST OR DURING ORTHOSTATIC stress in humans, sympathetic activity targeted to arm and leg skeletal muscle vasculature is largely homogenous (22, 29). However, at rest, the release of norepinephrine in these limbs is decidedly specific, with greater norepinephrine spillover from the arms than the legs (13, 16). Yet, with some exceptions (e.g., Refs. 5, 9, 26), the typical pattern of regional vascular resistance is directionally opposite (i.e., legs greater than arms) (8, 13, 16, 21, 28). These results suggest that the effects of sympathetic nerve stimulation are qualitatively and/or quantitatively different in the arms and legs of humans.
In this paper, we consider the possibility that differentiation of adrenergic receptors contributes to the high degree of specialization of sympathetic nerve transduction in the legs and arms. Pressure (i.e., transmural wall stress) is known to regulate growth and adrenergic responsiveness in vascular smooth muscle (23), and bipeds such as humans afford an unusual opportunity to study the prolonged effect of increased pressure on vascular regulation. During much of the day, hydrostatic pressure elevates leg blood pressure, causing the legs to be exposed to intermittent hypertension. To the contrary, the arms, lying near the approximate level of the heart, are less gravitationally dependent and are exposed to pressures closer to that experienced in the aorta. Thus one might theorize that human arms and legs exhibit differential hemodynamics and adrenergic responsiveness as a long-term consequence of the upright posture, exposing arm and leg vasculature to different loading conditions.
In the present investigation, we studied both forearm and calf vascular
responses to 1- and -adrenoreceptor agonists. We hypothesized that legs would exhibit greater responsiveness to an
infused 1-adrenergic agonist than arms as a long-term
consequence of intermittent exposure to "dependent hypertension"
(i.e., the sum of hemodynamic and hydrostatic pressures while
standing), whereas -mediated vasodilation would not differ between
limbs. Using local arterial infusions, we were able to characterize the functional effects of adrenergic-receptor stimulation in vascular smooth muscle while minimizing confounding reflex responses that would
result from changes in systemic arterial pressure. Our hypotheses were
largely confirmed in the present investigation, revealing a
heterogeneous distribution of 1-adrenergic
responsiveness in human limbs previously unappreciated.
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METHODS AND PROCEDURES |
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TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Subjects
Twelve healthy subjects (11 men, 1 woman) were studied in the morning after an overnight fast. Physical characteristics included the following: mean age of 24 ± 2 yr (range 18-35 yr), height 185 ± 23 cm, and weight 79 ± 3 kg. No subject smoked, used recreational drugs, or had significant chronic medical problems. Subjects were screened with a history and physical examination, resting electrocardiogram, and resting echocardiogram; potential subjects with vascular abnormalities were excluded. All subjects provided voluntary, informed consent. The Institutional Review Boards of both the University of Texas Southwestern Medical Center and the Presbyterian Hospital of Dallas approved the protocol.Measurements
Arterial pressure and heart rate. With the use of local anesthesia and modified Seldinger technique, a 5-cm, 3-Fr catheter (Cook Medical) was placed in the brachial artery of the nondominant arm, and a 12-cm, 4-Fr catheter (Cook Medical) was placed in the femoral artery of the nondominant leg at the level of the inguinal ligament. Pressure waveforms were transduced (Transpac IV, Abbott), amplified (Hewlett-Packard 78534A), and displayed on a strip-chart recorder (Astromed MT 95000) with at least 0.5-mmHg resolution. The zero for both pressure transducers was set at 5 cm below the sternal angle in the supine position.
After catheter insertion, at least 1 h elapsed before pressure measurement commenced. Each pressure wave was sampled at 200 Hz and integrated in real time with customized software. Heart rate (HR) was recorded from lead II of the electrocardiogram and sampled at 1,000 Hz. Both pressures and HR were stored in beat-to-beat format during the experiment; mean HR and blood pressure were calculated from the time-weighted average of these data.Limb volume. The volume of the infused arm and leg was determined by anthropometry. Limbs were modeled as a series of truncated cones that were summed to estimate the limb volume (27). Two sections were used to approximate the forearm, and 11 sections were used to approximate the leg. This method compares favorably with measurements made with water displacement (19).
Limb blood flow. Calf and forearm blood flows were determined by venous occlusion plethysmography. Flows were measured in both calves or both forearms during infusions, with the noninfused limb serving as a control for the infused limb. Changes in limb volume were transduced by using dual-strand mercury-in-Silastic strain gauges (12), amplified (Hokanson EC-4), and displayed on a strip-chart recorder (Astromed MT-95000) for post hoc analysis. Strain gauges were sized to approximate the largest circumference of the calf or forearm. Blood flow to the feet or hands was excluded from the measurement, with ankle or wrist arresting cuffs inflated to 250 mmHg just before flow measurements at each stage of the infusion and deflated between stages. Venous occlusion pressures of 50 mmHg were employed; the lower legs or forearms were elevated 20 cm above the subjects' midaxillary line to facilitate venous drainage between determinations. Limb vascular conductance, calculated as the quotient of limb blood flow and mean arterial pressure (MAP), was used to compare responses to local infusion, as this variable is linearly related to blood flow when perfusion pressure is not changing (17).
Procedures
Arterial infusion.
To assess 1-adrenergic responsiveness, phenylephrine HCl
(Neo-Synephrine, Sanofi Winthrop) was infused intra-arterially at rates
of 0.025, 0.05, 0.1, 0.2, 0.4, and 0.8 µg · 100 ml tissue volume1 · min1. -Adrenergic
responsiveness was determined with intra-arterial infusions of
isoproterenol HCl (Isuprel, Sanofi Winthrop) at rates of 0.075, 1.5, 3, 6, 12, and 24 ng · 100 ml tissue
volume1 · min1. Phenylephrine was
diluted in sterile, buffered, isotonic saline to a concentration of
16.7 µg/ml for arm infusions, and 50 µg/ml for leg infusions,
whereas isoproterenol was diluted to concentrations of 500 and 1,500 ng/ml for arm and leg infusions, respectively. On the basis of these
concentrations and the typical volumes of the limb segments (~1 liter
for the arm and 10 liters for the leg), the maximal volume infused was
~0.5 ml/min in the arm and 1.6 ml/min in the leg, or ~1% of the
resting flow in the brachial or femoral arteries.
1- and -adrenergic-receptor stimulation; thus
>1 h separated infusions in a given limb. Baseline resistance was
determined before each drug infusion; the mean of these values was used
to compare baseline resistance between the forearm and calf.
Maximal limb conductance. On a separate day, maximal conductance of the forearm and calf was determined by using a modification of published procedures (25). Maximal flows for both limbs were determined in the supine position by using venous occlusion plethysmography after an exhausting bout of ischemic exercise. For the forearm, subjects performed wrist flexion, extension, pronation, and supination, whereas, for the calf, subjects performed heel and toe raises. For either limb, fatigue occurred in 2-4 min. Occlusion pressures of 300 mmHg were used on the upper arm or leg; subjects were repositioned supine before release of the cuffs. Flow determinations commenced within 6 s of cuff release and remained elevated at maximal levels up to 90 s thereafter. Blood flow was determined at 10-s intervals; usually the highest value was obtained with the first or second measurement after cuff release. Simultaneously, blood pressure was determined with an automated auscultatory device (Suntech 4240) for the calculation of conductance as the quotient of maximal limb blood flow and MAP.
Dose-response curves. To determine adrenergic responsiveness in the calf and forearm, individual responses to infusion of each agonist were normalized to each subject's maximal conductance for the respective limb. The averages of these data, plotted as a function of the log-transformed infusion rates, were used to construct dose-response curves based on a four-parameter logistic model. From these equations, we calculated the maximal response (Emax) and the dose of each agonist that produced the half-maximal response (ED50) in each limb. Because the vasomotor responses were normalized to maximal conductance and the infusion rates were normalized to limb volume, we were able to compare adrenergic sensitivity between the forearm and calf while avoiding the problems with interpretation caused by unequal local concentrations of agonist (13).
Statistical Analyses
To determine whether a systemic effect of drug infusion had occurred, HR responses were compared within each of the four local infusions by using one-factor, repeated-measures analysis of variance. Local hemodynamic responses to infusion (infused vs. control limb or forearm vs. calf) were compared by using two-factor, repeated-measures analyses of variance (dose × limb). Significant differences were probed post hoc by using t-tests with a Bonferroni correction for multiple comparisons. Between-limb differences in baseline resistance and maximal conductance were assessed with paired t-tests. Logistic models were fit iteratively with nonlinear regression (SigmaPlot 2.1, Jandel Scientific); unpaired t-tests were used to identify between-limb differences in the Emax and ED50 for each agonist. The probability of rejecting the null hypothesis (no difference from infusion or between limbs) was set at 5%.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Systemic Drug Effects
Figures 1 and 2 illustrate the HR responses to infusion of adrenergic agonists. During arm infusions of isoproterenol, the baseline HR was 63.9 ± 1.3 beats/min and did not change throughout the infusion protocol. To the contrary, HR increased during leg isoproterenol infusions from a baseline of 65.9 ± 2.6 to 93.3 ± 1.3 beats/min at the highest rate of infusion (P < 0.0001 vs. baseline).
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Systemic MAP (i.e., leg MAP during arm infusions, arm MAP during leg
infusions) did not change from baseline during arm infusions but
was significantly less than baseline (
6.7 ± 1.4 mmHg)
during leg isoproterenol infusion at 12 ng · 100 ml tissue
volume1 · min1 (P = 0.0003). The HR and MAP changes, coupled with the observation that limb
blood flow was increasing in the contralateral (control) limb at the
highest rate of leg isoproterenol infusion (P = 0.01 vs. control), led us to conclude that systemic spillover of
isoproterenol was occurring during leg isoproterenol infusions. We
therefore terminated the highest rate of leg isoproterenol infusions in 7 of the 12 subjects and excluded the highest infusion rate from subsequent analysis. In contrast, no rate of phenylephrine infusion altered HR, MAP, or blood flow in the control limb.
Regional Resistance to Blood Flow During Resting and Maximally Vasodilated Conditions
Resting limb resistance for each subject is depicted in Fig. 3 based on the mean of three determinations at different times during the experiment. Resting calf vascular resistance was greater than forearm vascular resistance in 11 of 12 subjects, with a mean value of 26.9 ± 2.0 vs. 38.8 ± 2.5 mmHg · 100 ml · min · ml1
(P < 0.001 by paired t-test). These
findings are echoed in the differences in maximal vascular conductance
as shown in Fig. 4. Maximal calf
conductance was less than forearm conductance in 10 of 12 subjects,
with a mean value of 46.1 ± 11.9 vs. 59.4 ± 13.4 ml · ml1 · min1 · mmHg1
(P < 0.03 by paired t-test). Thus
resistance to flow was greater in the calf, both at rest and during
maximally vasodilated conditions.
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Regional Drug Effects
The responses of limb vascular conductance to-adrenergic
stimulation are shown in Fig. 5. Proper
positioning of the brachial arterial catheter could not be obtained in
one subject; thus the results from agonist infusion are limited to a
total of 11 subjects. During isoproterenol infusions, flow and
conductance steadily increased, and conductance was significantly
increased above the level in the corresponding control limb at the four
highest levels of isoproterenol infusion (P < 0.0001).
Conductance did not differ between the forearm and calf at either rest
or any of the five levels of infusion compared. Analysis of the
determinants of conductance (shown in Table
1) revealed that changes in pressure
contributed only modestly to the changes in conductance. Local MAP did
not change during arm isoproterenol infusion. However, it fell
progressively during leg isoproterenol infusion and was significantly
lower than baseline at the four highest rates of infusion, reaching a
maximum level of 10.0 ± 1.3 mmHg (P < 0.0001).
As a result, the pressure difference between local (leg) and systemic
(arm) pressure widened and was significantly different from zero at two
of the three highest infusion rates (P < 0.05).
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With infusion of phenylephrine (Fig. 6),
vascular conductance fell progressively in both limbs and was
statistically decreased from baseline in the forearm at the three
highest infusion rates (P < 0.0001) and in the calf at
the five highest infusion rates (P < 0.0001). Unlike
the responses to isoproterenol infusion, a statistically significant
interaction between infusion rate and limb was noted, such that the
calf responses were significantly greater than the corresponding
forearm responses for four of the doses of phenylephrine
(P < 0.0001). Decreases in conductance could be
attributed mainly to reductions in blood flow (Table 1). Local, but not
systemic, pressure was modestly, but significantly, elevated above
baseline during the highest rate of phenylephrine infusion in the leg
(+4.5 mmHg, P = 0.02), whereas significant changes in
either local or systemic pressure were not detected during arm
infusion.
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Adrenergic-receptor Sensitivity
Results from nonlinear regression of the normalized dose-response data are shown in Figs. 7 and 8. Neither the ED50 (forearm: 6.9 ng · min1 · 100 ml1; calf:
9.9 ng · min1 · 100 ml1)
nor the Emax (forearm: 50.2%; calf: 57.4%) differed
between limbs during isoproterenol infusions.
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In contrast, analysis of the responses to phenylephrine infusion
revealed that the ED50 was significantly different between limbs. The ED50 was more than threefold higher for the
forearm (0.157 µg · min1 · 100 ml1) compared with the calf (0.045 µg · min1 · 100 ml1;
P < 0.001), whereas the Emax was virtually
indistinguishable between limbs (forearm: 2.4%; calf: 2.3%).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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The major finding of the present investigation is that, for an
equal concentration of phenylephrine, decreases in vascular conductance
were greater in the calf compared with the forearm. To our knowledge,
this is the first observation that 1-adrenergic responsiveness is heterogeneous in human skeletal muscle arterial vasculature. To the contrary, when -adrenergic receptors were stimulated with infusions of isoproterenol, vasodilatory responses were
similar in the forearm and calf circulations. Thus the heterogeneity of
adrenergic responses in human limbs that we identified was confined to
1-adrenergic receptors.
Unique to this investigation is the use of local arterial infusions normalized to limb volume to produce equal concentrations of agonist in the forearm and calf vasculature. This approach holds distinct advantages over the alternative approach (i.e., systemic infusion). First, determination of local pressure in the infused limb afforded more accurate calculations of changes in limb vascular tone. A modest, although statistically significant, pressure disparity between the infused limb and control limb was noted during local infusions. For example, pressure in the leg decreased by ~6-7 mmHg relative to the control limb (arm) during calf isoproterenol infusions, whereas the opposite effect tended to occur during phenylephrine infusions. Thus local arterial pressure was affected by changes in downstream vascular tone independent of systemic arterial pressure, but we can only speculate to what extent these changes propagated through the forearm and calf circulations.
Second, using intra-arterial infusions rather than a systemic infusion
allowed us to determine regional vascular responses while minimizing
confounding baroreflex-mediated effects on HR and/or sympathetic
activity. Despite this approach, HR increased, systemic MAP decreased,
and the contralateral calf vasodilated in the majority of subjects
during the highest rate of leg isoproterenol infusion. Each of these
subjects reported sensations associated with an increase in cardiac
contractility (palpitations). The other infusion trials (arm and leg
infusion of phenylephrine, arm infusion of isoproterenol) appeared to
be free of such changes. We are, therefore, confident that some
systemic spillover of isoproterenol occurred during leg infusions,
resulting from the combined effect of hyperemia and the total dose of
isoproterenol needed to achieve the desired normalized dose. (The leg
dose, if given systemically, was within the therapeutic range for a
cardiac effect.) Because we cannot completely exclude the possibility
that reflex effects associated with systemic spillover of isoproterenol
from the leg elicited increases in sympathetic activity that opposed
the vasodilation evoked by direct -adrenergic-receptor stimulation,
the isoproterenol data should be interpreted judiciously.
Finally, by normalizing the infusions to limb volume, pharmacological
models could be constructed to compare the forearm and calf responses
at the same agonist concentrations, obviating the problems caused by
infusing a fixed dose of agonist in limbs with different vascular
volumes (13). Because the measured leg volume was ~10
times larger than forearm volume, ~10-fold more phenylephrine was
infused into the femoral artery compared with the brachial artery.
Although the same point holds true for the isoproterenol infusions,
responses to isoproterenol were similar between the limbs. This
observation suggests that our findings are not an artifact of procedure
(i.e., infusing a larger total dose of agonist in the leg), rather that
there exists a true difference between upper and lower limbs in
response to 1-adrenergic stimulation that is not
manifested with -adrenergic stimulation. Assuming that Poiseuille's
law can be applied to the limb circulations under these steady-state
conditions, the 50-60% decrease in conductance in response to
phenylephrine and the 400-500% increase in conductance in
response to isoproterenol are consistent with ~30% decreases and
~50% increases in mean vessel diameter, respectively. These estimates are comparable to data obtained from isolated rat skeletal muscle microvasculature (e.g., Refs. 4, 18).
Why Is the Response to Phenylephrine Greater in the Calf?
One interpretation of our primary finding is that1-adrenergic receptors are distributed unevenly in human
limbs, with relatively greater numbers and/or sensitivity found in the
lower leg compared with the forearm, leading to greater release of
calcium in vascular smooth muscle in response to sympathetic
activation. Additionally, two other explanations should be considered.
First, it is hypothetically possible that a smaller response to
phenylephrine in the forearm circulation could reflect greater
presynaptic 2-adrenergic inhibition of endogenous
norepinephrine release, masking the response to phenylephrine. Although
the presynaptic mechanism plays an important role in the human forearm
(10, 15), no data exist that investigates the presence or
magnitude of this mechanism in the human calf. However, we believe this
mechanism cannot fully explain the relative difference in adrenergic
responsiveness that we observed, as the contribution of endogenous
norepinephrine spillover to vascular resistance is relatively small in
the resting state (13, 16).
Alternatively, it is possible that greater accumulation of vascular
smooth muscle in the calf led to a greater contractile response without
a difference in 1-adrenergic-receptor sensitivity. Such
an effect could explain both the lower resting and maximal calf
vascular conductance (Figs. 2 and 3). Other notable examples from
nature implicate this mechanism. In an extreme case, the ratio of wall
thickness to lumen radius of arteries from the lower legs of giraffes
is >400% greater than that found in arteries from the neck
(11)! Thus vascular hypertrophy could affect resting and
maximal blood flow and play a role in amplifying the response to
1-adrenergic stimulation.
Why Would Vascular Hypertrophy Predominate in the Legs?
1-Adrenergic receptors belong to the heptahelical
family of receptors that share common features with angiotensin II and endothelin-1A receptors, among others. These receptors are linked to
the phosphatidylinositol pathway via Gq. The products of
this pathway (inositol trisphosphate and diacylglycerol) elicit two major types of responses. The first is contractile, mobilizing intracellular Ca2+ through inositol
trisphosphate-stimulated release from sarcoplasmic reticulum. This
response plays an important role in orthostatic regulation, controlling
the rate at which blood is redistributed to capacitance vessels in
peripheral extremities. If this mechanism is blocked, rapid pooling of
blood in dependent regions of the circulation causes profound
orthostatic intolerance (1). The second response is
synthetic, where diacylglycerol activates several transcriptional
pathways via protein kinase C, causing hypertrophy and further
expression of -adrenergic receptors.
With some clinical conditions, altered pressure gradients are
associated with lasting effects on microvessel architecture. For
example, greater 1-receptor sensitivity has been
reported in pulmonary and "essential" hypertension
(23). In a unique "experiment of nature," Gidding et
al. (8) studied the vasoconstrictor responses to
norepinephrine infused in the arms and legs of patients after surgical
correction of coarctation of the aorta. As the stenosis is
characteristically located in the descending or abdominal aorta, the
typical pressure gradient between the upper and lower limbs is
reversed, causing upper body hypertension often greater than the lower
body-dependent hypertension. Despite the 6-yr average length of time
from surgery until study, residual hypertension existed in the arms of
the patients (arm-to-leg systolic pressure gradient of 8.5 ± 4.3 and 75 ± 13.5 mmHg at rest and after exercise, respectively). In
patients, responses to graded, systemic infusion of norepinephrine were
greater in the forearm than the calf, whereas control subjects
exhibited directionally opposite results (i.e., calf responses were
greater than forearm, much like in the present study). These results
indicate that perfusion pressure is an important stimulus for vascular
hypertrophy and -adrenergic responsiveness. In humans, this effect
appears to exhibit long-term effects, being present even when the
pressure stimulus is removed for extended periods.
If pressure is the primary stimulus for these events, can acute
reversal of the hydrostatic pressure gradients typically encountered in
the cardiovascular system change the pattern of vascular hypertrophy and -adrenergic responsiveness? Several reports support this assertion. Prolonged head-down tilting in tail-suspended rats causes
atrophy in dependent arteries (2) and attenuates
constriction resulting from adrenergic stimulation (4).
Conversely, the basilar artery hypertrophies in this model because of
the increase in hydrostatic pressure cephalad to the heart
(30). However, in humans, the attenuation of hydrostatic
gradients by bed-rest deconditioning failed to affect vasoconstriction
in the lower limb in response to systemic phenylephrine infusion after
14 days of head-down tilt (3) or to norepinephrine in the
upper limb after 12 days of bed rest (24). Although the
discrepancy between the human and animal investigations is not yet
resolved, we speculate that the time course of vascular smooth muscle
adaptation to bed-rest deconditioning may be longer than that produced
by hindlimb unloading in tail-suspended rats.
Limitations to Interpretation
Measurement of vascular responses. We quantified vascular responses as changes in conductance, rather than resistance, because the former is linearly related to flow when pressure remains relatively constant (17, 20). Because the relationship between resistance and conductance is reciprocal, large changes in resistance yield proportionally smaller changes in conductance if flow is low. This "floor effect" may have limited our ability to discern statistical differences in conductance at very high doses of phenylephrine. Although we believe that the pharmacological parameters ED50 and Emax best portray the physiological differences between the forearm and calf, the reader is provided with the primary data in Table 1 so that either variable may be calculated.
Adrenergic-receptor subtypes.
No attempt was made in this investigation to discriminate between
1- and 2-adrenergic receptors, which vary
in density and proportion through the vascular tree. For example,
Flavahan et al. (7) reported the responses of isolated
conduit and peripheral arteries obtained from amputated legs or arms
for nonvascular complications. After pretreatment with yohimbine, a
greater loss of constriction was observed in the peripheral arteries,
suggesting that relatively more 2-receptors were located
in the peripheral arteries. The authors reported that the proportions
of 1- and 2-receptors were not different
between arms and legs; however, no comparisons of the absolute
differences between limbs are available from this study (J. T. Shepherd, personal communication). An important follow-up to the
present study would be to identify differences in -receptor
distribution at successive generations of the arterial network in upper
and lower limbs of humans.
Perspectives
Several stimuli have been reported to produce heterogeneous regional vascular responses in skeletal muscle. For example, orthostatic stress (5, 6), cold stress (13), and ventricular chemoreceptor activation (14) may elicit differential responses. Despite lower norepinephrine spillover from legs compared with arms (13, 16), neural traffic to arm and leg skeletal muscle during orthostatic stress appears to be relatively uniform (22, 29). The results from the present investigation suggest that the greater efficacy of1-adrenergic stimulation in the lower legs of humans may
offset the effects of lower norepinephrine spillover, thus normalizing or magnifying the vascular response in the legs to changes in sympathetic activity.
The lower limbs of bipeds routinely experience large changes in
pressure resulting from the combined effect of arterial and hydrostatic
gradients. Results from the present investigation suggest that
accentuated 1-adrenergic responses mitigate this effect
in daily life. Moreover, chronic exposure of the legs to such pressures
may be associated with functional or morphological differences between
the legs and arms that are manifested in higher resting vascular
resistance and lower maximal conductance in the calf compared with the
forearm. These adaptations would act synergistically to serve two
important roles: first, to limit the extent of venous pooling during
quiet standing when muscle pumping is not active, and second, to
regulate capillary hydrostatic pressure so that capillary filtration in
the legs does not become excessive.
In summary, results from this investigation reveal that adrenergic
responsiveness in human limbs is not uniform. Whereas the dilator
responses to -receptor stimulation do not differ between the calf
and forearm, the constrictor responses to phenylephrine are more
efficacious in the calf compared with the forearm. We hypothesize that
the long-term combination of arterial and elevated hydrostatic pressure
leads to this greater response. The extent to which acute reductions in
hydrostatic pressure gradients can modify this effect in humans remains unclear.
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ACKNOWLEDGEMENTS |
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The outstanding technical support from Stacey Blaker, Robyn Etzel, Kevin Harper, Susie McMinn, and Julie Zuckerman is gratefully appreciated. We thank the subjects for cheerful cooperation and Dr. C. Gunnar Blomqvist for continued guidance and advice.
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FOOTNOTES |
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This work was supported by National Aeronautics and Space Administration (NASA) Center for Outreach, Research and Training Grant NGW 3582, National Institutes of Health Grant MO1-RR-006633, and NASA Grant NAGW 3489 (to J. A. Pawelczyk).
Address for reprint requests and other correspondence: J. A. Pawelczyk, 129 Noll Lab., The Pennsylvania State Univ., Univ. Park, PA 16802 (E-mail: jap18{at}psu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published December 21, 2001;10.1152/japplphysiol.00979.2001
Received 25 September 2001; accepted in final form 20 December 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS AND PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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) and the infused limb
(
) are shown. Calf vascular conductance for the highest
level of isoproterenol has been omitted because the infusion was
terminated when systemic responses were observed in 7 of 12 subjects.
There was no significant difference between limbs at any dose. Values
are means ± SE.
