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1 Departments of Health and Kinesiology and 2 Medical Physiology and 3 Biomedical Engineering Program, Texas A&M University, College Station, Texas 77843
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Exercise capacity and skeletal
muscle blood flow during exercise are reduced with advancing age. This
reduction in blood flow capacity may be related to increased reactivity
of skeletal muscle resistance vessels to vasoconstrictor stimuli. The
purpose of this study was to test the hypothesis that aging results in
increased vasoconstrictor responses of skeletal muscle resistance
arterioles. First-order (1A) arterioles (90-220 µm) from the
gastrocnemius and soleus muscles of young (4 mo) and aged (24 mo)
Fischer-344 rats were isolated, cannulated, and pressurized via
hydrostatic reservoirs. Vasoconstriction in response to increases in
norepinephrine (NE; 1 × 10
9-1 × 104 M) and KCl (20-100 mM) concentrations and
increases in intraluminal pressure (10-130 cmH2O) were
evaluated in the absence of flow. Responses to NE and KCl were similar
in both soleus and gastrocnemius muscle arterioles from young and aged
rats. In contrast, active myogenic responses to changes in intraluminal
pressure were diminished in soleus and gastrocnemius arterioles from
aged rats. To assess whether alterations in the mechanical properties
of resistance arterioles underlie altered myogenic responsiveness,
passive diameter responses to pressure and mechanical stiffness were
evaluated. There was no effect of age on the structural behavior
(passive pressure-diameter relationship) or stiffness of arterioles
from either the soleus or gastrocnemius muscles. These results suggest that aging does not result in a nonspecific decrease in vasoconstrictor responsiveness of skeletal muscle arterioles. Rather, aging-induced adaptations of vasoreactivity of resistance arterioles appear to be
limited to mechanisms that are uniquely involved in the signaling of
the myogenic response.
norepinephrine; potassium chloride; orthostatic hypotension; stiffness; myogenic response
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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EXERCISE PERFORMANCE declines with advancing age. This decline in exercise capacity is due, in part, to an age-related decrease in the functional ability of the cardiovascular system to provide oxygen to working muscles. Although previous research demonstrates that part of the decreased functional capacity of senescent individuals is due to a diminished ability of the heart to elevate cardiac output during exercise (20, 22, 30, 34), age-related changes in the mechanisms of local vascular control also appear to contribute to reduced blood flow in skeletal muscle during exercise.
Reductions in skeletal muscle blood flow during exercise and muscle stimulation have been reported in aged humans and animals. Irion and co-workers (28) evaluated in situ hindlimb muscle blood flow during electrical stimulation and found that the flow capacity was reduced in old rats. Wahren and colleagues (29, 51) showed in humans that the rise in leg blood flow during exercise was less in older male subjects. Recently, Proctor et al. (39) reported that leg blood flow and vascular conductance during submaximal cycling exercise at a given level of whole body oxygen consumption are lower in older men compared with their young counterparts. The reduction in skeletal muscle blood flow capacity could be due to alterations in the intrinsic vasomotor responsiveness of resistance arteries or due to changes in the mechanical or structural properties of the vessels. More specifically, greater responsiveness to vasoconstrictor stimuli, increased vessel stiffness, or a reduced maximal diameter of resistance arteries could limit the exercise hyperemia in muscles of older individuals. Therefore, the purpose of the present study was to determine whether myogenic or agonist-induced vasoconstriction, stiffness, or maximal diameter of skeletal muscle arterioles is different between young and old animals. We hypothesized that the vasoconstrictor responses and stiffness of skeletal muscle resistance arterioles from both the soleus muscle, which is composed predominantly of slow-twitch fibers (18), and the gastrocnemius muscle, composed predominantly of fast-twitch fibers (18), would be greater in aged Fischer-344 rats.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
All procedures performed in this study were approved by the Texas A&M University Laboratory Animal Care Committee. All methods conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (National Research Council, Washington, DC, Revised 1996).Forty young (4 mo old) and thirty-eight aged (24 mo old) male Fischer-344 rats were obtained from Harlan (Indianapolis, IN). The animals were housed in a temperature-controlled (23 ± 2°C) room with a 12:12-h light-dark cycle. Water and rat chow were provided ad libitum.
Microvessel Preparation
The rats were anesthetized with pentobarbital sodium (60 mg/kg ip) and euthanized by decapitation. The gastrocnemius-plantaris-soleus muscle group from each hindlimb was carefully dissected free and placed in cold (4°C) physiological saline solution (PSS) with 1 g/100 ml bovine serum albumin as previously described (13). First-order (1A) arterioles from the soleus muscle and the superficial white portion of the gastrocnemius muscle were isolated and removed from the surrounding muscle tissue. In soleus muscle, 1A arterioles were defined as the first branch that occurred after the feed artery had entered the muscle tissue. In gastrocnemius muscle, 1A arterioles were defined as the first branch off the feed artery that runs over the superficial portion of the muscle. The arterioles (0.5-1.0 mm in length, 90-220 µm in inner diameter) were transferred to a Lucite chamber containing PSS equilibrated with room air. Each end of the arteriole was cannulated with a micropipette (60- to 80-µm-diameter tip) and secured with sutures (Alcon 11-0 nylon monofilament). After cannulation, the microvessel chamber was transferred to the stage of an inverted microscope equipped to measure and record arteriolar intraluminal diameter (13). Arterioles were initially pressurized to 60 cmH2O with two independent hydrostatic pressure reservoirs. Leaks were detected by pressurizing the vessel, closing the valves to the reservoirs, and then verifying that intraluminal pressure remained constant. Arterioles that exhibited leaks were discarded. Arterioles that were free from leaks were warmed to 37°C.Experimental Design
To determine whether vasoconstrictor responsiveness, stiffness, or maximal diameter of skeletal muscle arterioles is altered by old age, three series of experiments were performed. Each of the series involved isolation and cannulation of 1A arterioles from the soleus and gastrocnemius muscles. One arteriole from the soleus muscle and one arteriole from the gastrocnemius muscle were studied from each animal. In the first series of experiments, spontaneous tone development, active myogenic response, and maximal inner arteriolar diameter were determined. In the second series of experiments, KCl and norepinephrine (NE) responses were sequentially determined, and intraluminal maximal diameter was measured. Finally, in the third series of experiments, the passive pressure-response relationship and maximal diameter were determined. The vessels were then fixed and sectioned for measurement of wall thickness (WT) and vessel cross-sectional area (CSA) to determine whether the stress/strain relationship (stiffness) is altered with old age.Series 1: evaluation of myogenic response. Vessels were equilibrated at 37°C and 60 cmH2O for 60 min, which allowed for the development of spontaneous tone. After equilibration, intraluminal pressure was increased in increments of 10 cmH2O up to 130 cmH2O, decreased from 130 to 10 cmH2O, and finally raised back up to 60 cmH2O. After each step change in intraluminal pressure, diameter was recorded continuously for 5 min. All pressure changes occurred in the absence of intraluminal flow.
To determine maximal diameter at 60 cmH2O, the vessel chamber and pressure lines were filled with calcium-free PSS containing 2.0 mM EDTA. Arterioles were rinsed every 15 min during a 60-min period to facilitate complete relaxation of the arteriolar smooth muscle. In a subset of arterioles, 100 µM sodium nitroprusside was also added to the bathing solution. The diameter of vessels in calcium-free PSS did not increase further when supplemented with sodium nitroprusside.Series 2: evaluation of vasoconstrictor responses to pharmacological agents. A concentration-response relationship to the non-receptor-mediated vasoconstrictor agent KCl was established by measuring changes in vessel diameter that occurred in response to cumulative additions of KCl (20-100 mM) to the vessel bath. Results from the first series of experiments demonstrated that soleus muscle arterioles from aged animals developed less spontaneous tone than those from young rats. To avoid the potential problem of comparing agonist-induced vasoconstrictor responses between groups having different levels of baseline tone, KCl (and NE) responses were initiated before the development of significant spontaneous tone, i.e., the level of spontaneous tone was minimal and similar between arterioles from all groups. After each addition of the vasoconstrictor agonist, diameter was monitored continuously until a steady-state constriction was recorded.
To determine the vascular reactivity to a receptor-mediated vasoconstrictor agent, the adrenergic agonist NE was used. Diameter changes that occurred in response to cumulative additions of NE (1 × 109-1 × 104 M) to the bathing
solution were recorded continuously after each dose. At the end of the
experiment, maximal diameter was determined in calcium-free PSS as
described above.
Series 3: evaluation of passive pressure-diameter relationship
and stiffness.
Because alterations in the mechanical or structural properties of
arteries can affect active myogenic vasoconstriction, passive pressure-diameter relationships and stiffness were determined in
arterioles from young and old animals. Previous investigation of
arteries from normotensive and hypertensive animals indicates that the
structural behavior of a vessel segment may remain unchanged despite an
alteration in the material properties of the vascular wall
(40). Therefore, the passive pressure-diameter
relationship and measures of stiffness were used to assess the
structural behavior and material properties of the arterioles,
respectively. Arterioles equilibrated at 37°C for 60 min with the
vessel chamber and pressure lines filled with calcium-free PSS
containing 2.0 mM EDTA. The arterioles were rinsed every 15 min during
the 60-min period to induce complete vasorelaxation. The intraluminal
pressure was then lowered to 0 cmH2O, and a
pressure-diameter relationship was established by increasing pressure
in increments of 10 cmH2O up to 130 cmH2O. The
inner diameter was recorded continuously for 3 min after each step
increase in pressure. After the last pressure step, intraluminal
pressure was returned to 60 cmH2O for 5 min. The vessel was
then fixed with Bouin's solution, stained with eosin, and embedded in
paraffin. Paraffin-embedded vessels were cut into 5-µm-thick cross
sections, mounted on glass microscope slides, and stained with eosin
and hematoxylin. The medial CSA of arterioles was measured as
previously described (17). Medial wall thickness at each
pressure step was then calculated according to the following equation
![V<IT>=&pgr;</IT>[(ID<IT>+</IT>2WT)<SUP>2</SUP><IT>−</IT>ID<SUP>2</SUP>]<IT>L=&pgr;</IT>[(ID<SUB>o</SUB><IT>+</IT>2WT<SUB>o</SUB>)<SUP>2</SUP><IT>−</IT>(ID<SUB><IT>o</IT></SUB>)<SUP>2</SUP>]<IT>L</IT>](/content/vol282/issue5/fulltext/H1843/img001.gif)
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(1) |
) and circumferential second
Piola-Kirchhoff stresses (S) (6, 26) were calculated from intraluminal pressure (IP), inner diameter, and wall thickness in the
following manner
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(2) |
![S<SUB>&thgr;</SUB> = &sfgr;<SUB>&thgr;</SUB> × [1/(&lgr;<SUB>&thgr;</SUB>)<SUP>2</SUP>]](/content/vol282/issue5/fulltext/H1843/img003.gif)
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(3) |
is the principal stretch (extension)
ratio in the circumferential direction, which equals current inner
radius (r) divided by initial inner radius (R).
In these arterioles, can be accurately represented
by measurements of the inner radius because the wall thickness is
minimal, i.e., on average, wall thickness is ~4% of outer diameter.
Because the deformations of the arterioles are large, principal stretch
ratios were appropriate measures for this study (6). The
Cauchy stress, or true stress, is defined as the actual force acting on
an oriented differential area in the current (deformed) configuration
and is related to the principal stretch ratio (). The second
Piola-Kirchhoff stress, on the other hand, is defined as a theoretical
force acting on an oriented differential area in the reference
(undeformed) configuration and is conjugate to the Green's strain
(E), where conjugate indicates that the stress can be
determined directly from an energy function by differentiating with
respect to the conjugate measure of deformation (26). The
circumferential Green's strain is calculated in the following manner
![E<SUB>&thgr;</SUB>=½[(&lgr;<SUB>&thgr;</SUB>)<SUP>2</SUP>−1]](/content/vol282/issue5/fulltext/H1843/img004.gif)
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(4) |
Data Analysis
The development of spontaneous tone was expressed as the percent constriction relative to maximal diameter and was calculated as follows
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(5) |
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(6) |
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(7) |
where IDb is the initial baseline diameter recorded
immediately before the addition of the vasoconstrictor agonist and
IDs is the steady-state diameter measured after each dose
of the drug. Two-way repeated-measures ANOVA was used to detect
differences between (young vs. old or soleus vs. gastrocnemius) and
within (drug concentration or pressure level) factors. Post hoc
analyses were performed using Scheffé's test for pairwise
comparisons. Differences in animal weight between old and young groups
were compared with t-tests. All data are presented as
means ± SE. In all statistical analyses, n is the
number of animals from which vessel responses were measured.
Significance was defined as P 
0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Body weight was significantly greater with old age. Young rats weighed 348 ± 6 g and aged rats weighed 420 ± 7 g.Characteristics of Isolated Vessels
Vessel characteristics are reported in Table 1. Maximal inner diameters of arterioles from the soleus muscle ranged from 59 to 214 µm in young animals and from 80 to 213 µm in aged animals, with no differences between age groups. Maximal inner diameters of arterioles from the superficial gastrocnemius muscle of young rats ranged from 108 to 196 µm and in aged rats from 122 to 214 µm; maximal diameter of the old animals tended to be larger (P = 0.06) than that of the young group. The average diameter of soleus muscle 1A arterioles was significantly less than the diameter of gastrocnemius muscle 1A arterioles in both age groups.
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The level of development of spontaneous tone at 60 cmH2O varied with age and muscles (Table 1). Arterioles from the soleus muscle of young animals developed more tone than those from aged animals. Average tone development in arterioles from the gastrocnemius muscle did not differ between young and old animals (P = 0.12). Finally, arterioles from the soleus muscle displayed greater spontaneous tone than arterioles from gastrocnemius muscle (P < 0.05).
Myogenic Responses
Figure 1 illustrates active and passive pressure-diameter relationships as intraluminal pressure was increased stepwise from 10 to 130 cmH2O. Arterioles from both the soleus and gastrocnemius muscles of young and old rats displayed active myogenic constriction. In addition, active responses of arterioles from both the soleus and gastrocnemius muscles from aged rats were significantly less than those of arterioles from young rats and more closely resembled passive responses to increasing pressure. The differences between the active responses of arterioles from young and old animals were present either when pressure was increased or decreased from 10 to 130 cmH2O. No significant hysteresis was detected in the active responses to pressure in any group.
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Arterioles from the soleus muscle displayed significantly greater myogenic responses than arterioles from the gastrocnemius muscle in both young and old animals.
Vasoconstrictor Responses to Pharmacological Agents
There were no age-related or muscle type-related differences in the vasoconstrictor responses to pharmacological agents. Both sensitivity (EC50) and maximal constriction to KCl and NE were similar in arterioles from young and old animals and from the soleus and gastrocnemius muscles (Figs. 2 and 3).
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Pressure-Diameter Relationship and Stiffness
Passive changes in diameter that occurred as pressure was increased from 0 to 130 cmH2O were not altered by age in arterioles from either the soleus or gastrocnemius muscle (Fig. 1). Stress/stretch analysis indicated that the mechanical behavior of arterioles from young and old animals did not differ once a minimal load (10 cmH2O intraluminal pressure) was placed on the vessels. If the initial, undeformed radius used to calculate stretch was defined as the radius measured when intraluminal pressure was zero, a separation was present in the stress/stretch relationships for arterioles from young and old animals (Figs. 4A and 5A). If the stress/stretch relationship was established using the radius measured when intraluminal pressure was set at 10 cmH2O, this difference in the curves was eliminated (Figs. 4B and 5B). Linear regression analysis and calculation of the slope of the incremental stiffness-stretch relation in each vessel indicated that this measure of nongeometric stiffness of arterioles (for calculations, see Fig. 6, A and B) tended to be higher in soleus muscle arterioles from old rats (young: 2.45 ± 0.60 dyn/cm2; old: 3.78 ± 0.54 dyn/cm2, P = 0.10) but was not different in arterioles from the gastrocnemius muscle (young: 3.69 ± 0.67 dyn/cm2; old: 3.57 ± 0.57 dyn/cm2, P = 0.38). Additionally, this measure of stiffness was not different between arterioles from the soleus and gastrocnemius muscles in either young or old rats.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Previous work has demonstrated that skeletal muscle hyperemia during exercise is reduced with old age in rats (28) and humans (39, 51). The purpose of the present study was to test the hypotheses that with old age, skeletal muscle arterioles 1) are more reactive to vasoconstrictor agents or transmural pressure changes; 2) are passively more resistant to distension, i.e., they are stiffer; and 3) have structurally remodeled so that maximal diameter is smaller. Six main findings emerge from this investigation. First, aging reduces rather than increases myogenic responses of 1A arterioles from both the gastrocnemius and soleus muscles. Second, vasoconstrictor responses to the pharmacological agents KCl and NE are not altered by age in 1A arterioles from either muscle type. Third, wall thickness increases with age in soleus muscle arterioles, whereas maximal diameter of 1A arterioles from the soleus and gastrocnemius muscles is not altered by old age. Fourth, the functional mechanical properties and material properties (i.e., the passive pressure-diameter relationship and stiffness) of resistance arterioles from the soleus and gastrocnemius muscles are similar in young and old rats. Fifth, spontaneous tone development and myogenic activity differ between arterioles from the soleus muscle, a highly oxidative postural muscle, and the highly glycolytic portion of the gastrocnemius muscle (18). Finally, the mechanical distensibility (stretch) of skeletal muscle arterioles exceeds that of other arterial vessels reported in the literature.
The effects of aging on the intrinsic responsiveness of arteries to
vasoconstrictor stimuli appear to vary along the arterial vascular
network and between tissues. For example, in the rat aorta, maximal
tension produced by NE, vasopressin, and KCl decreases with aging
(16). In human subcutaneous resistance arteries, it has
been reported that maximal constrictor responses to 
-adrenergic agents are also decreased by aging (38). In contrast, Cook
et al. (7) reported that NE-induced vasoconstriction was
not altered in resistance arterioles from the cremaster muscle (a
striated muscle that does not have skeletal connections) of aged rats. In the present study, we were specifically interested in evaluating the
effects of age on vasoconstrictor responses of resistance arterioles
from skeletal muscle. We found that the responses to both NE, which
causes contraction through receptor binding and activation of an
intracellular second messenger system to increase intracellular
Ca2+ in smooth muscle, and KCl, which acts through a
receptor-independent mechanism to increase intracellular
Ca2+, were similar in arterioles from young and old rats.
However, responses to transmural pressure changes (the myogenic
response) were blunted by old age. This differential effect of aging on vasoconstrictor responses to pharmacological agents and the myogenic response suggests that, unlike the general blunting of vasoconstrictor responses reported in the aorta of senescent rats (16),
aging-induced adaptations in skeletal muscle arterioles stem from a
change in mechanisms uniquely involved in the myogenic response.
Therefore, changes in components of the signaling pathways that are
common to KCl-, NE-, and pressure-induced constriction, such as
Ca2+ entry through voltage-gated channels, Ca2+
release from the sarcoplasmic reticulum, and contractile protein activity (9, 10, 33, 35, 36), are unlikely to have been
altered by aging in these vessels.
One means through which myogenic responsiveness can be altered is via a change in vascular structure. For example, in rats where the hindlimb has been unloaded via tail suspension, there is a diminished myogenic responsiveness of gastrocnemius muscle arterioles to incremental changes in transmural pressure (13); this myogenic alteration is paralleled by a structural remodeling of the arteriole, i.e., smooth muscle atrophy and thinning of the medial layer (17). In the hindlimb unloading model, the thinning of the arteriolar media blunted both the myogenic response and vasoconstriction induced by pharmacological agents (13). Therefore, if gross structural changes were responsible for the blunted myogenic responsiveness that occurs with old age, a reduction of all vasoconstrictor responses might be expected. Instead, aging selectively impaired the myogenic response, and this reduction in the myogenic responsiveness was accompanied by an increase in arteriolar wall thickness. These results suggest that the impaired myogenicity of skeletal muscle resistance arterioles from aged rats does not result from gross structural changes in the vascular smooth muscle but may be due to an alteration of the relative composition of the vascular wall, i.e., changes in collagen isoforms or extracellular matrix proteins.
To determine whether the change in the myogenic response was related to a change in the structural behavior or the intrinsic material properties of arterioles from aged animals, we recorded passive diameter in response to pressure changes and calculated vascular stiffness. The data indicate that the structural behavior of these vessels remains constant with age (Fig. 1). Furthermore, the data indicate that aging did not alter the intrinsic material properties of either soleus or gastrocnemius muscle arterioles (Figs. 4B and 5B). The shift in the stress/stretch relationship that occurred (Figs. 4A and 5A) may indicate that the vessels do change with age, resulting in a resetting of this relationship. The wall thickness of soleus muscle arterioles was significantly increased in aged animals. As a result of this increase, the maximal stress recorded in soleus muscle arterioles was reduced compared with arterioles from young animals. Similarly, the maximal stress recorded in gastrocnemius muscle arterioles was lower than that recorded in soleus muscle arterioles because of the difference in wall thickness. Data from the present study suggest that arterioles from soleus muscle do undergo some remodeling with age, but this does not impact the mechanical response of the vessels as pressure (stress) increases. Therefore, the decrease in the myogenic tone in skeletal muscle arterioles is likely due to an impairment of a pressure-sensitive signaling mechanism (possibly linked to a change in the composition of the vascular wall) but not directly related to a structural impairment of the vessel wall.
Another means through which myogenic responsiveness could be blunted with old age is through alterations in the vascular endothelium. For example, an increased release of endothelium-derived vasodilator substances in arterioles from old animals could function to attenuate active constrictor responses to increases in transmural pressure. Preliminary evidence from arterioles of the soleus and gastrocnemius muscles, however, does not support such a contention (45, 46). We have found that neither acetylcholine nor flow-induced vasodilation is increased in arterioles from old rats; on the contrary, these endothelium-dependent vasodilatory responses are diminished with aging. Although these preliminary results do not definitively exclude the involvement of endothelium in the diminished myogenic responsiveness, they do suggest it is not likely the result of an enhanced release of an endothelium-derived vasodilator substance.
Finally, it is possible that aging-induced alterations in skeletal muscle fibers could modify the chemical milieu surrounding the resistance vasculature to provide a stimulus for vascular adaptation. For example, there is evidence in human skeletal muscle that aging alters both the fiber composition and oxidative capacity of muscle (25). In the aging rat, there does not appear to be significant alterations in muscle fiber composition (1, 5), particularly in the soleus muscle, but there are age-related reductions in the oxidative capacity of slow-twitch and fast-twitch muscles (47). Thus one could speculate that age-induced alterations in skeletal muscle metabolism could alter metabolite release and correspondingly influence the intrinsic myogenic responsiveness of vascular smooth muscle.
Evidence from rats and human subjects suggests that skeletal muscle blood flow capacity is reduced by old age (28, 39, 51). In contrast to our hypothesis that increased reactivity of skeletal muscle arterioles to vasoconstrictor agents could contribute to the phenomenon of reduced skeletal muscle blood flow, we found that vasoconstrictor responses to KCl and NE were unchanged and that the myogenic response was reduced in aged rats. Although these results do not appear to explain the reduction in blood flow capacity that occurs with advancing age, impaired myogenic responses of skeletal muscle resistance arterioles may be important in determining overall control of skeletal muscle blood flow in the elderly. The myogenic response has been postulated to contribute to the maintenance of constant blood flow and capillary hydrostatic pressure during changes in arterial pressure (11, 21). For example, during the assumption of an upright posture in humans, myogenic constriction of resistance arterioles buffers against an increase in capillary hydrostatic pressure in the lower extremities and contributes to an increase in total peripheral resistance (21, 27). Approximately 20% of the increase in total peripheral resistance during orthostasis occurs as a result skeletal muscle vasoconstriction (41). Thus an old age-induced blunting of the myogenic responsiveness of skeletal muscle arterioles could impact the ability of skeletal muscle to increase vascular resistance and, therefore, overall peripheral vascular resistance. This is consistent with observations that the mechanisms that mediate increases in peripheral vascular resistance in response to head-up tilt and orthostatic challenges are altered in the elderly (12, 37, 43, 44, 48). Furthermore, it has been reported that older subjects increase splanchnic resistance to a greater extent but demonstrate less of an increase in skeletal muscle vascular resistance in response to head-up tilt (37, 43, 48). Thus a diminished myogenic vasoconstrictor responsiveness of the rodent skeletal muscle resistance vasculature with aging is consistent with these observations in humans.
The results of this study also indicate that the intrinsic ability of
blood vessels to respond to changes in transmural pressure is
differentially regulated in resistance arterioles from muscles composed
of different fiber types, e.g., the highly oxidative soleus muscle and
the glycolytic superficial portion of the gastrocnemius muscle. In
contrast, constrictor responses to KCl and NE were similar in
arterioles from these two muscle types. In addition to the oxidative
capacity and fiber composition (18), the recruitment order
(2, 3, 18) and blood flow patterns at rest and during exercise (2, 14, 32) vary between these two muscle types. Any of these differential characteristics could influence the intrinsic
responses of the resistance arteries within the muscle. Laughlin and
Armstrong (31) showed that in conscious rats,
-adrenergic blockade increased blood flow to fast-twitch muscle but
did not change blood flow to slow-twitch muscle. Delp and Armstrong
(14) have shown that under resting conditions, blood flow
is much greater in the soleus muscle compared with the white portion of
the gastrocnemius muscle; however, upon denervation, blood flow to the
white gastrocnemius muscle increases, whereas blood flow to the soleus
muscle decreases. These findings suggest that under normal resting
conditions, higher adrenergic tone is present in the white portion of
the gastrocnemius muscle, composed of fast-twitch fibers, whereas blood
flow to highly oxidative soleus muscle is predominantly under metabolic control. The difference in tonic adrenergic input between these two
muscles may influence the myogenic responsiveness of the resistance vasculature, resulting in a greater development of a myogenic mechanism
in the soleus muscle, where adrenergic tone is less dominant.
Results of the present investigation indicate the intrinsic material
properties of skeletal muscle arterioles are unique compared with other
arterial vessels. This is based on the findings that the stretch ratios
measured in the skeletal muscle arterioles (Figs. 4 and 5) are greater
than those reported for conduit arteries (8, 40) and
cerebral arterioles (24). We presume that the variation in
arteriolar distensibility between vascular beds is functionally
important and reflects differences in the perfusion demand among
organs. For example, exercise represents a significant metabolic stress
for both the brain (15, 49) and skeletal muscle (2,
4, 42). In going from rest to high intensity exercise, brain
blood flow increases ~20-40
ml · min1 · 100 g1, which
represents approximately a 25-50% increase in perfusion (15, 49). In contrast, skeletal muscle perfusion is
elevated up to 200-500
ml · min1 · 100 g1 above
that at rest, a 10 to 20-fold increase (2, 4, 42). Although there are a number of mechanisms through which the skeletal muscle vasculature can accommodate such high flow rates during exercise
(19), a high stretch ratio of skeletal muscle arterioles appears to be a necessary feature.
In addition to higher stretch ratios relative to other arteries, the stretch ratios for skeletal muscle arterioles in the present study are greater than what can be estimated from pressure-diameter relationships previously published for isolated cheek pouch (11) and isolated gracilis muscle arterioles (50). These differences may be related to differences in the resting vessel length established by the investigator. In the present study, arterioles were pressurized at 60 cmH2O and then stretched longitudinally to a length at which no bending of the vessel was evident. Images published by Davis and Gore (11) indicate that similar vessel lengths were used in the study of isolated cheek pouch arterioles; however, the resting length of gracilis muscle arterioles was not published (50). Differences in the stretch ratios of skeletal muscle arterioles among the present and previously published studies may also be attributable to our use of an undeformed vessel radius measured at an intraluminal pressure of 0 cmH2O (Figs. 4A and 5A). If arteriolar diameter at an intraluminal pressure of 10 cmH2O is used as the undeformed radius in calculating arteriolar distensibility [the lowest pressure previously used to establish a pressure-diameter relation for skeletal muscle arterioles (11, 50)], then the stretch ratios of skeletal muscle arterioles from the present study (Figs. 4B and 5B) are virtually identical to those that can be estimated from these previous reports. Therefore, these data suggest that the stretch ratio of skeletal muscle arterioles may be fairly uniform across muscles when a true undeformed vessel radius is determined and that skeletal muscle arteriolar distensibility is greater than that of conduit arteries and arterioles in other tissue.
In summary, the results of the present study demonstrate that neither myogenic, KCl, nor NE vasoconstrictor responses are enhanced in skeletal muscle 1A arterioles with aging. Rather, these data demonstrate that myogenic responses of isolated resistance arterioles from both the soleus and the superficial portion of the gastrocnemius muscles are impaired in aged Fischer rats. This impairment of the myogenic response is not a result of a generalized reduction of all vasoconstrictor responses in these resistance arterioles, because responses to KCl and NE were similar between young and aged rats. In addition, the reduction of the myogenic response is not a consequence of altered stiffness in arterioles from either soleus or gastrocnemius muscles. These findings suggest that aging specifically alters mechanisms that are critical to transduction of the myogenic response. Such an alteration in the myogenic responsiveness of the resistance vasculature of skeletal muscle may impact the ability of the aged skeletal muscle vasculature to elevate resistance during varying physiological challenges, such as during the assumption of an upright posture. Results from the present study also demonstrate that spontaneous tone development and myogenic activity are greater in arterioles from the soleus muscle, a highly oxidative postural muscle, than in resistance vessels from the highly glycolytic, low-oxidative portion of the gastrocnemius muscle (18). Finally, the mechanical distensibility of skeletal muscle arterioles exceeds that of other arterial vessels previously reported in the literature.
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ACKNOWLEDGEMENTS |
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This work was supported by American Heart Association, Texas Affiliate, Grant 98BG801 (to J. Muller-Delp), a Sam Houston State University Institutional award (to J. Muller-Delp), National Institute on Aging Grant AG-19248-01 (to J. Muller-Delp), and National Aeronautics and Space Administration Grants NAGW-4842 and NAG5-3754 (to M. D. Delp).
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. M. Muller-Delp, Dept. of Health and Kinesiology, Texas A&M Univ., College Station, TX 77843 (E-mail: jmd{at}hlkn.tamu.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 6, 2001;10.1152/ajpheart.00666.2001
Received 27 July 2001; accepted in final form 1 November 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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