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Department of Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, Indiana 46202
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Lash, Julia M., and H. Glenn Bohlen. Time- and
order-dependent changes in functional and NO-mediated dilation during exercise training. J. Appl. Physiol.
82(2): 460-468, 1997.
Arterial vessel responses to sodium
nitroprusside (SNP) and acetylcholine (ACh) were measured in the
spinotrapezius muscle of sedentary (Sed) and treadmill-trained (Tr)
rats to determine whether these endothelium-dependent (ACh) and
-independent (SNP) mechanisms contribute to the
training-induced increase in functional vasodilation previously
observed. Control and maximal vessel diameters were similar between Sed
and Tr. After 8 wk of training, functional dilation (2-, 4-, and 8-Hz
contractions) was enhanced in all orders of vessels studied
[terminal feed artery (FA), largest arterioles (1A), and
intermediate-sized arterioles (2A)], but responses to SNP were
increased only in FA. Responses to ACh were not significantly increased
in any vessel order. After 16 wk of training, functional dilation had
regressed in Tr such that only the FA response to 4 Hz was
significantly elevated relative to Sed. However, the FA and 1A
responses to SNP were significantly greater in Tr than in Sed, as were
the 1A and 2A responses to ACh. These results show a dissociation of
functional dilation and SNP- or ACh-mediated responses, as well as
age-dependent interactions, a time-dependent progression, and vessel
order specificity in the adaptations to training.
nitric oxide; endothelium-derived relaxation factor; skeletal
muscle blood flow; exercise hyperemia; microcirculation; muscle
contractions
INTRODUCTION AEROBIC EXERCISE TRAINING enhances the blood flow to
active skeletal muscles during acute bouts of exercise (1, 18, 21). This increase in blood flow is likely due to a combination of functional and anatomical vascular adaptations to the training stimulus. During low- to moderate-intensity contractions, the relative
dilation of skeletal muscle arterioles is 25-100% greater in
trained (Tr) than sedentary (Sed) animals (14, 16). However, the
precise vascular regulatory adaptations responsible for increased functional dilation in Tr animals are relatively unknown. Some studies
have suggested that the endothelium-mediated dilation is enhanced by
aerobic training (3, 12, 29, 32), whereas others have found no change
(6, 22, 23).
Historically, it was assumed that blood flow during skeletal muscle
contractions was regulated by dilation of the microvessels within the
metabolically active tissue. However, more recent studies demonstrate
that the small feed arteries, upstream from the microcirculation and
outside of the tissue proper, contribute significantly to the total
flow response during muscle activity (2, 14, 33). Because these vessels
are not directly exposed to the chemical environment of the active
tissue, dilatory mechanisms other than direct metabolic control must be
responsible for functional dilation of these vessels. One possible
mechanism for the transduction of the dilator stimulus is flow-mediated
vasodilation (26). Theoretically, metabolic dilation of the
microvascular arterioles results in an increase in muscle blood flow
and a concurrent increase in flow through the arterial and arteriolar
feed vessels. This enhanced flow may, in turn, elicit additional
dilation of the larger feed arteries through flow-mediated release of
endothelium-derived relaxing factors (EDRF; 12, 13, 26). In Sed
animals, ~50% of the functional dilation of the largest arterioles
can be attributed to the action of nitric oxide (NO), one of the EDRF
(8). Exercise training has been shown to increase the dilation of the
terminal feed artery (FA) and the largest arterioles (1A) of the rat
spinotrapezius muscle during muscle contractions (14, 16), and
flow-mediated dilation is enhanced in intermediate-sized arterioles
(2A) from the gracilis muscle of exercise-trained rats (12). These
results suggest that flow-mediated vasodilation may play an important role in the enhanced functional hyperemia resulting from aerobic exercise training.
Based on this rationale, the purpose of the present study was to
determine whether the vascular responses to acetylcholine (ACh) or
sodium nitroprusside (SNP) are altered as a result of aerobic exercise training. In many vessel types, local application of
ACh results in the endothelium release of NO (11), one of the
identified EDRF and a potential mediator of flow-induced vasodilation (13). In contrast, SNP serves as an exogenous NO donor (20). Therefore,
both ACh and SNP elicit vasodilation through the NO pathway, with the
ACh effect being dependent on endothelium function. By comparing the
vascular responses to these two drugs, it is possible to distinguish
between endothelium and vascular smooth muscle adaptations in the NO
response. The resistance vessels studied included the terminal FA and
1A and 2A of the rat spinotrapezius muscle to evaluate both parenchymal
and extraparenchymal vessels. This particular muscle preparation was
chosen because of its suitability for microvascular observations and
the fact that exercise training increases functional dilation in both
the macro- and microvessels perfusing this tissue (14, 16). Experiments
were performed after 8 and 16 wk of exercise training to determine
whether the vascular adaptations to aerobic exercise training evolve
over time.
METHODS
3 M at 10, 25, 50, 100, and 200 nA; SNP, 2 × 104 M at 10, 25, 50, 100, 200, and 500 nA. These parameters were determined in preliminary
experiments and were chosen to elicit the widest possible range of
responses for the three orders of vessels studied. Adequate recovery
time (>2-3 min) was allowed during the repositioning of the
pipette to ensure the complete restoration of normal resting diameter
between experimental manipulations, and post hoc statistical analyses
revealed no significant differences between repeated measurements of
resting diameter at any vessel location.
After completion of data acquisition for the drug dose-response
relationships, images of each of the three vessels were obtained in the
resting muscle and immediately after 2 min of muscle contractions at
frequencies of 2, 4, or 8 Hz. Previous studies have demonstrated that
steady-state functional vasodilation is achieved within ~90 s after
the onset of muscle contraction and is maintained for >5 min of total
contraction time (17), and 8-Hz contractions elicit near maximal
functional dilation of the spinotrapezius muscle arterioles in Sed and
Tr rats (14, 16). Contraction frequencies were presented in random
order, and a minimum of 10-min recovery time was allowed after the
cessation of muscle contractions. Resting diameters were consistently
restored between stimulation periods.
In some experiments, the final manipulation was to retest the response
of the terminal FA to a submaximal (25 nA) dose of ACh. An inhibitor of
NO synthase,
NG-monomethyl-L-arginine
(L-NMMA; Sigma Chemical), was
then added to the superfusion solution (0.1 mM). After ~30 min, the
vascular response to a 25-nA present dose of ACh was again recorded for the terminal FA to determine the extent to which this response was
mediated by NO. Subsequently, the dilator responses to 2-, 4-, and 8-Hz
muscle contractions were determined in the presence of
L-NMMA in a manner similar to
that previously described. In a few animals, venular
SO2 were determined in the resting and contracting muscle before and after application of
L-NMMA, as previously described
in detail (15).
Citrate synthase activity.
At the end of the experimental procedures, the right spinotrapezius and
plantaris muscles were removed and stored at 
20°C until
enzymatic analyses were performed. Homogenized solutions (10%
spinotrapezius, 5% plantaris) of each muscle were prepared in 0.1 M
tris(hydroxymethyl)aminomethane buffer containing 0.1% Triton X-100,
and citrate synthase activity was determined by using the method
described by Srere (27). Samples were analyzed at 30°C in duplicate
or triplicate by using a Spectronic 401 spectrophotometer (Milton Roy).
The average coefficients of variation for repeated samples were 3.6%
for the spinotrapezius and 4.2% for the plantaris. Citrate synthase
activity was expressed as micromoles per minute per gram of muscle
tissue.
Data analysis.
Measurements of luminal vessel diameters were determined from the
digitized images by using the image-analysis software previously described. The system was calibrated by using the image of a stage micrometer marked with 10- and 100-µm increments. Dimension
calibrations were performed in both the
x and
y directions to account for any optical distortions inherent to the system. Maximal vessel diameters were considered the largest absolute diameter measured at a given location during drug application or muscle contractions. For
measurements of vascular responses to drug application and muscle
contractions, diameters were expressed relative to the resting or
control diameter (response diameter/resting diameter). All results are
presented as means ± SE. Analyses of variance were performed by
using the CSS:Statistica software package (StatSoft, Tulsa, OK).
Repeated-measures analyses of variance were performed across drug doses
and contraction frequencies to evaluate group differences due to
training status and training duration (Sed or Tr × 8 or 16 wk × dose or frequency). Post hoc tests were performed by using
least significant difference analyses with statistical significance
established at P < 0.05.
RESULTS
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Functional vasodilation. There was no age-dependent change in functional vasodilation of the three vessel types studied in Sed animals (Fig. 2). As previously shown (14, 16), after 8 wk of training, functional vasodilation was enhanced in Tr animals for all vessel types studied. However, the magnitude of the functional dilation appeared to decrease between the 8th and 16th wk of training, and comparable vasodilation was found between the 1A and 2A of Sed and Tr animals at the older age. Functional dilation of the terminal FA remained slightly greater in Tr than Sed animals after 16 wk of training.
Pharmacological dilation. For each vessel order studied, the dilatory responses to SNP and ACh are presented in Figs. 3, 4, 5, A and B, respectively. After 8 wk of training, the responses of the terminal FA to SNP were significantly enhanced in Tr, relative to Sed, animals. After 16 wk of training, this adaptation was further enhanced in the FA, and a similar adaptation was then evident in the 1A. The adaptation in 1A can be attributed to both an increase in the dilatory response of vessels in Tr animals and a regression of the response in Sed animals between the 8th and 16th wk. The vascular responses to ACh were enhanced in the 1A and 2A of Tr animals after 16 wk, but not after 8 wk, of training. In fact, after 8 wk of training, the responses to ACh tended to be suppressed in these vessels. The FA responses to ACh were not affected by training. In summary, the larger vessels of Tr animals, the terminal FA, demonstrated an increased response to SNP within the first 8 wk of training, whereas the smaller 2A vessels demonstrated an increased response to ACh, which developed between the 8th and 16th wk of training. The larger 1A arterioles exhibited an increased response to both drugs, but only after 16 wk of training.
Effects of L-NMMA. Superfusion of the tissue with 0.1 mM L-NMMA reduced the terminal FA dilatory response to a 25-nA present dose of ACh by 40 and 30% in the younger and older age groups, respectively; there was no apparent effect of training status on the L-NMMA suppression of this response. These results suggest that L-NMMA suppressed, but did not eliminate, the release of NO in response to ACh. Superfusion with this concentration of L-NMMA had no effect on MAP, as was seen in preliminary experiments with slightly higher doses. The presence of L-NMMA tended to reduce, but did not significantly change (P > 0.25), resting diameters of the terminal FA in both age groups studied (Figs. 6 and 7, Rest). However, smaller vessels tended to dilate in the younger animals and constrict in the older animals (Table 2). In all animals, blood flow velocity appeared to decrease during the application of L-NMMA. Measurements of venular blood SO2 in the resting muscle were reduced from 48 to 24% SO2 with the application of L-NMMA (Fig. 6B), providing circumstantial evidence that blood flow was in fact reduced. In both age groups, the presence of L-NMMA was associated with smaller terminal FA diameters during submaximal functional vasodilation (Figs. 6 and 7), but there was no such effect on 1A and 2A diameters (Table 2). In a small subgroup of the younger animals, measurements of venular blood SO2 were shown to decrease only slightly during muscle contractions under control conditions, remaining well above 30% SO2 (Fig. 6B). However, during perfusion with L-NMMA, venular blood SO2 were reduced to ~25% SO2 in the resting muscle and fell to below 10-15% SO2 during contractions.
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DISCUSSION
The results of this study indicate that the in vivo regulation of functional vasodilation and vascular reactivity to SNP and ACh are affected by the age of the animals, the location of a vessel in the branching pattern, and the duration of exercise training. Whereas functional vasodilation remained relatively constant in Sed animals between the ages of 12 and 20 wk, the vascular responses to SNP tended to decrease, and those to ACh tended to increase. In contrast, the enhanced functional dilation that has been observed in Tr animals after 8 wk of treadmill running (14, 16) appeared to regress in the following weeks so that functional dilation was similar between Sed and Tr animals after 16 wk of training (Fig. 2). In addition, compared with Sed animals, the terminal FA of Tr animals demonstrated an increased response to SNP within the first 8 wk of training (Fig. 3), whereas 2A demonstrated an increased response to ACh which developed between the 8th and 16th wk of training (Fig. 5). The larger arterioles, the 1A, exhibited an increased response to both drugs that developed between the 8th and 16th wk of training (Fig. 4).
The observed regression of functional vasodilation with prolonged exercise training (Fig. 2) was not an expected result. We anticipated a maintenance of enhanced functional dilation to support the increased aerobic capacity of Tr skeletal muscle. However, without direct measurements of blood flow, we cannot conclude that the magnitude of functional hyperemia also regressed during this time. It is important to note that, although the 1A and 2A responses to muscle contraction were similar between Sed animals and those trained for 16 wk, functional dilation of the terminal FA remained somewhat enhanced, relative to Sed animals, after 16 wk of training (Fig. 2), and the possibility exists that an enhanced functional hyperemia was maintained due to increased vasodilation of these vessels and a potential recruitment of even larger feed vessels. Despite this possibility with regard to local vascular reactivity, we propose that the responses observed in animals after 16 wk of training are most representative of steady-state vascular changes with chronic aerobic training, and those observed after 8 wk of training reflect intermediate or transitional changes.
The training-induced changes in vascular reactivity to SNP and ACh appear to be somewhat dissociated from the changes in functional dilation. It is possible that the increased terminal FA response to SNP reflects a mechanism contributing to the enhanced functional dilation observed after 8 wk of training (Figs. 2 and 3). However, in these vessels, functional dilation tended to regress between the 8th and 16th wk of training, whereas the response to SNP was further enhanced, suggesting that the vascular response to other mediators of functional dilation were also changing during this time period. A similar argument can be made regarding the 1A responses to SNP and muscle contractions (Figs. 2 and 4).
In contrast, the 1A and 2A responses to ACh were significantly enhanced after 16 wk but not after 8 wk of training (Figs. 4 and 5). Therefore, changes in the endothelium response to ACh do not appear to contribute to the enhanced functional dilation observed after 8 wk of training (Fig. 2). The increased reactivity to ACh in the absence of enhanced functional dilation after 16 wk of training further suggests that the endothelium release of NO may play only a minor role in the functional dilation of these vessels. These conclusions are based on the assumption that ACh produces vasodilation primarily through the endothelium release of NO (11), although other mechanisms are proposed to be contributing factors (7, 10, 31). A minor role for NO in the functional dilation of 1A and 2A vessels is also suggested by the absence of a significant effect of L-NMMA on functional dilation of these vessels (Table 2). However, it should be noted that L-NMMA suppressed, but did not eliminate, the dilatory effects of ACh (see RESULTS), and it is possible that an adequate amount of NO was released during muscle contractions in the presence of L-NMMA to elicit the full contribution to functional dilation. There are also indications that additional mechanisms of vasodilation may have been active during L-NMMA application. Although the change in venular SO2 from rest to muscle contractions was similar before and after L-NMMA application, the absolute values were substantially lower in the presence of L-NMMA, falling to ~10% SO2 during contractions (Fig. 6B). These numbers correspond roughly to a local PO2 of ~10 Torr, a level that has been associated with vasodilation (4, 5). It is likely that other metabolic conditions were also compromised, presumably due to the lower tissue blood flow. Therefore, metabolic vasodilation of these smaller vessels may have been enhanced in the presence of L-NMMA to the extent that it compensated for any suppression of NO formation. Considering the SO2 data, the present data suggest that NO plays a major role in the regulation of blood flow in both the resting and contracting spinotrapezius muscle, with the primary effects being on the FA. These results are consistent with those of others who have studied the effects of NO blockade on resting and exercise blood flows in the dog (25) and rat (9) hindlimbs and the rat cremaster muscle (8). However, the present results also suggest that when NO production is suppressed, other vasodilatory mechanisms can elicit near normal functional vasodilation in the arteriolar vessels. Our results were not adequate to fully explore the potential differential effects of L-NMMA between Sed and Tr animals.
The training-induced increase in the 2A reactivity to ACh observed in the present study (Fig. 5) is similar to that observed in 2A isolated from the rat gracilis muscle (12, 29). Sun et al. (29) found that as little as 3 wk of treadmill training enhanced the endothelium-dependent dilator responses of the 2A to ACh and L-arginine by 20-40%; the endothelium-independent responses to SNP were similar between Sed and Tr animals. Koller et al. (12) have found a similar enhancement of flow-dependent dilation in these vessels after 3 wk of training, and this dilation was attributed to endothelium release of both prostaglandins and NO. The primary difference between the present and past studies is the time required for the expression of the adaptation, that is, 16 vs. 3 wk of training. It is likely that the degree to which a muscle is recruited during a training bout plays a role in determining the nature, time course, and magnitude of any vascular adaptations. The primary function of the rat spinotrapezius muscle is to stabilize the shoulder girdle during standing and locomotion (30), and treadmill training has minimal effects on the oxidative capacity of this tissue (14, 16) (Table 1). In contrast, the gracilis muscle contributes to leg adduction and experiences at least transient increases in blood flow during treadmill running (1). We suspect that the stimulus for endothelium adaptations, possibly increases in luminal blood flow (19), is more intense in the gracilis than in the spinotrapezius muscle during treadmill running. Therefore, we would expect the adaptations to occur more rapidly in the gracilis muscle. Similarly, the minimal training-induced changes in spinotrapezius muscle oxidative capacity suggest that the vascular adaptations observed in the present study may be representative of other inactive tissues and may be very different from those found in highly recruited skeletal muscles.
The adaptations of the 1A vessels appear to be a compilation of those of the terminal FA and the 2A (Fig. 4). As in the terminal FA, the 1A response to SNP was enhanced by training, and this adaptation was apparent to some extent after only 8 wk of training. After 16 wk of training, the response to ACh was also enhanced relative to Sed animals, as seen in the 2A. Although ACh may produce vasodilation through NO-independent mechanisms (7, 10, 31), the endothelium release of NO is thought to be a principal component of the response (11). Therefore, it is likely that at least a portion of the increased 1A response to ACh was secondary to the increased vascular smooth muscle response to NO. Unfortunately, we cannot determine the extent to which this is the case. With the use of a similar line of reasoning, it is somewhat surprising that the increased reactivity of the terminal FA to SNP was not also apparent during ACh application (Fig. 3), opening the possibility that the response of the terminal FA endothelium to ACh was actually suppressed as a result of exercise training.
As previously noted, the vascular responses in Sed animals were different between 12- and 20-wk-old animals (Figs. 3, 4, 5). In general, the terminal FA and 1A responses to SNP decreased with time and age, whereas the 2A responses to ACh increased. Thus exercise training essentially reversed or inhibited the "natural" decline in the terminal FA and 1A responses to SNP, magnified the "natural" increase in the 2A response to ACh, and enhanced the 1A response to ACh. Therefore, a portion of the training effect may be attributed to a slowing or reversal of the "natural" effects of aging in Sed animals, and a potential interaction of aging and training effects may be important to consider in future work.
This study is the first to evaluate simultaneously the in vivo regulation of functional and pharmacological vasodilation at various levels of the skeletal muscle microcirculation in exercise-trained animals. For the largest vessels observed in this study, the terminal FA of the rat spinotrapezius muscle, the primary vascular adaptation to exercise training was an enhanced vascular smooth muscle response to SNP, a nitrosamine compound. For the smallest vessels studied, the 2A, the primary adaptation was an enhanced endothelium-mediated response to ACh. Adaptations of both types were observed in the intermediate-sized 1A. For all sizes of vessels studied, functional vasodilation tended to regress between the 8th and 16th wk of training, and there was an apparent dissociation between the enhancement of vasodilation elicited by muscle contractions and that elicited by SNP and ACh. A comparable dissociation was apparent in Sed animals over time, as functional dilation was similar between 12- and 20-wk-old animals, but during the same period of time, dilation in response to SNP tended to decrease and dilation in response to ACh tended to increase. Therefore, age, training duration, vascular branching order, and the specificity of the vasoactive stimulus must all be considered when evaluating the effects of exercise training on microvascular function.
ACKNOWLEDGEMENTS
This work was supported by National Heart, Lung, and Blood Institute Grants HL-47483, HL-20605, and HL-25824.
FOOTNOTES
Address for reprint requests: H. G. Bohlen, Dept. of Physiology and Biophysics, Indiana Univ. School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202.
Received 20 May 1996; accepted in final form 25 September 1996.
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 S. A. Spier, M. D. Delp, J. N. Stallone, J. M. Dominguez II, and J. M. Muller-Delp Exercise training enhances flow-induced vasodilation in skeletal muscle resistance arteries of aged rats: role of PGI2 and nitric oxide Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3119 - H3127. [Abstract] [Full Text] [PDF]
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S. A. Hahn, L. F. Ferreira, J. B. Williams, K. P. Jansson, B. J. Behnke, T. I. Musch, and D. C. Poole Downhill treadmill running trains the rat spinotrapezius muscle J Appl Physiol, January 1, 2007; 102(1): 412 - 416. [Abstract] [Full Text] [PDF]
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R. M. McAllister, J. L. Jasperse, and M. H. Laughlin Nonuniform effects of endurance exercise training on vasodilation in rat skeletal muscle J Appl Physiol, February 1, 2005; 98(2): 753 - 761. [Abstract] [Full Text] [PDF]
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M. H. Laughlin, L. J. Rubin, J. W. E. Rush, E. M. Price, W. G. Schrage, and C. R. Woodman Short-term training enhances endothelium-dependent dilation of coronary arteries, not arterioles J Appl Physiol, January 1, 2003; 94(1): 234 - 244. [Abstract] [Full Text] [PDF]
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H. T. Yang, J. Ren, M. H. Laughlin, and R. L. Terjung Prior exercise training produces NO-dependent increases in collateral blood flow after acute arterial occlusion Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H301 - H310. [Abstract] [Full Text] [PDF]
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H. G. Bohlen and G. P. Nase Arteriolar nitric oxide concentration is decreased during hyperglycemia-induced {beta}II PKC activation Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H621 - H627. [Abstract] [Full Text] [PDF]
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M. P. Massett, A. Koller, and G. Kaley Hyperosmolality dilates rat skeletal muscle arterioles: role of endothelial KATP channels and daily exercise J Appl Physiol, December 1, 2000; 89(6): 2227 - 2234. [Abstract] [Full Text] [PDF]
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H. T. Yang, M. H. Laughlin, and R. L. Terjung Prior exercise training increases collateral-dependent blood flow in rats after acute femoral artery occlusion Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1890 - H1897. [Abstract] [Full Text] [PDF]
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D. P. Thomas and O. Hudlicka Arteriolar reactivity and capillarization in chronically stimulated rat limb skeletal muscle post-MI J Appl Physiol, December 1, 1999; 87(6): 2259 - 2265. [Abstract] [Full Text] [PDF]
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J. L. Jasperse, C. R. Woodman, E. M. Price, E. M. Hasser, and M. H. Laughlin Hindlimb unweighting decreases ecNOS gene expression and endothelium-dependent dilation in rat soleus feed arteries J Appl Physiol, October 1, 1999; 87(4): 1476 - 1482. [Abstract] [Full Text] [PDF]
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J. M. Lash, G. P. Nase, and H. G. Bohlen Acute hyperglycemia depresses arteriolar NO formation in skeletal muscle Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1513 - H1520. [Abstract] [Full Text] [PDF]
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H. G. Bohlen Invited Editorial on "Vasomotor responses of soleus feed arteries from sedentary and exercise-trained rats" J Appl Physiol, February 1, 1999; 86(2): 439 - 440. [Full Text] [PDF]
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J. L. Jasperse and M. H. Laughlin Vasomotor responses of soleus feed arteries from sedentary and exercise-trained rats J Appl Physiol, February 1, 1999; 86(2): 441 - 449. [Abstract] [Full Text] [PDF]
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J. M. Lash Exercise training enhances adrenergic constriction and dilation in the rat spinotrapezius muscle J Appl Physiol, July 1, 1998; 85(1): 168 - 174. [Abstract] [Full Text] [PDF]
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