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J Appl Physiol 85: 1649-1654, 1998;
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Vol. 85, Issue 5, 1649-1654, November 1998

Skeletal muscle vasodilation at the onset of exercise

John B. Buckwalter, Stephen B. Ruble, Patrick J. Mueller, and Philip S. Clifford

Departments of Anesthesiology and Physiology, Medical College of Wisconsin and Veterans Affairs Medical Center, Milwaukee, Wisconsin 53295

    ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

The purpose of this study was to determine whether beta -adrenergic or muscarinic receptors are involved in skeletal muscle vasodilation at the onset of exercise. Mongrel dogs (n = 7) were instrumented with flow probes on both external iliac arteries and a catheter in one femoral artery. Propranolol (1 mg), atropine (500 µg), both drugs, or saline was infused intra-arterially immediately before treadmill exercise at 3 miles/h, 0% grade. Immediate and rapid increases in iliac blood flow occurred with initiation of exercise under all conditions. Peak blood flows were not significantly different among conditions (682 ± 35, 646 ± 49, 637 ± 68, and 705 ± 50 ml/min, respectively). Although the doses of antagonists employed had no effect on heart rate or systemic blood pressure, they were adequate to abolish agonist-induced increases in iliac blood flow. Because neither propranolol nor atropine affected iliac blood flow, we conclude that activation of beta -adrenergic and muscarinic receptors is not essential for the rapid vasodilation in active skeletal muscle at the onset of exercise in dogs.

blood flow; autonomic nervous system; muscarinic; beta -adrenergic; dogs

    INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

VASODILATION IN ACTIVE SKELETAL MUSCLES during exercise reflects the transition from the low oxygen demands at rest to the high oxygen demands associated with exercise. The mechanism by which vasodilation occurs in active skeletal muscles is poorly understood, but a neural mechanism is particularly appealing because of the rapidity of the increase in skeletal muscle blood flow at the onset of exercise. Although beta -adrenergic receptors and muscarinic receptors are present in the arterial vasculature of skeletal muscle (6, 17, 22, 48), there is limited evidence suggesting that sympathetic beta -adrenergic (17, 23, 26, 36) and sympathetic cholinergic (40, 44) receptors may play a role in skeletal muscle hyperemia during exercise. In addition, it has been postulated that acetylcholine spillover from the neuromuscular junctions of exercising skeletal muscles may provide a source of acetylcholine for muscarinic-mediated vasodilation during exercise (41, 49). A recent study by Buckwalter et al. (8) concluded that neither beta -adrenergic receptors nor muscarinic receptors are essential in maintaining vasodilation during steady-state exercise. However, the design of that study precluded examination of skeletal muscle blood flow at the onset of exercise. It has been suggested that the mechanism mediating the intial skeletal muscle hyperemia at the onset of exercise may be different from that which sustains blood flow during steady-state exercise (16).

The purpose of the present study was to examine the role of beta -adrenergic- and muscarinic-mediated vasodilation in active skeletal muscles at the onset of exercise. We used a unique experimental approach that allowed manipulation of blood flow to one hindlimb without affecting systemic hemodynamics or blood flow in the contralateral limb in conscious exercising dogs. We hypothesized that beta -adrenergic and muscarinic receptors play an essential role in skeletal muscle vasodilation at the onset of exercise.

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

All experimental procedures were approved by the Institutional Animal Care and Use Committee and conducted in accordance with the American Physiological Society's "Guiding Principles in the Care and Use of Animals." Seven mongrel dogs, weighing between 16 and 24 kg, were selected for their willingness to run on a motorized treadmill and were instrumented in a series of sterile surgical procedures. Anesthesia was induced with thiopental sodium (15-30 mg/kg; Gensia Pharmaceuticals, Irvine, CA). After intubation with a cuffed endotracheal tube, a surgical level of anesthesia was maintained through mechanical ventilation with 1.5% halothane (Halocarbon Laboratories, River Edge, NJ) and 98.5% oxygen. Antibiotics (cefazolin sodium, Apothecon, Princeton, NJ) and analgesic drugs (buprenorphine hydrochloride, 0.3 mg; Reckitt and Colman, Kingson-upon-Hull, UK) were given postoperatively. During the first surgical procedure, the carotid arteries were placed in skin tubes in the neck so that they could be cannulated percutaneously to measure arterial blood pressure (31, 33). In the second surgery, all dogs were instrumented with flow probes (4- or 6-mm ultrasonic transit-time flow probes, Transonic Systems, Ithaca, NY) around the external iliac arteries to measure hindlimb blood flow. The cables were tunneled under the skin to the back, and the dogs were given 2 wk to recover from flow probe implantation. In the final surgery, a heparinized catheter (0.045 in. OD, 0.015 in. ID, Data Science International, St. Paul, MN) was implanted chronically through a side branch of the femoral artery for drug infusion. The catheter was tunneled to the back of the dog. The catheter was flushed daily with saline and filled with a heparin lock (100 IU heparin/ml in 50% dextrose solution) to maintain patency. The dogs were given at least 2 days to recover from the final surgery before any experiments were performed.

All experiments were performed in a laboratory in which the temperature was maintained below 20°C. A 20-gauge Teflon catheter (Insyte, Becton Dickinson, Sandy, UT) was inserted retrogradely into the lumen of the carotid artery and attached to a solid-state pressure transducer (Ohmeda, Madison, WI). The flow probes were connected to a transit-time flowmeter (Transonic Systems). Immediately before the start of exercise, 1 mg propranolol (nonselective beta -adrenergic-receptor antagonist), 500 µg of atropine, (muscarinic antagonist), both drugs, or a saline (as a control) was infused intra-arterially into one hindlimb. The dogs then ran on a motorized treadmill at 3 miles/h (mph; 4.8 km/h), 0% grade, which represents a mild workload. Between 1 and 2 min of exercise, either a nonselective beta -adrenergic-receptor antagonist (0.2 µg isoproterenol, Abbott Laboratories, Chicago, IL) or a muscarinic-receptor agonist (1 µg acetylcholine, Sigma Chemical, St. Louis, MO) was infused intra-arterially to test the effectiveness of receptor blockade. These doses of the receptor agonists and antagonists have been previously used in this laboratory (8). At least 24 h separated each experiment, all experiments were performed in duplicate, and data were averaged for each dog.

Arterial blood pressure and right and left external iliac blood flow were simultaneously written to paper on a polygraph recorder (model 7, Grass, Warwick, RI) and stored on both a videocassette data recorder (model D, Vetter, Rebersburg, PA) and computer (Apple 8500 Power PC) by using a MacLab system at 100 Hz (ADInstruments, Castle Hill, Australia). Data were analyzed off-line by using the MacLab software to calculate mean arterial pressure, heart rate, and iliac blood flow. Blood flow was averaged over 10 s of rest preceding the initiation of exercise and over 1-s intervals for the first 30 s of exercise. The peak blood flow attained and the time to peak blood flow at the onset of exercise were also analyzed for each condition. Hemodynamic variables were averaged over 15 s before agonist infusion and over 1-s intervals after infusion. The peak response was recorded, and, where no response was obvious, the peak response was chosen over the same interval where it occurred during the control (no antagonist) experiment.

Statistical analyses of the data were performed with a two-way repeated-measures (drug × time) analysis of variance for the blood flow averages at 5-s intervals over the first 30 s of exercise. One-way repeated-measures analyses of variance were used to examine the peak blood flow response at the onset of exercise, time to peak blood flow, blood pressure, and heart rate. A paired t-test was used to examine the magnitude of agonist-induced increases in blood flow. An alpha  level of 0.05 was used to establish statistical significance. Where significant F-ratios were found, a Tukey's post hoc test was performed. All descriptive statistics are presented as means ± SE.

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Table 1 provides heart rate and blood pressure data during exercise with the four different receptor-blockade conditions. There were no statistically significant differences in heart rate or blood pressure among any of the conditions in these experiments.

                              
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  		Table 1.   Hemodynamic values during exercise at 3 mph, 0% grade, after intra-arterial antagonist infusion

Figure 1A is an original tracing from an individual dog beginning exercise on the treadmill at 3 mph, 0% grade, after pretreatment with saline. There were immediate increases in blood flow in the experimental and control hindlimbs that exceeded the eventual steady-state values. Between 1 and 2 min of exercise, an intra-arterial bolus of 0.2 µg of isoproterenol was given and caused an immediate increase in blood flow in the experimental hindlimb with no change in heart rate, blood pressure, or blood flow in the contralateral limb. Mean data from seven dogs revealed a statistically significant increase in experimental hindlimb blood flow with isoproterenol (465 ± 22 to 923 ± 40 ml/min; P < 0.0001). Figure 1B is an original tracing from the same dog beginning exercise after pretreatment with propranolol. As before, there were immediate increases in blood flow in both hindlimbs. The intra-arterial bolus of 0.2 µg of isoproterenol given between 1 and 2 min of exercise did not affect experimental limb blood flow. For all dogs, experimental limb blood flow averaged 427 ± 14 ml/min before infusion of isoproterenol compared with 405 ± 18 ml/min postinfusion (P > 0.05).


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  		Fig. 1.   Original tracings from 1 dog at onset of exercise at 3 miles/h, 0% grade. There were immediate increases in iliac blood flow at onset of exercise. In A, intra-arterial bolus of saline was given before exercise (not shown) while dog was sitting on treadmill. Subsequent infusion of 0.2 µg of isoproterenol markedly increased iliac blood flow. In B, intra-arterial bolus of 1 mg of propranolol was given before exercise (not shown) while dog was sitting on treadmill. Subsequent infusion of 0.2 µg of isoproterenol did not increase iliac blood flow. None of the intra-arterial bolus infusions altered heart rate, systemic blood pressure, or blood flow in control limb.

Figure 2A is an original tracing from an individual dog beginning exercise on the treadmill after pretreatment with saline. Note again that there were immediate increases in blood flow in the experimental and control hindlimbs that exceeded the eventual steady-state values. Between 1 and 2 min of exercise, an intra-arterial bolus of 1 µg acetylcholine was given and caused an immediate increase in blood flow in the experimental hindlimb with no change in heart rate, blood pressure, or blood flow in the contralateral limb. For the group, blood flow in the experimental hindlimb increased with acetylcholine from 491 ± 25 to 914 ± 49 ml/min (P = 0.0002). Figure 2B is an original tracing from the same dog beginning exercise after pretreament with atropine. As before, there were immediate increases in blood flow in both hindlimbs. The intra-arterial bolus of 1 µg of acetylcholine between 1 and 2 min of exercise did not affect experimental limb blood flow. Mean blood flows for the 7 dogs were 555 ± 27 ml/min before infusion of acetylcholine and 554 ± 30 ml/min postinfusion (P > 0.05).


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  		Fig. 2.   Original tracings from 1 dog at onset of exercise at 3 miles/h, 0% grade. There were immediate increases in iliac blood flow at onset of exercise. In A, an intra-arterial bolus of saline was given before exercise (not shown) while dog was sitting on treadmill. Subsequent infusion of 1 µg of acetylcholine markedly increased iliac blood flow. In B, intra-arterial bolus of 500 µg of of atropine was given before exercise (not shown) while dog was sitting on treadmill. Subsequent infusion of 0.2 µg of acetylcholine did not increase iliac blood flow. None of the intra-arterial bolus infusions altered heart rate, systemic blood pressure, or blood flow in the control limb.

Figure 3 presents the iliac blood flow response in the experimental hindlimb over the first 30 s of exercise for the four different conditions. As can be readily appreciated from inspecting Fig. 3, there was a significant effect of time on blood flow (P < 0.0001). However, statistical analysis of blood flow data revealed no statistically significant differences among any of the drug conditions (P > 0.05), and there was no significant interaction between time and drug condition (P > 0.05). Analysis of the peak blood flow response and the time to peak blood flow among the four conditions yielded similar results (Table 1). There were no significant differences in peak blood flow responses or times to peak blood flow among any of the drug conditions (P > 0.05).


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  		Fig. 3.   Iliac blood flow response at onset of exercise after pretreatment with saline, propranolol, atropine, or propranolol and atropine. Data were averaged over 1-s intervals (time 0 = rest). SE bars are excluded for clarity of presentation, but SE measurements over 30 s of exercise under 4 conditions ranged from 7 to 51 ml/min. There were no statistically significant differences in blood flow response among any of the pretreatments.

    DISCUSSION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

We observed no changes in the time course or the magnitude of the blood flow response in the canine hindlimb at the onset of mild exercise after blockade of beta -adrenergic or muscarinic receptors. The lack of an effect indicates that neither beta -adrenergic nor muscarinic receptors are required for the immediate skeletal muscle hyperemia at the onset of mild exercise in the dog.

The experimental design in this study provides several distinct advantages over previous attempts to examine the role of beta -adrenergic or muscarinic receptors during exercise. 1) Intra-arterial infusion of small doses of receptor antagonists creates a functionally isolated hindlimb in which localized blockade is produced in the experimental limb without confounding systemic changes in heart rate, mean arterial pressure, or blood flow in the control hindlimb. 2) Continuous recordings of blood flow with transit-time flow probes, as contrasted with discrete measurements with radioactive microspheres, allow more thorough characterization of the time course of blood flow changes. 3) We employed a mild intensity of exercise because we reasoned that this would minimize the metabolic contribution to vasodilation and thus provide the optimal conditions to unmask a neural component. The time course of changes in blood flow shows an overshoot at this workload (Fig. 3). Substantial overshoot has been shown in previous studies at mild exercise intensities (25, 37) and has been attributed to neurally mediated vasodilation (4).

Differential reactivity of arterioles to intravascular vs. extravascular administration of agonists has been demonstrated (19, 28, 29), leading to the suggestion that there is a barrier to diffusion of water-soluble molecules from the lumen to smooth muscle of arterioles (29). Because both propranolol and atropine are lipophilic molecules, we assume that both intraluminal and extraluminal receptors are blocked by intra-arterial infusions of these receptor antagonists. In addition, we have previously shown that intra-arterial infusion of the alpha 1-adrenergic-receptor antagonist prazosin interrupts tonic sympathetic nerve activity in the hindlimb, causing vasodilation (7). This indirect evidence suggests that the receptor antagonists in this study would bind the receptors accessible to norepinephrine released from sympathetic nerve terminals in the canine skeletal muscle vasculature. However, it must be acknowledged that the accessibility of smooth muscle beta -adrenergic and muscarinic receptors with intra-arterial infusion of propranolol and atropine is a potential limitation of this study.

beta -adrenergic-receptor blockade. Previous studies examining the role of beta -adrenergic-mediated vasodilation during exercise have come to conflicting conclusions with several studies reporting a reduction in blood flow to working skeletal muscles (2, 17, 23, 26, 36), whereas others found no effect (8, 18, 22). In the studies that found reductions in skeletal muscle blood flow during exercise with systemic nonselective beta -blockade, there were also markedly lower heart rates (2, 17, 23, 26, 36). The reductions in skeletal muscle blood flow were most likely the result of reduced cardiac output and arterial pressure due to beta 1-blockade in the heart rather than to peripheral beta 2-blockade. In support of this, systemic propranolol administration in anesthetized cats increased total peripheral resistance via baroreceptor-mediated increases in sympathetic constriction rather than via abolition of tonic beta 2-mediated vasodilation (30). In contrast, the studies that showed no effect of beta -adrenergic blockade on skeletal muscle blood flow employed localized administration of the antagonist with no systemic effects (8, 18, 22).

Only one of the previous studies examined the effect of beta -blockade on the transient changes in blood flow at the onset of exercise. Laughlin and Armstrong (26) found reduced muscle blood flow in all the rat thigh muscle samples at 30 s of exercise with propranolol pretreatment and statistically significant reductions in blood flow in 8 of 32 muscles sampled. These differences were observed at mild, but not heavy, exercise intensities. The present study is the first to quantitatively assess the rapid increase in blood flow to working skeletal muscles throughout the first 30 s of dynamic exercise. The influence of beta -adrenergic receptors was examined by using small doses of a nonselective beta -antagonist to avoid confounding systemic cardiovascular changes. The nonselective beta -adrenergic antagonist propranolol was chosen because of previously reported beta 1- and beta 2-mediated vasodilation in the skeletal muscle vasculature of dogs (48). Because of the small dose of propranolol and its localized effect, no beta 1-mediated reductions in heart rate were apparent and any changes in blood flow would reflect beta -adrenergic-mediated vasodilation alone. However, the results provide no evidence of beta -mediated vasodilation at the onset of exercise in the hindlimb vasculature of dynamically exercising dogs. Thus we find little support for a role of beta -adrenergic receptors in the rapid hyperemia at the onset of exercise.

We reasoned that activation of beta -adrenergic receptors at the onset of exercise would be mediated by increased norepinephrine release from sympathetic nerve terminals. The evidence suggests that there is an increase in efferent sympathetic nerve traffic to skeletal muscle during dynamic exercise. Direct measurements of postganglionic sympathetic nerve activity to the hindlimb (lumbar sympathetic trunk) in rats and cats showed that there was an immediate and sustained increase in lumbar sympathetic nerve activity in response to dynamic exercise (11, 20). Furthermore, our group (7) and others (21, 35, 47) have demonstrated that there is substantial sympathetic restraint of skeletal muscle blood flow at mild, moderate, and heavy exercise intensities. We interpret these results to indicate that there is release of norepinephrine from sympathetic nerve terminals in the canine skeletal muscle vasculature. The data from the present study suggest that vascular beta -adrenergic receptors are not activated by the norepinephrine released from these nerve terminals at the onset of exercise.

Muscarnic-receptor blockade. The existence of sympathetic cholinergic-mediated vasodilation in the skeletal muscle vasculature has been demonstrated in a number of studies (5, 6, 9, 40). Sympathetic cholinergic dilator fibers have been shown to be activated by the defense reaction (9). Interestingly, the cardiovascular changes associated with initiation of exercise, such as tachycardia, increases in blood pressure, vasoconstriction in visceral organs, and vasodilation to skeletal muscle, are remarkably similiar to those seen with electrical stimulation of regions of the brain eliciting the defense reaction (1, 9, 10, 13). Besides sympathetic cholinergic fibers, another potential physiological mechanism for muscarinic-receptor activation during exercise is spillover of acetylcholine from the neuromuscular junction (41, 49). This is an attractive hypothesis that would provide a link between muscular contraction and blood flow because motor nerve activity and skeletal muscle blood flow both increase at the onset of exercise and are augmented in an intensity-dependent manner. We hypothesized that activation of muscarinic receptors is involved in the elevated blood flow to dynamically exercising skeletal muscle at the onset of exercise, but our data do not support this hypothesis.

There are few data regarding the role of muscarinic-receptor-mediated vasodilation at the onset of exercise. Bolme and Novotny (5) reported that muscarinic blockade did not change the magnitude of the iliac blood flow response, but the rise was less abrupt at the onset of treadmill exercise in dogs. However, in the present study, intra-arterial atropine did not affect the peak blood flow response or the time to peak blood flow after initiation of treadmill exercise. Armstrong and Laughlin (3) also reported no difference in skeletal muscle blood flow in rats at 30 s of exercise on a treadmill after pretreatment with atropine. A particular strength of the present investigation, besides quantifying the increase in blood flow at the onset of exercise, is that, unlike in previous investigations (3, 5, 36), atropine was given in a small, localized dose. This allowed for interpretation of the data without confounding increases in heart rate due to blockade of cardiac muscarinic receptors. However, we find no evidence for muscarinic-receptor-mediated vasodilation in the hindlimb of the dog at the onset of exercise.

The possibility of muscarinic-receptor-mediated vasodilation compensating for the removal of beta -adrenergic-receptor-mediated vasodilation during selected blockade and vice versa was tested by intra-arterial infusion of both receptor antagonists in the same trial. Combined beta -adrenergic- and muscarinic-receptor blockade did not affect the blood flow response at the onset of exercise. This suggests that beta -adrenergic receptors and muscarinic receptors do not function as reciprocal, redundant vasodilator mechanisms at the onset of exercise.

Potential mechanisms. The physiological mechanism responsible for skeletal muscle exercise hyperemia has been a topic of investigation for over 100 years, since Gaskell's proposal (14) that vasodilation occurred in contracting muscle due to the release of metabolites by the muscle fibers. Although skeletal muscle blood flow and metabolic activity increase in an exercise intensity-dependent manner, a mechanistic link between these two events has not been established. A number of vasodilators such as adenosine, potassium, hypoxia, osmolarity, and ATP have received attention over the years without definitive support as being essential for skeletal muscle hyperemia (16, 27). The rapidity of the increase in skeletal muscle blood flow at the onset of exercise and the immediate decrease in blood flow at the cessation of exercise suggest a neural component. However, data from the present study as well as data demonstrating the failure of total autonomic blockade to alter systemic vascular conductance (42) or hindlimb conductance (39) argue against a neural mechanism. There is evidence in support of the muscle pump hypothesis, i.e., that rhythmic muscle contractions help propel blood through the muscles (24, 42, 46). However, the finding that increased venous filling did not change blood flow during contractions is not consistent with this hypothesis (32, 43). Recently, there has been interest in the potential role of nitric oxide release due to increased shear stress (38) or release from hemoglobin (45). The experimental results show that nitric oxide synthase blockade has, at most, a modest effect on exercising blood flow in dogs (34) and humans (12, 15, 44, 50). After more than 100 years of research, the physiological mechanism responsible for skeletal muscle exercise hyperemia remains elusive.

In conclusion, the results from the present study show that there is a population of beta -adrenergic and muscarinic receptors that are functionally present and accessible to intra-arterial infusions of agonists and antagonists. However, these receptors do not mediate the rapid skeletal muscle hyperemia at the onset of dynamic exercise in dogs.

    ACKNOWLEDGEMENTS

The authors acknowledge the valuable technical assistance of Paul Kovac.

    FOOTNOTES

This project was supported by the Medical Research Service of the Department of Veterans Affairs and by the National Heart, Lung, and Blood Institute.

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. §1734 solely to indicate this fact.

Address for reprint requests: P. S. Clifford, Anesthesia Research 151, VA Medical Center, 5000 W. National Ave., Milwaukee, WI 53295 (E-mail: pcliff{at}mcw.edu).

Received 6 March 1998; accepted in final form 6 May 1998.

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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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J APPL PHYSIOL 85(5):1649-1654
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