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1Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623; 2Department of Health and Human Performance, Auburn University, Auburn, Alabama 36849-5323; 3Dipartimento di Scienze e Tecnologie Biomediche, Universita' degli Studi di Milano, I-20090 Segrate (MI); and 4Dipartimento di Medicina DiMCO, Universita di Milano, I-20142 Milano, Italy
Submitted 3 March 2003 ; accepted in final form 26 May 2003
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ABSTRACT |
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oxygen uptake; exercise; muscle pump
Although the pulsatile nature of muscle blood flow has been known to significantly influence mean blood flow, there have been few studies in which the percent contribution of the two muscle phases to total muscle blood flow have been carefully examined when duty cycle and metabolic rate are varied. In the present study, we tested the hypothesis that increasing muscle contraction frequency, which alters the duty cycle and metabolic rate, would increase the contribution of the contractile phase to mean venous blood flow in isolated skeletal muscle during rhythmic contractions.
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METHODS |
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Surgical preparation. The left gastrocnemius-flexor digitorum superficialis muscle complex (for convenience referred to as gastrocnemius) was isolated as described previously (13). Briefly, the muscle was isolated from nearby muscle groups, and all vessels draining into the popliteal vein except for those from the gastrocnemius were ligated to isolate the venous outflow from the gastrocnemius. The arterial circulation to the gastrocnemius was isolated by ligating all vessels from the femoral and popliteal artery that did not enter the gastrocnemius. The left popliteal vein was cannulated, and the venous outflow from the isolated muscle was returned to the animal via a jugular catheter.
The right femoral artery was catheterized for arterial blood sampling. This catheter was connected to the left femoral artery so that the isolated muscle was perfused by blood from this contralateral artery. Perfusion was accomplished via a Sigmamotor pump to control perfusion pressure. All experimental conditions were conducted with perfusion pressure controlled by the pump. A pressure transducer in this line at the head of the muscle constantly monitored perfusion pressure. A carotid artery was also catheterized to monitor systemic blood pressure. The left sciatic nerve, which innervates the gastrocnemius, was doubly ligated and cut between ties. To prevent cooling and drying, all exposed tissues were covered with saline-soaked gauze and with a sheet of Saran. After the muscle was surgically isolated, the Achilles tendon was attached to an isometric myograph to measure force development.
The hindlimb was fixed at the knee and ankle and attached to the myograph with struts to minimize movement. Known weights were used at the end of each experiment to calibrate the force myograph. The isometric force developed by each muscle was normalized to the weight of that muscle. Before each contraction period, the resting muscle was passively stretched until the force produced by a single twitch contraction was maximal.
Experimental protocol. Rhythmic, isometric muscle contractions
(tetanic) were elicited by stimulation of the sciatic nerve with square wave
impulses (6-8 V) of 0.2-ms duration at a rate of 50 impulses/s, with this
train of impulses lasting 0.2 s (10 impulses during each contraction). Each
muscle was stimulated to contract in a sequential manner for 3 min at each of
three stimulation frequencies: 1 contraction every 4 (0.25 contractions/s), 3
(0.33 contractions/s), and 2 (0.5 contractions/s) s. Muscle perfusion pressure
for these three stimulation patterns was kept at 
130 mmHg. We have
previously demonstrated (8),
using muscle contractions similar to those used in this investigation, that a
steady-state blood flow and O2 uptake are achieved by the end of 2
min.
Measurements. Arterial blood samples from the arterial line entering the muscle and venous samples from the left popliteal vein (as close to the gastrocnemius as possible) were drawn anaerobically at the end of each rest period and at the end of each 3-min contraction period. These samples were kept on ice for the brief time before measurement. A 6-mm bore, in-line ultrasonic flowmeter (100-Hz frequency response; Transonic Systems T108, Ithaca, NY) inserted in the venous outflow line provided rapid (50 Hz) venous blood flow measurements. The flow probe was calibrated within each experiment by comparing the recording of mean venous flow measured with the flow probe to venous blood flow measurements made simultaneously by timed blood collections into a graduated cylinder. A Biopac Systems MP100WSW (Santa Barbara, CA) analog-to-digital converter was used to transform the analog force and venous flow signals, and the digital data were collected and analyzed with AcqKnowledgeIII 3.2.6 software (Biopac Systems).
Muscle force development was determined from the computer acquisition system and reported as Newtons per 100 g of muscle mass. The time during which muscle force development was produced (contractile phase) and the time during which no force development occurred (noncontractile phase) were measured for the last 10 contractions at each stimulation frequency. Muscle blood flow for the contractile and noncontractile phases was calculated by averaging the appropriate blood flow waveform integrals for each of these 10 duty cycles. Mean venous muscle blood flow was measured as the venous outflow over the last 30 s of each contractile period (steady state of blood flow is achieved well before this time), except for the 0.25-Hz treatment in which the last 32 s were used (so that 8 complete contractile cycles could be measured). The mean muscle vascular resistance (not taking into account the blood flow changes within a contraction cycle) was calculated for each stimulation condition by dividing the mean arterial muscle perfusion pressure by the mean venous steady-state blood flow. Muscle fatigue was calculated as the decline in muscle force development with time and reported as the force development at that time as a percentage of the initial force development for that condition. The muscle was removed and weighed at the end of each experiment.
Blood PO2, PCO2, and pH were measured within 5-8 min with a blood-gas analyzer (IL model 813) at 37°C, and hemoglobin concentration, % O2 saturation, and O2 concentration were measured with an IL 282 CO-oximeter. These instruments were calibrated before each experiment and regularly throughout each experiment.
Statistics. Repeated-measures analysis of variance was used for the statistical analysis. When significance was found for a variable, Duncan's multiple-range test was used to determine which contraction frequencies were significantly different from each other. Values are expressed as means ± SE. In all statistical analyses, the 0.05 level of significance was used.
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RESULTS |
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The arterial PO2 (95 ± 7 Torr), arterial PCO2 (45 ± 2 Torr), arterial pH (7.36 ± 0.02), arterial HCO3- concentration (26 ± 2 mM), arterial Hb concentration (15.1 ± 0.6 g/100 ml), and arterial O2 concentration (17.1 ± 0.8 ml/100 ml) were similar among experiments and did not change through the three work periods (0.25, 0.33, and 0.5 contractions/s). Perfusion pressure to the muscle was kept constant at 130 ± 8 mmHg for the three contraction periods.
Peak muscle force development was not significantly different for the three contraction frequencies: 450 ± 80, 440 ± 71, and 409 ± 68 N/100 g, respectively. Figure 1 shows the developed force and simultaneous venous blood flow measurement for two contractions in one muscle at the 0.33-Hz contraction frequency. The time that the muscle produced force (contractile phase) was not significantly different among the three contraction frequencies (0.56 ± 0.02, 0.55 ± 0.02, and 0.53 ± 0.02 s). The time in the noncontractile phase decreased significantly with increasing contraction frequency, from 3.44 ± 0.04 to 2.45 ± 0.03 to 1.46 ± 0.03 s. Therefore, the ratio of the time the muscle spent in the contractile phase to time spent in the noncontractile phase (duty cycle) increased significantly with increasing contraction frequency (0.17 ± 0.01, 0.22 ± 0.01, and 0.37 ± 0.03, respectively).
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O2 uptake and the work performed by the muscle (tension-time index) over the 3-min contractile period increased proportionally with the increase in contraction frequency. Mean venous muscle blood flow increased significantly in a linear fashion with increasing contraction frequency (71 ± 6, 84 ± 9, and 107 ± 11 ml·100 g-1 · min-1 during 0.25, 0.33, and 0.5 contractions/s, respectively). As expected with a significant increase in mean blood flow and constant perfusion pressure, mean muscle vascular resistance fell significantly (P < 0.05) with increasing contraction frequency (1.83 ± 0.05, 1.55 ± 0.04, and 1.22 ± 0.04 mmHg · ml-1 · min-1 · 100 g-1, respectively). Figure 2 illustrates that the blood flow during the contractile (106 ± 6, 139 ± 8, and 145 ± 8 ml · 100 g-1 · min-1) and noncontractile phases (64 ± 3, 78 ± 4, and 91 ± 5 ml · 100 g-1 · min-1) increased (all significantly different, except for the contractile phase in the 0.33 and 0.5 contractions/s) with increasing contraction frequency.
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Although there was no significant difference in the developed force or time in the contractile phase for an individual contraction among the three contraction frequencies. Figure 3 illustrates that the blood flow expelled from the muscle per unit of contractile force increased significantly with increasing contraction frequency (0.24 ± 0.03, 0.32 ± 0.02, and 0.36 ± 0.03 ml · N-1 · min-1, respectively). The result of both the reduced time in the noncontractile phase and the greater blood expulsion per contraction (Fig. 3) resulted in the contribution of the contractile phase to mean blood flow becoming significantly greater (21 ± 4, 30 ± 4, and 38 ± 6%, respectively; Fig. 4) as contraction frequency increased.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Muscle blood flow has been characterized as being pulsatile during rhythmic exercise (6), such that the mean blood flow is a summation of the flows that occur during the contraction and noncontraction periods (see Fig. 1). When the vasculature of the muscle is forcefully compressed during the contractile phase of the duty cycle, arterial inflow is inhibited and blood is rapidly expelled from the muscle into the extramuscular venous circulation. On muscle relaxation, arterial flow into the muscle is restored and venous flow returns to steady-state values. At the onset of steady-state contractions, before neural, metabolic, endothelial, and myogenic factors are capable of initiating substantial vasodilation, the initial contractile expulsion of blood from the muscle has been suggested to contribute significantly to the immediate increase in muscle blood flow (3, 23, 26). However, during steady-state rhythmic contractions, after the vasodilatory processes have been successfully activated, it is controversial whether the contractile ejection of blood flow ("muscle pump" effect) is a determinant of steady-state muscle flow (see Ref. 19). Although evidence from some studies (1, 16, 17, 24) has suggested that the action of the muscle pump may partially determine the overall muscle blood flow response during rhythmic contractions, other studies have provided results that demonstrate little or no importance of the muscle pump in helping set steady-state blood flow (4, 10, 19, 22).
Irrespective of whether the "muscle pump" effect is a significant determinant of the overall blood flow response during steady-state rhythmic contractions, it is clear that the contraction and relaxation phases of a single contractile cycle result in very different temporal blood flow profiles during steady-state contractions (see Fig. 1), with each phase contributing quite differently to the overall steady-state blood flow response. It would be expected that the contribution of the contractile phase to overall mean blood flow during rhythmic contractions may depend on the strength of the contraction, the volume of blood contained in the muscle at the onset of contraction, and the ratio of the time in which the muscle is in the contractile and noncontractile phases (duty cycle). The intent of the present study was not to study whether the "muscle pump" per se is an important determinant of steady-state muscle blood flow but to characterize in an isolated muscle model the overall contribution of the contractile and noncontractile phases to the mean venous muscle blood flow at different contraction frequencies. By using an isolated muscle model in which all fibers were simultaneously activated, we were able to avoid issues related to differences in fiber-type recruitment patterns and blood flow heterogeneity that can confound interpretation of other muscle model systems as contraction frequency is varied. In addition, with all fibers activated maximally at each contraction frequency, work output and metabolic rate increased in conjunction with contraction frequency and duty cycle. This is in contrast to studies that have examined the effect of differences in contraction frequency, at similar power outputs, on metabolic and blood flow responses (5, 11, 12).
As has been demonstrated (2, 4, 9, 15, 20, 21), arterial blood inflow into contracting muscle is significantly diminished during the contractile phase owing to vascular compression, and muscle perfusion is reestablished during the noncontractile phase. If the duration of the contractile phase of the duty cycle is large, then this can have detrimental effects on overall muscle perfusion and result in inadequate delivery of O2 and diminished muscle contractility (fatigue). In addition, if the frequency (and not necessarily duration) of contractions becomes so great that blood flow and filling between contractions is of a short duration, then the mean muscle blood flow can again be compromised and contractility may be attenuated (5, 11, 25). In the present study, the frequency and duration of contractions was below the threshold for any negative effect of this impediment of blood flow to occur, and muscle contractility was not affected, as demonstrated by the maintenance of steady-state force development at all contraction frequencies.
An important component of the present study was that muscle work and
O2 uptake rose proportionally with contraction frequency.
Therefore, the changes demonstrated in the contribution of the contractile and
noncontractile phases to muscle blood flow were influenced by both the
increased metabolic rate and duty cycle. Mean venous muscle blood flow rose
proportionally with increased contraction frequency, demonstrating the tight
coupling of O2 supply to increased metabolic demand
(14). The factors that are
known to couple muscle blood flow to the metabolic rate during steady-state
rhythmic contractions are numerous and complex in their interaction (see Ref.
18). In the present study, as
metabolic demand rose because of increased contraction frequency, these
factors caused increases in muscle vasodilation (as demonstrated by the
decreased mean muscle vascular resistance) that resulted in the increase in
blood flow. In the noncontractile phase of the duty cycle, the greater
vasodilation with increased contraction frequency and metabolic rate resulted
in a higher blood flow during that time period, as shown in
Fig. 2. However, it is
important to take into account that the time period of the noncontractile
phase of the muscle duty cycle was progressively reduced as contraction
frequency increased, from 3.44 ± 0.04 to 2.45 ± 0.03 to 1.46
± 0.03 s for 0.25, 0.33, and 0.5 contractions/s, respectively. The
overall effect was that even though the blood flow during the noncontractile
time period was elevated (see Fig.
2), the reduced time of the noncontractile phase blunted the
relative importance of this increase. In contrast, even though the time that
the muscle spent in the contractile phase of an individual contraction
remained constant (0.5 s) among the three different contraction
frequencies, the total overall time (per minute) that the muscle spent in the
contraction phase increased as contraction frequency increased (doubling as
the frequency of contractions increased from 1 every 4 s to 1 every 2 s). The
decreased overall time spent in the noncontractile phase coupled with the
increased time spent in the contractile phase was an important factor in the
increased percent contribution of the contractile phase to overall mean blood
flow, as shown in Fig. 4.
However, one of the important observations of the present study, as shown in Fig. 2, was that the amount of blood pumped from the muscle during the muscle contractile phase rose as the contraction frequency increased. As the force and duration of each individual contraction remained constant throughout all three contraction frequencies, the amount of blood expelled from the muscle during the contractile phase for a given force development (Fig. 3) rose significantly with increased contraction frequency and metabolic rate. This interesting observation suggests that the volume of blood contained in the muscle was greater with increasing contraction frequency. A greater volume of blood contained in the muscle allowed for a greater ejection of blood for a given contraction. This expansion of the muscle blood volume as contraction frequency increased was a result of the muscle vascular bed being expanded by vasodilatory processes that occurred with increased metabolic rate, and occurred even though the time between contractions ("filling" time) decreased. In effect, some other factor regulates arterial inflow and the muscle simply expels whatever blood is contained in the muscle vasculature. Therefore, the increased time that the muscle spent in the contractile phase (per minute), together with the greater amount of blood expelled per contraction, resulted in the total percent contribution of the contractile phase blood expulsion becoming a significantly larger portion of the overall mean muscle blood flow (Fig. 4) as contraction frequency was increased.
In conclusion, these results demonstrate that, during rhythmic tetanic contractions, the contribution of the contractile phase of the muscle duty cycle becomes a significantly larger percentage of the mean muscle blood flow response as contraction frequency (and thereby metabolic rate) increases, and that this is in part due to a significantly greater amount of blood expelled for a given force development during the contractile phase.
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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O2peak in contracting
muscle. Med Sci Sports Exerc
26: 997-1002,
1994.[ISI][Medline]
O2 on-kinetics in
isolated in situ canine muscle. J Appl Physiol
85: 1394-1403,
1998.O2 of
contracting muscle. Med Sci Sports Exerc
27: 43-46,
1995.[ISI][Medline]
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