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POINT-COUNTERPOINT
Department of Physiology
Wayne State University School of Medicine
Detroit, Michigan
e-mail: doleary{at}med.wayne.edu
Imposed reductions in oxygen delivery to active skeletal muscle during dynamic exercise in conscious dogs evoke a powerful pressor response, termed the muscle metaboreflex. During submaximal work rates, the major mechanism used by this reflex is to increase cardiac output (CO), which generates a greater perfusion pressure for blood flow and thereby partially restores the blood flow deficit in the active skeletal muscle.
We directly demonstrated this concept in conscious dogs during submaximal treadmill exercise (20). We measured hindlimb blood flow via a blood flow transducer placed on the terminal aorta just proximal to the iliac arteries. In resting dogs, 87% of hindlimb blood flow is to skeletal muscle (6), thus during exercise the vast majority of this flow signal is flow to the skeletal muscle. We implanted a vascular occluder distal to the flow probe and we measured the arterial pressure both above and below the occluder. When we partially inflated the vascular occluder, the resistance to flow in the hindlimb increased (because we measured the pressure above and below the occluder as well as the flow, the resistance could be directly calculated for the occluder and the vascular resistance of the hindlimb; the sum of these resistances in series is the total hindlimb resistance). According to Ohm's Law, if no increase in arterial pressure occurs, then with the imposed increase in hindlimb resistance, hindlimb blood flow must decrease in proportion to the rise in resistance. Indeed, this is what occurred initially with the inflation of the occluder. Flow fell to the level predicted (HLBFP) by the imposed increase in resistance. However, over the next several minutes, the muscle metaboreflex became engaged and a pressor response developed [previous and subsequent studies using this preparation have shown that this pressor response occurs via increases in CO during submaximal workloads (2, 9, 16, 28)]. With this muscle-metaboreflex-induced increase in perfusion pressure, the observed level of hindlimb blood flow (HLBFO) rose substantially above the predicted level and reached steady state at about one-half between the initial level of flow before partial vascular occlusion (HLBFI) and the HLBFP. We calculated the closed-loop gain of the muscle metaboreflex (GCL) as GCL = (HLBFO – HLBFP)/(HLBFI – HLBFP).
GCL reflects the ability of a reflex to partially restore any perturbation (e.g., the closed loop gain of the arterial baroreflex would reflect the ability of the baroreflex to correct for a change in arterial pressure). When the muscle metaboreflex was activated, GCL averaged 
0.50 during both mild and moderate exercise, meaning that 50% of the blood flow deficit was restored. During mild exercise, the reflex was not activated until substantial reductions in HLBF were induced, whereas during moderate exercise, any reduction in HLBF evoked a pressor response and the reflex partially restored flow. Fundamentally, the reflex causes large increases in CO, which has to go somewhere, and a portion goes to the ischemic muscle. Furthermore, we demonstrated that significant increases in hemoglobin concentration occurred with muscle metaboreflex activation, which significantly increased arterial O2 content (17). GCL calculated based on recovery of O2 delivery rather than just flow revealed an even greater strength of the reflex. Because Sheriff et al. (26) showed in this model that the reflex is activated by decreases in O2 delivery, not just blood flow, analysis based on restoration of O2 delivery may be even more informative than only restoration of blood flow. Both Augustyniak et al. (1) and Mittlestadt et al. (12) showed that this reflex also increases flow to nonischemic muscle (forelimb). The vast majority of the pressor response is abolished by sectioning of the afferents from the hindlimb, blockade of afferent neuronal traffic in the spinal cord, or efferent ganglionic blockade, reflecting the reflex nature of the response (10, 11, 18).
Certainly situations exist when this reflex does not or cannot partially restore blood flow to the ischemic muscle. The most obvious example is during strong static muscle contractions when the substantial rise in tissue pressure physically compresses blood vessels (analogous to a baroreflex pressor response to carotid hypotension cannot restore pressure within an isolated carotid sinus). Also, when the ability to increase CO is impaired (heart failure or when cardiac output is already at maximal levels), the reflex pressor response is attenuated and occurs via peripheral vasoconstriction (2, 7, 19). What target bed(s) are vasoconstricted has not been well addressed, but given that most of the CO is directed to skeletal muscle, it is likely that vasoconstriction in the muscle occurs (14). This potentially could limit restoration of flow to the ischemic muscle; however, the concept of sympatholysis (21) would predict that the vasoconstriction would be less in the ischemic muscle, thus vasoconstriction within the nonischemic muscle could redistribute flow toward the ischemic active skeletal muscle (24). This has yet to be tested.
To my knowledge, no study measuring the complex hemodynamics needed to quantitatively and accurately assess metaboreflex function has been performed in humans. Indeed, most studies investigating metaboreflex function in humans have relied on the technique of postexercise circulatory occlusion. However, with this approach, the metaboreflex responses are observed during the recovery from exercise rather than during exercise per se, thus the hemodynamic responses may be very different. For example, when activated during dynamic exercise, the major mechanism of this reflex is to increase CO. This occurs via increases in heart rate, ventricular performance, and central blood volume mobilization (15, 16, 25). In contrast, when activated via postexercise circulatory occlusion, bradycardia occurs rather than tachycardia. Sometimes CO is increased, sometimes not, sometimes peripheral vasoconstriction occurs, sometimes peripheral vasodilation (even across subjects within the same study) (3, 22).
With the use of external pressure presumably to reduce limb blood flow during exercise, two previous studies in humans have attempted to discern whether this reflex restores flow to active muscle but came to opposite conclusions (8, 23). However, both relied on highly indirect methods of measuring blood flow [O2 saturation of venous blood (%SvO2)]. As we discussed in detail (20), %SvO2 can change due to changes O2 consumption as well as changes in the admixture of blood draining adjacent nonactive areas. This is particularly the case in the study by Joyner (8) in that intermittent static muscle contractions aspirate blood from skin veins into the deep muscle veins [where the blood samples were taken (4)]. The external pressure would be expected to reduce skin flow by 75%, meaning there would be less O2-rich skin flow to admix with the muscle flow. Changes in venous admixture coupled with potential changes in O2 consumption may render %SvO2 an unreliable index of blood flow as concluded by others (27). Using similar methods (external box pressure), but with a more direct measurement for flow (Doppler), Daley et al. (5) concluded that at 50 mmHg external pressure, flow was not restored by a reflex pressor response due to vasoconstriction in the active muscle; yet given that no significant change occurred in the calculated vascular conductance, this conclusion is perplexing. Furthermore, because only 1-min periods for a given box pressure were used and the latency of the CO component of this reflex approaches 1 min during mild treadmill exercise (1), it is unclear to what extent steady state was achieved.
REFERENCES
Department of Physiology
Wayne State University School of Medicine
Detroit, Michigan
e-mail: doleary{at}med.wayne.edu
Mayo Clinic College of Medicine
Rochester, Minnesota
e-mail: joyner.michael{at}mayo.edu
The idea that signals from contracting muscles govern (in part) the cardiovascular responses to exercise is an old one clearly dating back to the late 1800s and perhaps before (10, 18). In the 1930s two remarkable studies by Alam and Smirk (1, 2) working in Egypt showed in humans that the rise in arterial blood pressure during exercise (leg kicking) was increased by skeletal muscle ischemia, and this pressor response was maintained when the exercise stopped but the ischemia continued. Furthermore, the rise in blood pressure during postexercise ischemia was absent in a subject with a selective sensory deficit in the leg that had been exercising (2). From these two studies the idea that there might be some metabolic or chemical signal from the active muscles that evokes a reflex rise in arterial blood pressure was clearly established. It was also suggested that by raising arterial pressure such a signal might serve to improve blood flow to contracting muscles that are underperfused.
This idea was further advanced by Lorentsen (8) who studied the blood pressure responses to one-leg cycle exercise in patients with unilateral high-grade (but not complete) stenosis of the arterial supply to the legs. The blood pressure responses during cycle exercise with the underperfused leg were higher than those with the normal leg. Again, the interpretation was that the augmented rise in pressure was a reflex response to exercise with "undeperfused" active muscles designed to improve blood flow to these muscles.
This interpretation became even more accepted with the development of the "Seattle model" in chronically instrumented conscious dogs (22). In this model, a terminal aortic occluder in combination with a flow probe in close proximity is used to suddenly reduce blood flow to the hindlimb muscles of dogs running on a treadmill. Depending on the speed and grade of the effort along with the magnitude of occlusion, there is a predictable rise in systemic blood pressure that occurs when blood flow is reduced enough to either cause (or increase) acidosis in the active muscles. Thus the rise in pressure is triggered by sensory information from the underperfused active muscles. Additionally, the pressor response is primarily due to a rise in cardiac output and restores about two-thirds of the flow deficit and is limited by arterial baroreflexes (12, 14-16, 22).
Unfortunately because the blood pressure responses to exercise with either underperfused or ischemic muscle is similar in dogs and humans, the data from dogs showing an improvement or restoration of blood flow has been broadly extrapolated to the human situation with only limited experimental evidence. So why doesn't the muscle metaboreflex restore blood flow to contracting human muscles?
In humans, stimulation of the muscle metaboreflex (it is also called the muscle chemoreflex) evokes a large increase in vasoconstricting sympathetic nerve traffic directed toward skeletal muscles (9, 20).
In humans, blood vessels in the active muscles remain under sympathetic control for the purposes of blood pressure regulation (19). Due to the relatively "small heart" and "limited" cardiac output in humans, sympathetic restraint of metabolic vasodilation in the active muscles is especially important for arterial blood pressure regulation during large muscle mass exercise (13).
In humans performing forearm handgrip exercise that is likely to evoke metaboreflex activation, blood flow to the contracting muscles is augmented by 
-adrenergic blockade or sympathetic nerve block in a way consistent with the idea that the reflex rise in muscle sympathetic nerve activity is restraining the blood flow and limiting the ability of the pressor response to restore the flow (7, 17, 21).
In humans, when external positive pressure is applied to the forearm during rhythmic handgripping, there is evidence that the external pressure reduces blood flow to the active muscles and evokes a reflex rise in arterial pressure (3, 6). However, several lines of evidence show that the reflex increase in arterial pressure does not improve or "restore" the flow to the active muscles. Thus in this human analog of the Seattle model the rise in pressure does not restore the flow.
In humans, selective activation of the muscle metaboreflex in the diaphragm by respiratory loading during heavy cycle exercise can evoke a reflex reduction in leg blood flow (5).
In dogs, as noted above, most of the flow restoring rise in arterial pressure is caused by an increase in cardiac output. Additionally, whereas there can be sympathetic vasoconstriction in the active skeletal muscle of dogs, this constriction is probably less robust than in humans and it is unclear if activation of the muscle metaboreflex normally evokes large increases in muscle sympathetic nerve activity in dogs (11, 22).
Finally, my "opponent" has used the Seattle model to study the muscle metaboreflex in dogs with congestive heart failure (CHF). In the CHF animals, activation of the muscle metaboreflex continues to cause a systemic pressor response, but this response is caused primarily by peripheral vasoconstriction and fails to restore blood flow to the active muscles (4). Because normal humans have limited cardiac pump capacity relative to normal dogs, perhaps the situation in CHF dogs is similar to that seen in the normal human.
In summary, "underperfusion," "hypoperfusion," and frank ischemia can augment the pressor response to muscle contraction in both humans and dogs performing voluntary exercise. In both cases, fine afferents in the active muscles sense a "metabolic error signal" associated with a mismatch between muscle blood flow and metabolic demand, evoking a reflex increase in arterial pressure. In humans, the reflex pressor response is marked by an impressive rise in vasoconstricting muscle sympathetic nerve activity that limits the ability of the rise in pressure to improve blood flow to the underperfused contracting muscles.
REFERENCES
Department of Physiology
Wayne State University School of Medicine
Detroit, Michigan
e-mail: doleary{at}med.wayne.edu
Mayo Clinic College of Medicine
Rochester, Minnesota
e-mail: joyner.michael{at}mayo.edu
REBUTTAL FROM DR. O’LEARY
Dr. Joyner does not challenge our conclusions that during submaximal dynamic exercise, the muscle metaboreflex does restore blood flow to contracting muscles in conscious dogs (5, 7). Rather, my "opponent" provides rationales as to why this reflex may not operate effectively to restore flow in humans; some of these arguments are not that compelling. Like humans, in dogs, active skeletal muscle blood flow is restrained by the sympathetic nervous system (6) and substantial reflex vasoconstriction in active skeletal muscle can occur (1). Although metaboreflex activation from the diaphragm in humans does vasoconstrict active muscle, these observations were made during maximal exercise when increases in cardiac output (CO) are limited (2). Although on a relative basis humans have smaller hearts than dogs, humans are capable of substantial increases in CO. Rather than conclude a "species difference" exists in the fundamental efficacy of this reflex, I submit that no study has quantitatively addressed the question at hand in humans during dynamic (locomotory) exercise with the same degree of methodological precision as has been done in experimental animals (for perhaps obvious reasons). If the reflex rise in arterial pressure occurs primarily via increases in CO (as it does in normal dogs), then flow to muscle likely increases. Sundberg and Kaijser (8) observed that increased external pressure on the legs in humans during dynamic exercise decreased leg blood flow (measured via dye dilution), which elicited substantial pressor and tachycardic responses (parenthetically, the fall in leg %SvO2 was over twice as large as the fall in blood flow, again indicating the limitation of %SvO2 as an accurate measurement of flow). Importantly, a small vasodilation occurred in the legs rather than the vasoconstriction proposed by my opponent. If stroke volume remained constant with the reflex tachycardia [a reasonable assumption (4)] then a substantial increase in CO did occur and this increase in CO would then account for most of the pressor response. Indeed, these authors (8) concluded that the measured fall in leg blood flow with positive pressure was less than one-half that expected "if no compensatory changes had occurred." These conclusions from quantitative observations in humans are strikingly similar to those we drew from our studies, e.g., the muscle metaboreflex does act to partially restore blood flow to ischemic active skeletal muscle.
REFERENCES
O'Leary's "point" about the role of the muscle metaboreflex as a blood flow-"restoring" mechanism in underperfused contracting muscle succeeds in three main ways.
First, he succinctly summarizes the rationale, evidence, and interpretation of the data he and his colleagues have collected in dogs that support his point.
Second, he describes the central role that a rise in cardiac output plays in generating the pressor response when blood flow to the hindlimbs is restricted in the exercising dog.
Third, he deftly (using selective interpretation) dismisses the human data as either irrelevant or incomplete.
However, his point also fails in three main ways.
First, in humans (and dogs with CHF), vasoconstriction including a rise in muscle sympathetic nerve activity (MSNA) is the main mechanism that drives the pressor response during metaboreflex activation (3).
Second, blood vessels in contracting skeletal muscle remain subject to sympathetic vasoconstriction. So, if MSNA to the active muscle rises, the blood vessels perfusing these muscles should constrict (1, 4, 5).
Third, during both small (hand gripping) and large (cycling) muscle mass rhythmic exercise in humans, there is evidence demonstrating that when the metaboreflex is engaged blood flow to the active muscles is reduced or restrained. In the case of small muscle mass exercise, it is difficult to imagine that cardiac output would be limiting. This demonstrates that in humans, even when there is a large excess of cardiac output available to raise arterial pressure, vasoconstriction is the dominant mechanism (1, 2, 6).
In summary, perhaps the normal dog with its very high O2 max and very high peak cardiac output represents the "best case" scenario for a flow-restoring muscle metaboreflex. Finally, the comments above not withstanding, I think that both Dr. O'Leary and I would agree that an unambiguous experimental model is needed in humans to address the ability of the muscle metaboreflex to restore blood flow to underperfused contracting human muscles.
POINT:COUNTERPOINT CALL FOR COMMENTS
Readers are invited to give their views on this issue by submitting a brief (250 word maximum; 3 references) Letter to the Editor (please upload to APSCentral: http://www.apscentral.org), which, if accepted, will appear in the earliest possible issue. If you have any questions about this call for comments, please contact Dr. Jerome Dempsey, Editor-in-Chief (608-263-1732 or jdempsey@wisc.edu).
REFERENCES
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  A. Crisafulli, R. Milia, A. Lobina, M. Caddeo, F. Tocco, A. Concu, and F. Melis Haemodynamic effect of metaboreflex activation in men after running above and below the velocity of the anaerobic threshold Exp Physiol, April 1, 2008; 93(4): 447 - 457. [Abstract] [Full Text] [PDF]
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 J. A. Sala-Mercado, M. Ichinose, R. L. Hammond, T. Ichinose, M. Pallante, L. W. Stephenson, D. S. O'Leary, and F. Iellamo Muscle metaboreflex attenuates spontaneous heart rate baroreflex sensitivity during dynamic exercise Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2867 - H2873. [Abstract] [Full Text] [PDF]
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M. Sander J Appl Physiol, April 1, 2007; 102(4): 1717 - 1717. [Full Text] [PDF]
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M. J. Joyner Go with the flow: sympathetic control of blood flow during recovery from heart failure J Appl Physiol, July 1, 2006; 101(1): 3 - 4. [Full Text] [PDF]
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M. E. Tschakovsky, K. Shoemaker, and M. A. Babcock Comment on Point:Counterpoint "The muscle metaboreflex does/does not restore blood flow to contracting muscles" J Appl Physiol, March 1, 2006; 100(3): 1084 - 1085. [Full Text] [PDF]
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T. Nishiyasu, M. Ichinose, W. G. Guntheroth, and H. L. Collins Comment on Point:Counterpoint "The muscle metaboreflex does/does not restore blood flow to contracting muscles" J Appl Physiol, February 1, 2006; 100(2): 750 - 751. [Full Text] [PDF]
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A. W. Sheel, F. Iellamo, P. B. Raven, and R. D. Wurster Commentary on Point-Counterpoint J Appl Physiol, January 1, 2006; 100(1): 371 - 371. [Full Text] [PDF]
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