In response to exercise there is going to be marked changes in autonomic output, often enormous increases in sympathetic activity and as we reach maximal exercise, virtual total inhibition of parasympathetic tone. The changes in autonomic output bring increases in heart rate, ventricular contractility, cardiac output, and vasoconstriction of the peripheral vascular beds, especially inactive vascular beds. The mechanisms responsible for these changes in sympathetic and parasympathetic activity as well as the release of vasoactive hormones are not completely understood, but since the last decade or so it’s known that it may be due to the interaction of three different mechanisms (Fig1).
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Figura 1.
Changes in autonomic output in response to exercise. Adapted from O’Leary and Potts, Advanced Exercise Physiology; Chapter 12, ACSM, 2006. |
One of these three mechanisms has been termed “Central Command”(23). It is widely accepted that there are neural projections from the motor cortex dawn to the vasomotor center of the medulla and that activation of these brain regions responsible for the recruitment of skeletal muscle motor units, concomitantly activate the cardiovascular areas within the brain stem. Central command is “a feed-forward mechanism which establishes a basal level of autonomic efferent activity that determines the cardiovascular responses during exercise. The level of activation of the cardiovascular areas (and motor units) is closely related to the intensity of the exercise. There is data that supports the notion that Central Command exerts strong control over the parasympathetic tone, and that the immediate tachycardia that accompanies the onset of exercise is likely due to the activation of Central Command, rapidly inhibiting parasympathetic activity. What it is still controversial is if Central Command controls sympathetic activity. It is debatable by reason of there is data supporting either sides (“yes” it does control sympathetic activity and “no” is does not). Sympathetic activity is clearly mediated by the activation of the second and third mechanisms that are the Arterial and Cardiopulmonary Baroreflex and the Skeletal Muscle Afferents (mechano-reflex & metabo-reflex also known as skeletal muscle chemo-reflex).
The Arterial Baroreflex (Fig 2) is a negative feedback control responsible for the moment-to-moment, beat-to-beat control of arterial blood pressure (16)
The afferents that reside in the carotid sinus and aortic arch are basically stretch receptors, so, at a normal level of blood pressure we have normal carotid sinus nerve activity and as blood pressure falls, the baroreflex afferent activity decreases, this information is related to the vasomotor center which results in a reduction in parasympathetic activity and turn on of the sympathetic nerves in an attempt to increase heart rate and contractility. Most importantly, there is excitation of sympathetic nerves of peripheral vasculature causing vasoconstriction as well as venoconstriction (Fig 3).
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Figura 3. Arterial Baroreflex |
These responses elevate blood pressure and then baroreceptors activity goes up, and in this case, there is a reflex increase in parasympathetic activity and inhibition of sympathetic activity. Dynamic exercise simultaneously increases arterial pressure and heart rate in relation to the exercise intensity. For this reason, for several years it was thought that during exercise the baroreflex was turned off, because blood pressure, heart rate and sympathetic activity increased during exercise all in concert. Within the last few decades there is enough evidence indicating that the arterial baroreflex is modulated during exercise. This paradox has been explained by previous studies showing that during dynamic exercise, the arterial baroreflex is reset to operate around the prevailing blood pressure generated (2). Thus, the baroreflex are reset to a higher blood pressure and heart rate; to a higher operating point. Just to mention, the relationship between sympathetic activity and arterial blood pressure is still sigmoid in shape (Fig 4).
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Figura 4. Exercise Resets the Baroreflex Operating Point to a Higher Level |
This phenomenon allows the simultaneous increase in both heart rate and arterial pressure during dynamic exercise. Both, central command and activation of skeletal muscle afferents have been proposed as the potential mechanisms responsible for resetting the arterial baroreflex during exercise (13). In addition, dynamic exercise alters the mechanism that the baroreflex uses to control blood pressure, in fact in strenuous exercise there is an enormous increase in cardiac output, vasoconstriction in inactive vascular beds, and markedly redistribution of this cardiac output due to vasodilatation of active skeletal muscle (12; 14; 15). Blood pressure is controlled by a combination of cardiac output (stroke volume * heart rate), and peripheral vasomotor tone, and is still well controlled during exercise despite this redistribution of cardiac output towards the active skeletal muscles (Fig 5).
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Figura 5. Cardiac Output distribution between rest and heavy exercise in dogs |
Now, interestingly, during dynamic exercise and with further increases in workload, metabolically active skeletal muscle does “not” vasoconstrict significantly (vascular resistance almost does not change) in response to increases in sympathetic nerve activity despite that (as previously shown in Fig 5) during heavy exercise most of the cardiac output is directed to skeletal muscle! This observation directed some investigators to refer to this situation as “Sympatholysis”(22) (where metabolic active skeletal muscle does not or weakly vasoconstrict in response to increase to sympathetic nerve activity). But the question that still remained was: How does the baroreflex control blood pressure if it could not control the vascular bed towards what most of cardiac output is directed? To address this very interesting question and to find a potential explanation to this so called sympatholysis, O’Leary, conducted an investigation and concluded that the results will depend on the way the data is analyzed (9). In order to evaluate a vascular response to a stimulus, we could either look at changes in vascular conductance (flow divided by pressure) or vascular resistance (pressure divided by flow). But it is important to note that we can come to opposite conclusions regarding the magnitude of vasoconstriction between rest and exercise depending upon which index of vasomotor tone is used (conductance or resistance). To illustrate this point check out Fig 6.
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Figura 6. Magnitude of vasoconstriction between rest and exercise depending upon which index of vasomotor tone is used (conductance or resistance). |
In terms of conductance a much smaller vasoconstriction (noted as VC in figure 6) occurred during rest (low blood flow), as opposed to exercise where blood flow is lot higher, but based on resistance a much larger vasoconstriction occurred at rest as opposed to during exercise. So, the results that can be obtained are intimately dependent on what index is used. O’Leary looked at this controversial topic on an elegant animal model (chronically instrumented dog) where he was able to measure cardiac output, renal blood flow, central venous and arterial pressure and terminal aortic blood flow (keep in mind that at rest ~ 90% of the terminal aortic blood flow in the dog represents flow to skeletal muscles, and that as the animal exercises flow to the exercising muscles increase to ~98%). To activate the baroreflex he placed occluders around the carotid arteries, to perform bilateral carotid occlusions [occluders were manipulated manually (inflated-deflated) by the investigator], which will decrease pulsation-pressure in the carotid sinus and elicit a pressor response (increase in sympathetic activity). With this model O’Leary investigated total vascular conductance and the individual vascular conductance in the renal and hind limbs vascular beds. He collected data at rest and with the dogs performing heavy exercise running on a motorized treadmill (8km/h with 15% elevation).
At rest, with bilateral carotid occlusion, a marked pressor response occurred (elevation in arterial pressure), mostly due to vasoconstriction (Fig 7). In this setting in terms of vascular conductance there was a small fall in the hind limbs and the renal vasculature. During heavy exercise, in response to carotid occlusion a pressor response still occured, (this supporting the idea that the baroreflex during exercise is not turned off but it does reset), with little change in cardiac output, and so all the rise in arterial pressure was due to vasoconstriction (a decrease in total vascular conductance). Thus, at rest and at heavy workload, there is a rise in blood pressure, although at the highest workload it was a little smaller. At this high workload, cardiac output didn’t change too much; so the increase in blood pressure is due to vasoconstriction. Total vascular conductance is the sum of all the individual vascular conductances (muscle + renal + skin + etc), and this allows for some manipulations mathematically to address the question: how much will blood pressure increase if only one vascular bed vasoconstricts? How much did that vasoconstriction contribute to the rise in blood pressure with the baroreflex activation? As work load increases, the base line of hind limb blood flow increases markedly and the relative quantity of the vasoconstriction in the skeletal muscle becomes greater and greater, such that at the highest work load, ~40% of the rise of blood pressure is attributable to vasoconstriction within the active skeletal muscle. If we consider that the skeletal muscle of the entire body is responding similarly then ~80% of the rise in blood pressure will be due to the vasoconstriction within the active skeletal muscle. In contrast, although the kidney vasoconstricts, at the highest workload each kidney is receiving a small fraction of the cardiac output, then this vasoconstriction is not physiologically significant to control blood pressure. So, if the kidney vasoconstricts completely it will only cause blood pressure to increase minimally (1 mmHg?), because it’s receiving only a little fraction of the total cardiac output (Fig 8).
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Figura 7. At rest, with bilateral carotid occlusion, a marked pressor response occurred (elevation in arterial pressure), mostly due to vasoconstriction |
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Figura 8.
Although the kidney vasoconstricts, at the highest workload each kidney is receiving a small fraction of the cardiac output, then this vasoconstriction is not physiologically significant to
control blood pressure |
In terms of baroreflex, as workload is progressively increased, active skeletal muscle becomes the primary target that the reflex uses in order to protect arterial blood pressure. Moreover, the quantification approach of the relative functional importance of the vasoconstriction obviates the discussion whether it should be resistance or conductance because you can reach the same conclusion using either.
So, the conclusions that can be driven from O’Leary’s study are that while neither resistance nor conductance is a perfect index of vasomotor responses, changes in regional conductance better reflect the significance and relevance of the response in pressure regulation than do changes in resistance.
The third mechanism mediating these large changes in autonomic output that can occur during exercise has to do with the role of skeletal muscle afferents (fig 1) (7; 8). It has been previously shown that the skeletal muscles are loaded with afferents both mechanically sensitive fibers (mainly group III) activated in proportion to the tension developed, and in addition chemically sensitive fibers (mainly group IV) (4-6). The latter ones are activated by changes in the interstitial concentration of metabolic products. I would like to focus the rest of this talk on these chemically sensitive fibers. The first investigation that clearly showed the existence of this reflex was a study performed by Alam & Smirk (Fig 9) (1). One of the experiments these investigators performed consisted on frequently monitoring arterial blood pressure on human subjects that were in sitting posture and had sphygmomanometer cuffs placed around both thighs.
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Figura 9.
The increase of blood pressure which we observe on exercise of muscles during arrest of their circulation is due to a reflex. The stimulus which starts and maintains this reflex is the accumulation of muscle metabolites in muscles. |
The subjects had a 12kg weight placed across their knees and after the cuffs were inflated rapidly to a pressure well above the subject's systolic blood pressure (in order to arrest the circulation through both legs) the subjects were instructed to raise and lower the knees about 5 cm repetitively. What they saw was that both systolic and diastolic blood pressures increased as a result of such exercise. But more interesting was the observation that on stopping exercise the blood pressure remained always above the normal level until the circulation through the legs was restored by releasing the pressure in the cuffs placed round the thighs. Thus, they stated that in circulatory arrest, where nerves are the only channel of communication, the maintained increase in the blood pressure is due to a reflex, and the stimulus for this reflex is the accumulation of muscle metabolites within the muscles. That’s why it’s called the “muscle metaboreflex”.
Just to clarify, the idea is that when there is a mismatch between oxygen demand and oxygen delivery, metabolites (lactic acid, H+, dipropionate phosphate, perhaps adenosine, etc) accumulate within the muscle and stimulate muscle afferents, which elicit a large increase in sympathetic activity, causing a massive pressor response. Shouldn’t we consider this reflex to be important in the increased sympathetic drive seen in patients suffering from heart failure and even more in those heart failure patients that are involved in exercising programs? What about the patients suffering from chronic claudication? YES, this reflex must be/is important!
Based on studies from different groups, it can be concluded that this reflex doesn’t participate on the normal cardiovascular adjustments to mild exercise unless blood flow is reduced to a threshold level where “then” a pressor response can be observed (Fig10). This means that unless flow to the exercising muscles is reduced to a certain level (threshold) this reflex will not be activated (11; 17-19).
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Figura 10.
Metaboreflex activation during light exercise. This reflex doesn’t participate on the normal cardiovascular adjustments to mild exercise unless blood flow is reduced to a threshold level where “then” a pressor response can be observed. |
However, as exercise intensity is increased, the threshold becomes closer and closer to the normal level of muscle flow such that at heavy workload “NO” threshold is seen, so this indicates that the reflex might be “tonically active”.
How does the metaboreflex elicit an increase in arterial blood pressure? In normal dogs, at mild exercise the rise in blood pressure generated by this reflex is mediated almost entirely by the increases in cardiac output. At moderate workloads, the pressor response is also almost entirely due to an increase in cardiac output. But in severe exercise, the reflex causes an attenuated rise in blood pressure, no significant increase in cardiac output is seen (because it is already elevated, indicating it might be almost at it maximum level), so in this setting the mechanism of the metaboreflex activation is shifted from an output based reflex to a small yet significant reduction in vascular conductance (vasoconstriction). So, normally the reflex uses output to raise blood pressure and can be defined as a flow-raising pressure-raising reflex, but when it cannot further increase output (as in severe exercise) it shifts to peripheral vasoconstriction.
When we compare the baroreflex and metaboreflex mechanisms to increase blood pressure, the baroreflex uses peripheral vasoconstriction (by a reduction in vascular conductance), and also a mild increase in cardiac output. On the other hand the muscle metaboreflex uses flow (cardiac output), and a little if any increase in vascular conductance depending on the exercise workload (Fig 11).
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Figura 11.
Arterial baroreflex and muscle metaboreflex. |
Therefore, the baroreflex prefers to modulate the peripheral vasculature and the muscle metaboreflex the heart, even though, this two reflexes interact with each other as they both send information to the nucleus tractus solitarius in the brain stem. This increase in cardiac output that the muscle metaboreflex activation elicits results from central blood volume mobilization, a rise in heart rate and in addition, an increase in ventricular contractility (20; 21). This reflex also generates an increase in vasoactive hormones and as previously stated, might be very important in heart failure conditions, where we can see an increased sympathetic activity at rest that can increase further with exercise, causing an important tachycardia, and also an extreme peripheral vasoconstriction and a large increase of neuro-hormonal secretion such as renin, angiotensin II, vasopresin, and catecholamines (3; 10).
In conclusion, at least three mechanisms are involved in the cardiovascular responses to dynamic exercise. At exercise onset, central command via parasympathetic withdrawal causes an increase in heart rate. The arterial baroreflex is also involved in the autonomic changes that occur with exercise. Baroreflex acts primarily via sympathetic modulation of peripheral vascular tone and is crucial for blood pressure elevation at onset of exercise and for blood pressure stabilization during mild exercise (before the threshold for the muscle metaboreflex), and it interacts with the muscle metaboreflex when it is activated at higher workloads. The muscle metaboreflex acts primarily via modulation of cardiac output. Finally, when there is a limitation in cardiac pumping capacity as in severe exercise or heart failure conditions, both the baroreflex and the muscle metaboreflex must regulate blood pressure via altering (vasoconstriction) peripheral vascular resistance (the active muscle vascular bed).
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