Regulation of circulation during exercise: Neural and mechanical controls.

Antonio Cevese

The aim of the heart and circulatory system during exercise is to deliver the required amount of oxygen to the working muscles, by enhancing cardiac output in a manner strictly (and linearly) related to whole body oxygen consumption, which in turn generally reflects the increased muscle metabolism

The main mechanism increasing the output of blood from the heart is a rapid fall in skeletal muscle arteriolar resistance; this is, however, not enough, because the heart must be adequately refilled to produce and maintain increased output, while total peripheral resistance shall be readjusted in order to prevent falls in arterial blood pressure

fall in skeletal muscle arteriolar resistance

total peripheral resistance shall be readjusted

All this is accomplished by concurrent overflow of blood from the central veins to the right atrium, which is made possible in first instance by mechanical factors, such as the pumping action of rhythmic muscle contractions and the increased intrathoracic negative pressure during deep inspirations.

overflow of blood from the central veins

Obviously, besides neural commands to the exercising muscles, the integrated response to exercise includes a vast array of neural and endocrine reactions that help enhancing the overall working capacity of any individual.

neural and endocrine reactions

Not all control systems are essential. For instance, the heart may loose its efferent autonomic nervous control, and still be able to serve its role and enhance cardiac output during exercise

Worldwide, the number of individuals surviving a cardiac transplant and carrying out pretty normal life styles has risen impressively in the last two decades: the allograft heart is denervated and, in most cases, it does not reinnervate. Nevertheless, those individuals can raise their cardiac output enough as to sustain skeletal muscle work to some extent.

Even after heavy aerobic training, their maximal performance does not rise to the levels of élite athletes; however, it has often been demonstrated that the limiting factor is not the heart ability to increase cardiac output, but it resides on the muscles, because of the long lasting illness that led to heart transplantation

This example is indeed quite remarkable, because it illustrates how auxiliary control systems help preserve a lost function. In the case of the heart, the Starling’s mechanism allows the stroke volume to increase as required and the sinus node, freed from autonomic nervous control, can still increase the heart rate, although slowly, in response to circulating catecholamines, in order to sustain the required cardiac output

auxiliary control systems help preserve a lost function

The first event leading to cardiovascular adaptation at the onset of exercise is a fall of local arteriolar resistance in the active muscles.

Several studies demonstrated that muscle contraction per se, besides metabolic events, contributes to raise muscle blood flow: since contraction squeezes the blood out of capillaries, the arteriovenous pressure gradient temporarily increases, thus easing the flow of blood from arterioles to capillaries

It is important to realise that muscle metabolism rises as a step function, in parallel with the sudden increase of developed force, while cardiovascular adjustments require a real time to rise to new steady state levels

muscle metabolism rises as a step function

The listing of putative vasodilating molecules is long and still uncertain, and does not deserve detailed citation. It is worth noting, however, that nitric oxide has been added to the list. It is evident, indeed, that the principal physiological stimulus for enhancement of e-NOS activity, i.e. shear stress, is strongly related to the increase in blood flow and velocity.

Of particular importance an early observation that combination of factors always elicits greater vasodilating effects than each factor taken alone

nitric oxide

combination of factors always elicits greater vasodilating effects than each factor taken alone

Whenever skeletal muscles start contracting, local factors decrease vascular resistance, releasing part of the hindrance to outflow of blood from the heart. This may have two main consequences: in the face of a reduced afterload, the heart can increase its output of blood; on the other hand, the reduction of peripheral vascular resistance lowers by itself arterial blood pressure that is the force pushing blood through arterioles to the capillaries of all body tissues. If the increased output were exactly balanced with decreased resistance, arterial pressure would not change; this, however, can hardly be accomplished without a selective control system, which operates to avoid excessive changes in pressure.

the heart can increase its output of blood

lowers by itself arterial blood pressure

The increase in cardiac output observed with a maximal exercise amounts to four to six folds, leading to over thirty litres per minute (in some cases even a larger cardiac output has been reported, but it is very difficult to measure it accurately during heavy exercise, in humans), in well-trained endurance athletes. This is accomplished by enhancing stroke volume and raising heart rate. The heart, however, must be continuously refilled with an equal amount of blood returning to the atria though central systemic and pulmonary veins.

very difficult

stroke volumeheart rate

refilled

To understand the potential for increasing venous return, it must be recalled that the bulk of circulating blood may be separated in two, albeit indistinguishable, components:

the unstressed volume and the volume in excess.

The first part is that volume which fills up all the cavities in the circulatory system, including the heart, without distending the elastic walls of the vessels

unstressed volume volume in excess

The second part is the volume of blood forced within the tubes, which must distend to accommodate it and in so doing generate pressure. The distending pressure has been named “mean circulatory pressure”. If the heart were suddenly stopped and the blood quickly pumped from arteries to veins, the pressure would rapidly decrease in the arteries and more slowly increase in the veins; when arterial and venous pressures are equal, so that any pressure gradient is abolished, the mean circulatory pressure is measured

mean circulatory pressure

In baseline conditions, the value generally reported for mean circulatory pressure is 7 mmHg. It is clear, therefore, that any factor changing mean circulatory pressure affects venous return, and therefore, cardiac output, provided the heart is accomplishing its pump function properly

Mean circulatory pressure, in turn, depends on the total volume of blood, on the unstressed volume, and on the compliance of the vessels.

The blood volume is kept rather constant by several neurohumoral mechanisms, involving, among others, the kidney and the haematopoietic tissues. The control of blood volume operates slowly, day after day. It must however be mentioned that total blood volume may be more or less quickly reduced by haemorrhage.

The ratio between total and unstressed volume, as well as vessel compliance, albeit determined by structural events, such as those accompanying body growth, can change rapidly and are under neurohumoral control.

Total blood volume is unequally distributed between the arterial and the venous vascular compartments, and more so the excess volume, which is almost entirely contained in the veins.

Our body in resting conditions holds a large pool of blood distributed in its veins that can quickly be mobilized on demand.

When respiratory mechanics is forced, blood is actively sucked towards the right atrium, and pumped out of the abdominal veins by contraction of abdominal muscles, which forces expiration. The largest part of venous blood, however, up to 80%, is located within venules and small veins, including those of skeletal muscles, which are particularly affected by the squeezing action of the contracting fibres.

respiratory mechanics

venules and small veins

All vessels receive a tonic vasoconstrictor sympathetic outflow, which can be modulated, in first instance, by cardiovascular reflexes, and, at a slower pace, by circulating vasoactive molecules, including catecholamines.

The most known effect of an increase in sympathetic vasoconstrictor outflow is a rise in total peripheral vascular resistance, generally leading to an increase (or prevention of a reduction) of arterial blood pressure.

Also the veins exhibit an increase of vascular smooth muscle tone, which exerts a large effect on venous capacitance and compliance.

The consequence of the increased venous tone consists in reducing unstressed volume (a larger proportion of total blood volume becomes volume in excess) and decreasing compliance. Therefore, venous return is made easier both by an increase in the volume of blood that actually circulates and by an increase in venous pressure.

The contribution of veins of different vascular districts to the sympathetically driven enhance-ment of venous return is not equally distributed: it is maximal in the splanchnic area, and minimal in skeletal muscles.

venous return is made easier both by an increase in the volume of blood that actually circulates and by an increase in venous pressure

The concept of a “peripheral heart” has been conceived, by assigning the central heart the task of pushing blood through arteries and arterioles, and the peripheral heart the task of continuously (and adequately) priming the central pump with the larger amount of blood that is needed to fulfil metabolic demands during skeletal muscle contraction.

peripheral heart

The surge of venous return that must feed the right atrium with enough blood to keep up with an increased cardiac output is generally quite adequate.

Only persons with severe incompetence of venous valves, disruption of autonomic control, or serious loss of circulating blood volume (of whatever origin) may experience acute insufficiency of this function, leading to brisk fall of arterial pressure with blurring sight, vertigo and eventually fainting.

THE STARLING’S LAW OF THE HEART

Within limits, the heart can increase its output in relation to diastolic filling, as stated by the Starling’s law of the heart. Its role in the normal cardiac performance during exercise, however, has been challenged when it was seen that the diastolic dimensions of the heart are not usually increased during exercise, and may even be reduced in mild exercise.

The role of the intrinsic mechanism remains crucial in keeping the balance between the right and the left sides of the cardiac pump.

If exercise is performed in reclining position, no increase in stroke volume occurs, since the volume ejected is already similar to that reached after starting exercise in standing position.

keeping the balance between the right and the left sides of the cardiac pump

The mechanism leading to the rapid increase in stroke volume while standing is associated to the need to compensate for the effects of gravity on venous return and does not add any further volume to cardiovascular dynamics during exercise.

THE AUTONOMIC NERVOUS SYSTEM

The autonomic nervous system is evidently implicated in cardiovascular adjustments to exercise. The typical response includes a widespread increase in the sympathetic output to the heart and the vessels and a decrease in the parasympathetic tone to the heart. These adjustments are called into play in first instance by the central command that coordinates skeletal muscle contractions and involves also the autonomic nervous system, both directly and indirectly, by resetting the reflex control systems.

central command

The reflex control of the circulation is assigned to two main sets of receptors: those located in the low-pressure compartments (central veins, atria and pulmonary veins), and those located in the high-pressure compartments (essential-ly, aortic arch and carotid bifurcation).

low-pressure compartments

high-pressure compartments

The low-pressure receptors are more properly conceived as volume receptors, as a result of the unequal distribution of blood volume already discussed. Their main role consists in enhancing hart rate when venous return increases (the well-known Bainbridge reflex), but also when the heart is unable to get rid of the amount of blood it receives, such as in heart failure. These receptors are mainly involved in the neurohumoral control of total blood volume.

Il volume di sangue è controllato dai fattori che regolano l’emopoiesi e dal rene, che controlla l’equilibrio fra assunzione e perdita di acqua e soluti.

L’equilibrio ionico è sotto il controllo dell’aldosterone (ormone della corteccia surrenale) la cui produzione, a sua volta, è stimolata dall’angiotensina (asse renina-angiotensina-aldosterone): presiede alla determinazione del riassorbimento facoltativo di soluti (e acqua)

L’assorbimento di acqua è regolato a livello dei dotti collettori dall’ormone antidiuretico (ADH – vasopressina).

L’ADH è prodotto nei nuclei sopraottico e paraventricolare dell’ipotalamo e accumulato nella neuroipofisi, che lo immette in circolo, secondo i seguenti stimoli:

L’osmolarità del plasma è avvertita dalle cellule dell’ipotalamo, dette anche “osmocettori”: quando questa aumenta, normalmente per eccessiva perdita di acqua, aumenta la liberazione di ADH e il riassorbimento renale

L’attività dei nuclei sopraottico e paraventricolare è regolata anche in via riflessa da fibre afferenti dai meccanocettori atriali (recettori di volume). Quando l’atrio si distende perché aumenta il ritorno venoso, la produzione di ADH è inibita e aumenta l’escrezione di urina diluita.

Il ritorno venoso può aumentare per mancanza dell’accelerazione di gravità (voli spaziali, decubito supino) o per eccessivo accumulo di acqua.

Gli atri si distendono anche quando la contrattilità ventricolare è ridotta

THE CONTROLLED VARIABLE

The variable classically designed as the controlled variable in the cardiovascular system is mean arterial pressure. Many different control systems join in the task of keeping mean arterial pressure essentially stable throughout most daily circumstances, with slow, medium and fast acting mechanisms. The fast mechanisms are those related to the autonomic nervous control.

The question, partially still open, is whether the baroreceptors keep operating during exercise, and, if they do, whether, and to what extent, their functioning changes.

On first look, one can conclude that the baroreflex fails its aim. Indeed, during dynamic exercise, arterial pressure does change, with the diastolic value tending to fall or keep constant, while the systolic value invariably rises, even to pretty high levels (180-200 mmHg). Consequently, mean arterial pressure is increased. Meanwhile, heart rate rises, even up to the highest possible levels for each individual.

baroreceptors keep operating

Fast shifts in pressure, such as those occurring during rapid changes in position, are still efficiently buffered, indicating that the baroreflex does control mean pressure levels, albeit around a higher controlled level. It is now rather clear, therefore, that the baroreceptor set point is reset to higher levels, probably as a consequence of the central command; the operative range is shifted to the right, while the gain is not changed.

baroreceptor set point is reset

Research on the baroreflex in humans is rather difficult, because to characterize a negative feedback loop-based control system it is theoretically necessary to open the loop. Classical experiments in animals (especially dogs) took advantage of surgical isolation of the carotid bifurcations, in order to be able to change the pressure level in the sinus regions independently of arterial blood pressure. Obviously, this cannot be done in humans.

The baroreflex was studied under close loop conditions, seeking for the relation between arterial pressure and heart rate changes. Spontaneous oscillations in these variables can be studied, either by repetitively calculating linear regression between the two variables for few consecutive heart beats all changing in the same direction, in a long strip of recorded beat, or by taking advantage of cross-spectral analysis.

On the other hand, fast changes in arterial pressure can be induced by alternate injections of a vasoconstrictor (phenylephrine) and a vasodilator (sodium nitroprussiate), while measuring heart rate, and again the slope of the relation between the two variables is obtained.

The baroreflex is also studied in open loop conditions, by applying positive and negative pressures into a cuff wrapped around the neck, strictly held by a rigid collar.

Aerobic training does not seem to be beneficial with respect to the baroreceptor function, since it has been frequently reported that the baroreflex gain tends to reduce after training. More research is needed to clarify this topic.

The efferent branch of the baroreflex involves both sections of the autonomic nervous system. Since the first step in cardiovascular adaptation to exercise is the fall in peripheral vascular resistance, produced by a large array of local factors, a sudden fall in arterial pressure might occur, which unloads the baroreceptors and elicits the reflex response.

the baroreflex gain tends to reduce after training

The vagal outflow to the heart is reduced or suppressed, producing a very rapid increase in heart rate. More slowly, the sympathetic is stimulated, which further enhances heart rate and increases vascular smooth muscle tone.

The arteriolar tone is increased, leading to widespread vasoconstriction, which does not spare the skeletal muscle vessels. In exercising muscles, the local vasodilatory effects largely overwhelm the neurally induced vasoconstriction. This observation led to the introduction of the term “functional sympatholysis”, indicating loss of any effect of vasoconstrictor sympathetic efferents on contracting skeletal muscles.

This concept was challenged by further research, demonstrating that sympathetic stimulation, as that induced by baroreceptor unloading, does reduce muscle vascular conductance during exercise. In all other tissues, including non working muscles, resistance is increased and blood flow is more or less cut down. Thus, during exercise, a profound redistribution of cardiac output takes place.

Changes in the autonomic outflow induce global alterations of the heart function.

The inotropic effect is especially important, because the heart pump function must increase adequately, to transfer the large volume of blood that returns from central veins during exercise and to support the required cardiac output.

The positive inotropic effect is associated to a well established lusitropic effect, which helps the heart to relax more quickly and effectively.

global alterations of the heart function

inotropic effect

lusitropic effect

Also the systole duration is shortened. The combination of these factors improves the capacity of the heart both to accept the increased venous return and to transfer oxygenated blood to the arteries.

systole duration

REDISTRIBUTION OF CARDIAC OUTPUT

While blood flow must increase in the working muscles, and also in the coronary arteries that obey the enhanced metabolic demand of the heart, it is severely lowered in the splanchnic area. Other relevant circulatory territories follow their own rules.

The skin is vasoconstricted, but subcutaneous circulation may be enhanced by thermo-regulation, so that exercise in a hot (and humid) environment may lead to an overt conflict between contrasting needs, taking away an increasing fraction of cardiac output from working muscles that are not able to reduce their flow

skin is vasoconstricted

Thermoregulation may be hampered and a heat shock is possible.

In contrast, cerebral circulation keeps its typical autoregulation.

The kidneys tend to autoregulate their blood flow: renal vasoconstriction does contribute to the general increase in vascular resistance in non-muscle tissues, but it is unrelated to workload.

The most debated issue about the increased vasoconstrictor sympathetic tone is whether skeletal muscle arterioles are involved in the vasoconstriction.

Although resting blood flow is low in non-working muscles, further vasoconstriction is possible, which helps keeping arterial pressure at enhanced values. On the other hand, blood flow cannot be cut down in muscles where metabolic needs are larger, due to ongoing rhythmic contractions. It has been demonstrated, however, that even contracting muscles receive vasoconstrictor signals from sympathetic endings, which limit the large vasodilatation induced by local factors.

contracting muscles receive vasoconstrictor signals

THE METABOREFLEX

If venous outflow from a working muscle group (e.g. an arm) is blocked, the typical cardiovascular responses outlast the contraction period and signs of widespread sympathetic stimulation persist until the hindrance to venous flow is removed. This has been interpreted as evidence of a so-called “metaboreflex”.

Afferent fibres have been recognized as small diameter group III and IV, the former being probably connected to mechanoreceptors, and the latter to chemoreceptors, although a large polymorphism was demonstrated.

metaboreflex

Mechanical stimuli are stretch and pressure (within the tissue). For the chemical signal, a large number of potential ions or molecules generally released by the contracting muscle, especially in ischemic conditions, has been postulated. However, the most obvious, such as hydrogen ions or lactic acid, have been ruled out, while an important role has often been assigned to K+.

Stimulation of muscle afferents inhibits the vagal control on the heart, thus enhancing exercise tachycardia, and activates sympathetic efferent fibres. The effect is an increase in total peripheral resistance and blood pressure. It has been postulated that this reflex counteracts the local vasodilating influences that widen vascular conductance in the working skeletal muscle.

The mechano-metabo reflex is altered in heart failure patients and is probably responsible for excessive sympathetic stimulation, with hypertension and reduced exercise tolerance in these subjects.

altered in heart failure patients