ORGANIZATION OF CENTRAL CARDIOVASCULAR CONTROL

Although sympathetic outflow to the cardiovascular system can be affected by pathways arising in many areas of the brain, there are for our purposes three primary sources of this activation (Fig. 7.1). The first is the cardiovascular control centre lying in the medulla of the hindbrain, which is the final common pathway for all descending sympathetic information. This hindbrain centre receives reflex inputs directly from peripheral sensory nerves, but also receives descending inputs from two areas of the forebrain. The most important of these are the limbic system, which includes the hypothalamus and several neighbouring nuclei, mediates emotional arousal and determines levels of consciousness, and the motor cortex from which all instructions for muscle movement must originate.

Figure 7.1 Diagrammatic saggital view of the brain, showing the locations of the hindbrain cardiovascular control centre and the two most powerful forebrain activators of hindbrain sympathetic drive; the limbic system and the motor cortex.

Neuroscientists are still unravelling the specific neural connections and neurotransmitters involved in mediation of hindbrain regulation of the cardiovascular system. However, we can regard the cardiovascular control centre as consisting of two sets of tonically active descending neurons, one producing continual activation of the sympathetic outflows to heart and blood vessels and one producing continual inhibition of heart rate via the vagus (Fig. 7.2). As a result of this ongoing activity, there is usually some degree of vasoconstrictor tone in both arterial and venous vessels, while the heart rate at rest reflects the algebraic sum of inputs to the sinoatrial node of both sympathetic and vagal activity.

Figure 7.2 A simplified version of the neural circuitry of the hindbrain cardiovascular control centre and its baroreceptor inputs. Primary sensory inputs from baroreceptive neurons communicate via a series of interneurons as shown, to activate vagal outflow and to inhibit sympathetic outflow. Excitatory and inhibitory synaptic inputs are indicated by (+) and (−).

LOW-PRESSURE AND HIGH-PRESSURE BAROREFLEXES

AROUSAL AND SYMPATHETIC CARDIOVASCULAR CONTROL: THE LIMBIC SYSTEM

The resting level of cardiovascular sympathetic drive is reduced when the level of cerebral arousal falls (for example, during sleep) and rises with heightened arousal, such as occurs during conversation or performing a mental task. The correlation of absolute heart rate and blood pressure with cerebral activation means that, in order to measure true ‘resting’ cardiovascular values, subjects should sit quietly and talk as little as possible for at least 10 min before measurements are commenced. Even so, it is often found that the additional arousal induced by measurement causes a transient increase in sympathetic activity; for this reason it is usual to record continuous data for at least 2–3 min and take at least three sets of intermittent data.

When cerebral arousal involves an emotional component – for instance, fright or anxiety – then the degree of sympathetic activation and the pressor response are greater. Emotionally oriented arousal often also produces an additional component of the response; an increase in limb muscle blood flow that is due to active vasodilation of the muscle arteriolar bed. The potential functional significance of this response has been the subject of extensive investigation over more than 50 years, without definitive resolution. Studies in cats and dogs have shown that the dilation is mediated by activation of sympathetic cholinergic vasodilator nerves. These nerves are activated from areas of the limbic system that also cause the behavioural changes known as the ‘flight and fight’ or ‘defence’ reaction, leading to the proposal that they might provide instantaneous high muscle blood flow at the commencement of exercise associated with escape or aggression.

In man, emotionally oriented arousal can cause profound forearm muscle vasodilation and this response has been shown in some studies to be dependent on sympathetic nerve integrity and abolished by acetylcholine antagonists, such as atropine. Other studies, by contrast, have found the response to be independent of local sympathetic innervation and sensitive to β-adrenoreceptor antagonists or inhibitors of nitric oxide, but not to atropine. Other studies again report that emotional stimuli evoke only generalized vasoconstriction. The basis of arousal-linked muscle dilatation in man is, therefore, still uncertain, except in so far that it is clearly not as straightforward as in some other species (Joyner & Dietz 2003). More importantly, it remains unknown whether such a response would confer any physiological advantage to muscle perfusion on initiation of exercise over and above that provided by local dilator factors released from the contracting muscle cells (see Chapter 6, p. 64). If there were a functional role, then it might be postulated to be most likely of significance for short, repetitive, sub-tetanic activity that does not release sufficient local factors from the muscle cells to induce optimal dilatation. So, for example, a role in playing musical instruments is possible. However, a role in whole-body exercise seems unlikely, although the rise in blood pressure induced by limbic arousal may itself provide some instantaneous benefit for muscle perfusion over the first few seconds of an anticipated exercise.

SYMPATHETIC CARDIOVASCULAR CONTROL DURING EXERCISE

Pressor effect of exercise

Once exercise commences, blood pressure rises rapidly and proportionately to the intensity of activity, regardless of whether or not the activity is anticipated. This pressor response involves a number of sympathetic effector pathways from the hindbrain cardiovascular centre together with release of adrenaline (epinephrine) from the adrenal medulla, causing generalized vasoconstriction of smooth muscle in both venous and arterial vessels. Decreased venous reservoir function increases venous return and stroke volume, decreased aortic compliance increases systolic blood pressure (SBP) and arteriolar constriction increases diastolic blood pressure (DBP).

Sites of peripheral resistance increase

Increased activity of arteriolar constrictor nerves during exercise appears to be generalized across all major regional beds except the brain. In terms of absolute resistance changes, the effects on circulations to the splanchnic region and the kidneys are most pronounced, with blood flows to these areas falling by as much as 70–80% during maximal exertion. In the kidneys, sympathetic activation preferentially constricts the efferent arterioles downstream of the glomeruli, so elevating glomerular capillary pressure. This allows relatively efficient filtration to continue despite the low absolute perfusion.

During exercise, absolute blood flow to skeletal and cardiac muscles rises with work intensity, reflecting the increased local metabolic needs and due in the main to a variety of local dilator processes (see Chapter 6, pp. 72–74). The maximum levels of flow achieved reflect the increments in tissue activity that occur, being 10–20-fold for skeletal muscle (from 1 l/min to 10–20 l/min) and around four-fold for the coronary circulation (from 250 ml/min to 1 l/min). However, the sympathetic activation that accompanies exercise is not region-specific, so there is increased vasoconstrictor drive to skeletal muscle and the heart as well as to splanchnic and renal beds. Thus, the maximum nutritional perfusion that can be achieved in these tissues are less than would be predicted on the basis of the dilator stimuli alone.

Several aspects of this interaction between dilator and constrictor processes bear mention. First, the presence of sympathetic vasoconstriction in skeletal muscle contributes to total peripheral resistance during intense dynamic exercise, and appears to be essential in order to allow maintenance of adequate blood pressure. Second, there is evidence that at near-maximum dynamic exercise intensities, muscle oxygenation may become limited by the sympathetic constrictor effect (Mortensen et al 2005). Third, although vasoconstriction limits the blood flow to exercising skeletal muscle to levels substantially lower than would exist if there were unopposed dilatation, nutritional capillary perfusion during exercise is significantly greater than indicated by the fall in muscle vascular resistance. This is because only around 30% of the capillary bed is perfused in resting skeletal muscle (see Chapter 6, p. 72). Recruitment of the remainder of the capillary bed by metabolite-induced reduction of metarteriolar critical closing pressure provides a threefold elevation in tissue perfusion before there is any requirement for reduced arteriolar resistance.

There is evidence that in the coronary circulation also, sympathetic activation has less effect on nutritional perfusion than is suggested by the absolute effect on regional resistance. This is due to the fact that, in the coronary vasculature, the α-adrenoreceptors are localized primarily to the largest arterioles and small arteries. The constrictor effect of sympathetic activation on these larger vessels stiffens them and actually increases flow to the deeper regions of myocardium, presumably because it reduces external compression during cardiac contraction (Tune et al 2004).

Finally, it is worth noting that whatever the degree of generalized sympathetic activation, the absolute effect on vascular resistance is greater in splanchnic and renal beds than in skeletal muscle and coronary circulations, because small arterioles in the latter two beds contain dilator β-adrenoreceptors as well as α-adrenoreceptors, while those in splanchnic and renal beds are devoid of β-adrenoreceptors.

Origin of signals for sympathetic activation

All forms of exercise depend on descending information from the upper motor neurons of motor cortex to the lower motor neurons controlling muscle contraction. The upper motor neurons also send excitatory inputs to the cardiovascular control centre, so that peripheral vasoconstriction, tachycardia and increased cardiac contraction occur proportionately to both the amount of musculature activated and the intensity of activation. This input to cardiovascular regulation from the motor cortex is known as central command. Although it has traditionally been viewed as originating solely from the cortex, recent studies using imaging and electrophysiological recording indicate that areas of the limbic system are also involved (Green et al 2007).

Two additional signals provide additional input to the cardiovascular control centre. Mechanoreceptors in the limb joints and in the limb musculature give information on the amount and speed of muscle contraction. As well, chemoreceptors within the muscle interstitium detect accumulation of metabolites. Both these signals have the capacity to enhance the sympatho-excitatory effect of central command during any modality of exercise, but limb mechanoreceptors will be activated predominantly during dynamic exercise, while chemoreceptors are activated far more during static exercise when muscle perfusion is minimized by external compression. Evidence from studies of static exercise indicates also that the effect of chemoreceptor activation (the so-called metaboreflex) is preferentially on vasoconstrictor function, with relatively little effect on cardiac function.

Figure 7.3 adds the factors discussed above to our flow chart of the exercise response.

Figure 7.3 Expansion of Figure 6.3, with the factors discussed in this chapter denoted in red.

Comparison of dynamic and static exercise

The different contributions from different signals of motor activity, together with the circulatory effects of the exercise itself, result in distinct patterns of pressor and cardioaccelerator responses to dynamic and to static exercise. During dynamic exercise, sympathetic activation is determined primarily by central command, so that maximal tachycardia and blood pressure are achieved only when a large proportion of the whole-body musculature is involved. Under these conditions, heart rate will attain its age-dependent maximum (see Chapter 4, p. 32) and SBP will rise substantially due to the combined effects of tachycardia, increased stroke volume and reduced aortic compliance. DBP is not usually elevated during dynamic exercise because of the large fall in total peripheral resistance. At low-to-moderate workloads, the reduced resistance is balanced by tachycardia and DBP remains unchanged from the resting value (Fig. 7.4A). At high workloads in the upright posture, by contrast, DBP often begins to fall because of the profound reduction in total peripheral resistance caused by maximal muscle vasodilation.

Figure 7.4 Representative changes in heart rate and blood pressure during increasing intensities of dynamic and static work. Note the very different effects on blood pressure of the two exercise modalities. Note also the inflections in heart rate and blood pressure curves at peak static workloads, due to obstructed venous return.

The picture seen during static exercise is strikingly different (Fig. 7.4B). For one thing, substantial elevation of SBP and heart rate occurs not only with whole-body exercise, but is seen with contraction of quite small muscle groups, such as those controlling handgrip. This is due in a large part to metaboreflex input, secondary to mechanical compression of the muscle vascular supply. In addition, since peripheral resistance does not fall during static exercise, but actually rises due to compression of the muscle vasculature, DBP rises with workload. Finally, increased intra-abdominal and intra-thoracic pressures during whole-body static activity progressively reduce venous return and stroke volume, leading to blood pressure actually falling slightly at peak workload.

Resistance exercises, such as rowing and weight-lifting, have some characteristics of both dynamic and static activities, and, not surprisingly, the circulatory responses also have a mixed pattern, the details of which vary widely with the intensity and duration of exercise. Thus, weight-training with low loads and many repetitions may have little more effect than purely dynamic exercise on blood pressure, whereas pressing a single 100% repetition-maximum load can raise SBP to the order of 300 mmHg – far more than is ever seen during dynamic activity.

BAROREFLEX RESETTING IN EXERCISE

It is clear from the preceding discussion that exercise is associated with maintenance of blood pressure at levels significantly higher than that during rest. This pressure elevation serves two purposes. First, it optimizes nutritional perfusion of the various organ systems in the face of increased regional vasoconstrictor tone. Second, suddenly stopping exercise would immediately stop muscle pumping in the legs, causing a fall in venous return and cardiac output that might prejudice cerebral perfusion in the upright posture. The pre-existence of elevated sympathetic vasoconstriction makes this less likely.

In order to achieve a sustained blood pressure elevation, it is necessary for there to be resetting of the baroreflexes that would otherwise tend to counteract the exercise-induced sympathetic activation. In terms of high-pressure baroreceptor function, this is achieved by upward adjustment of the baroreflex operating point, so that blood pressure is regulated around a value greater than at rest. The extent of the upwards shift in operating point is dependent on exercise intensity and presumably is mediated at least mainly by inputs to the baroreflex pathway of messages from central command. It is not known whether the function of low-pressure baroreflexes is also affected by exercise.

POST-EXERCISE HYPOTENSION

Cessation of exercise is necessarily associated with cessation of the central command for sympathetic activation. This could, in theory, lead to a temporary situation in which widespread vasodilation in skeletal muscle due to residual interstitial metabolites, unopposed by sympathetic vasoconstriction in both muscle and splanchnic beds, would cause a precipitous fall in blood pressure. The fact that this does not normally occur even after intense exercise may reflect the persistence of baroreflex resetting for a period after termination of activity.

Nonetheless, it has been found in a number of studies that blood pressure sometimes falls after dynamic exercise to values slightly below those recorded pre-exercise, over a period of 10–20 min, and that this post-exercise hypotension may be maintained for at least several hours; in some studies up to almost a day. The mechanisms underlying post-exercise hypotension are not well defined, except in as far as (by definition) it must involve some downwards resetting of baroreflex function. Studies in which sympathetic activity has been monitored show reduced vasomotor drive, but some other studies suggest a primary effect on neural control of cardiac function. Evidence from animals, in which a similar hypotensive response is seen, indicate that it involves effects on the baroreflex pathway of opioids released within the hindbrain during exercise.

Questions for revision