Experimental Physiology

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1 Experimental Physiology Physiological Society Symposium - Vagal Control: From Axolotl to Man Cardiac vagal control before, during and after exercise J. H. Coote * and Valerie F. Bothams + Department of Physiology, Medical Sciences, The University of Birmingham, Birmingham B15 2 TT, UK CONTENTS Summary Introduction Cause of the change in cardiac vagal tone Selective afferent influence on cardiac vagal tone Influence of group 111 and group IV muscle afferents Small fibre mechanoreceptors in man The baroreceptor reflex Conclusion References Experimental Physiology (2001) 86.6, PAGE Summary There is much evidence showing that the rapid rise in heart rate at the onset of exercise is due to a withdrawal of cardiac vagal tone. This short review discusses the main afferent mechanisms involved in this effect. In addition to signals from central motor command it is shown that muscle mechanoreceptors of group I11 afferent fibres also play a significant role. Recent studies in man demonstrating this by stretching muscles such as the triceps surae or by direct compression of muscles are briefly reviewed. The evidence also supports the idea that these small fibre mechanoreceptors inhibit the baroreceptor-heart rate reflex. Several studies suggest that skeletal muscle metaboreceptors (mainly group IV) are more important for increasing cardiac sympathetic and vasoconstrictor nerve activity. At the conclusion of exercise the cessation of mechanoreceptor stimulation is an important factor in determining the rapid return of heart rate to resting level. Introduction In most mammals studied, at the onset of exercise the pulse quickens so that the first diastolic period after exercise begins is shorter than during rest. In human studies, reviewed by Coote (1995) and by Secher (1999), the extent of this cardiac acceleration is dependent on the force of contraction and type of muscle. In general it takes only around 1 s to bring about a 25% increase in heart rate. During the next few seconds the acceleration increases further and within 1-3 min it reaches a steady level. By studying sustained contractions of limb muscles it has been shown that provided the changes in R-R interval are measured in the first 25 s after the start of a contraction, the increase in heart rate is entirely a consequence of a withdrawal of cardiac vagal tone (Maciel et al. 1987). The promptness with which the acceleration begins at the onset of exercise and its universal nature across animal species emphasises its importance. This probably ensures a close matching of cardiac output and oxygen delivery to the exercising muscle in the initial stage of work when the muscle vascular bed is dilating ahead of the slower sympathetic vasoconstriction occurring elsewhere. Clearly this mechanism can be of most value where resting cardiac vagal tone is high. Cause of the change in cardiac vagal tone Recently there has been renewed interest in understanding what brings about the withdrawal of cardiac vagal tone. There are two main possible mechanisms; central command Presented at the Oxford Meeting of the Physiological Society in March t Present address: Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester C04 3SQ, UK. Publication of The Physiological Society * Corresponding author: J.H.Coote@bham.ac.uk 2292

2 812 J. H. Coote and V. E Botharns Exp. Physiol whereby the heart rate change is initiated as part of the motor command from the brain to skeletal muscles, and a muscle reflex. There have been numerous experiments (reviewed by Coote, 1995; Secher, 1999) indicating the importance of central command. The most direct evidence comes from studies where mental effort has been shown to increase heart rate and blood pressure in proportion to imagined work in circumstances where there is no detectable increase in metabolism (Decety et al. 1993; Thornton et al. 2001) or where muscles were unable to respond because of regional paralysis (Gandevia et al. 1993). However, studies on experimental animals provide little doubt that feedback from contracting muscles is also able to elicit the acceleration in heart rate (McMahon & McWilliam, 1992; Coote, 1995). Furthermore, studies in man have electrically induced isometric muscle contraction of the triceps surae (Bull et al. 1989), or arm flexors (Al-Ani et al. 1997) to bypass central command and these show increases in heart rate that are identical to those induced by similar contractions produced voluntarily. These are also characteristic of the pressor response to exercise. Selective afferent influence on cardiac vagal tone There are though features of the heart rate increase which are quite different from the pressor response. Attention was drawn to this difference in a study by Lind et af. (1968) of a patient with asymetrical dissociated anaesthesia of the upper limbs caused by loss of small sensory fibres due to syringomyelia affecting one side. In this patient the pressor response was absent during sustained contraction of forearm muscles on the affected side yet the heart rate increase was still elicited. A similar dissociation was reported in a later study of normal subjects undergoing dynamic leg exercise before and during epidural anaesthesia to reduce muscle afferent input (Fernandes et al. 1990). Additional support comes from a study in our laboratory showing that significant increases in heart rate in response to graded isometric contraction of the triceps surae occur at muscle tensions below the threshold for the blood pressure response (Bothams, 2001). A further clear demonstration of differential control of the heart rate and blood pressure response to exercise emerged from studies of changes at the end of voluntary muscle contraction but with a maintained occlusion of the muscle circulation (Fig. 1). Whereas the blood pressure remains elevated, the heart rate rapidly returns to the control level unlike its slower recovery following contraction without ischaemia. Although these differences could be accounted for by assuming that central command dominates the autonomic control of the heart, it could not have been operating during involuntary contractions (Bull et al. 1989; Al-Ani et al. 1997). Several lines of evidence now suggest that in addition to central command, there is feedback from selected populations of small afferent fibres responding to mechanical or metabolic stimuli and each has a preferred effect either on cardiac or vasomotor tone (Fig. 2). Influence of group I11 and group 1V muscle afferents Studies in experimental animals reveal that the reflex cardiovascular changes arising from skeletal muscle contraction are due to activation of group 111 and group IV muscle afferents (reviewed by Coote, 1995). The afferent fibres display different sensitivity to local stimuli; group IV mainly responding to accumulation of metabolites (Kniffki et al. 1978; Kaufman & Rybicki, 1987), although some do respond to stretch, whereas group 111 are particularly affected by mechanical stimuli such as stretch (Kaufman et al. 1983; Mense & Stahnke, 1983). These properties of the afferent fibres make group I11 fibres likely candidates for eliciting heart rate changes and group IV fibres for eliciting blood pressure changes. Unfortunately the polymodal nature of the receptors (Kaufman et al. 1983) does not make the conclusion as simple as this. Electrical stimulation of group I11 muscle Figure 1 Changes in heart rate during isometric contraction. Schematic drawing showing the increase in heart rate during isometric contraction of skeletal muscle for 1 min and its recovery post-contraction (continuous line). The dashed line illustrates the more rapid decrease in heart rate that occurs when the circulation to the muscle is occluded postcontraction. 1 min 2 min

3 Exp. Physiol Cardiac vagal control in exercise 813 afferents increases sympathetic vasoconstrictor nerve activity (Coote & Perez-Gonzalez, 1970; Victor et al. 1989) as well as increasing heart rate. Also, activation of group I11 fibres by passive stretch of triceps surae in the anaesthetised cat and rat increases both heart rate and blood pressure (Stebbins et al. 1988; Wilson et al. 1994; Potts & Mitchell, 1998). However, the effect of stretching muscles on blood pressure is transient whereas the inhibitory effect on cardiac vagal tone is sustained (Murata & Matsukawa, 2001). Small fibre mechanoreceptors in man It has been more difficult to demonstrate an effect of mechanically sensitive afferents in man. The majority of evidence favours a significant function for metabolically sensitive afferent fibres in changing sympathetic activity and it is assumed that the central command is more important for the heart rate changes (Mark et al. 1985; Secher, 1999). This appears to be supported by a study in man, somewhat similar to that in the anaesthetised cat, which compared isometric contraction of triceps surae with passive dorsiflexion of the foot to stretch the plantar flexors, the latter causing no significant cardiovascular changes (Baum et al. 1995). However we have recently shown that similar stimuli of appropriate magnitude can evoke changes in heart rate (see below). Others have used elevations of intramuscular pressure to look at mechanically sensitive fibres. External leg compression in man induces an increase in blood pressure which is abolished by epidural anaesthesia (Williamson et al. 1994). Also McClain et al. (1993) have shown that elevation of interstitial pressure of active muscles during dynamic exercise augments the increases in heart rate and blood pressure. Somewhat in contrast, it has been reported that a reduction in extracellular muscle volume, produced by passively raising the legs above heart level and then rapidly occluding the leg circulation via thigh cuffs, enhances the increases in heart rate and blood pressure in response to isometric exercise (Baum et al. 1990) and to dynamic exercise (Essfeld et al. 1988). It seems likely that the different methods employed in these studies all resulted in distortion of mechanoreceptors so there is no real contradiction in the results. However, these experimental manipulations are unlikely to be mimicking the situation occurring in normal healthy muscle during contraction, although the results could be highly relevant to patients with heart failure and others where an increase in interstitial pressure at rest is common. In an attempt to determine whether muscle group I11 mechanoreceptors in humans are able to induce calrdiovascular changes when subjected to exercise-like stimuli we examined the effects of stretching the triceps surae (Bothams et al. 2000). These studies differed from those of Baum et al. (1995), in that the subjects were placed semi-supine to ensure a hgh degree of vagal tone and one leg was positioned in a specially designed apparatus which allowed full stretch of the plantar flexors (Bothams, 2001). Passive dorsiflexion of the foot sustained for 1 nlin significantly increased heart rate and reduced the respiratory-related heart rate variability without a concomitant significant change in blood pressure (Bothams et al. 2000; V. F. Bothams & J. H. Coote, unpublished observations). The rapid onset of the change in heart rate and the reduction in variability suggest that the action of muscle mechanoreceptors was primarily one of reducing cardiac vagal tone. Lengthening the muscle, as was done in our experiments, is clearly not the same as contracting muscles. However, experiments in the cat show that the same muscle group I11 receptor responds to stretch and muscle contraction (Kaufman & Rybicki, 1987), indicating they are distortion receptors not selectively length or tension receptors. It seems probable therefore that during exercise in humans such receptors will be activated immediately on muscle contraction and contribute to the changes in heart rate in addition to central command. Figure 2 Factors controlling heart rate during exercise. The diagram illustrates that muscle group I11 mechanoreceptors activated by contraction inhibit (minus sign) vagal cardiac neurones (VCN) either directly or by inhibiting baroreceptor (BAROS) excitation (plus sign) at the nucleus tractus solitarii (NTS) and thus cause an immediate increase in heart rate (HR). Muscle group IV metaboreceptors, activated more slowly by the build up of metabolites, mainly excite sympathetic cardiac (SCN) and vasomotor neurones and reset the baroreceptor reflex. Central motor command mimicks the action of muscle mechanoreceptors and less so the muscle metaboreceptors. Muscle a- group Ill / / Centrol motor -< command \

4 J. H. Cooteand V. F. Bothams Exp. Physiol The baroreceptor reflex The implied inhibition of cardiac vagal tone would mean that the baroreceptor-heart rate reflex is attenuated or blocked during muscle contraction. This has been directly shown in the cat (McWilliam & Yang, 1991) and indirectly by a decrease in sensitivity of the blood pressure-heart rate relationship in man (Mancia et al. 1978; Iellamo et al. 1999). The muscle metaboreceptors appear to have a lesser inhibitory effect on the baroreceptor-heart rate reflex since, when they are active alone during a period of postcontraction circulatory occlusion, heart rate descends steeply to control values (Fig. 1). This is more'marked because blood pressure remains high during vascular occlusion. The fall in heart rate can be prevented by offsetting the blood pressure effect at the carotid baroreceptors by increasing the pressure around the carotid sinus using pressure in a neck cuff (Bothams, 200 1). Therefore the muscle mechanoreceptors and metaboreceptors differ in the way they influence parasympathetic and sympathetic components of the cardiovascular control system (Fig. 2). On the one hand, baroreceptor reflex activation of cardiac vagal neurones is prevented by muscle contraction (McWilliam & Yang, 1991) whilst on the other hand baroreceptor inhibition of sympathetic outflow is still present, although reset to work around a higher operating point (Coote & Dodds, 1976). In fact the presence of the baroreceptor reflex is important for the cardiovascular changes because if baroreceptors are removed and exercise is performed blood pressure decreases dramatically at the start of contraction after which there is an augmented increase in blood pressure (Walgenbach & Donald, 1983). Conclusion Whilst it is clear that central motor command plays a part in eliciting cardiovascular changes that accompany exercise, the evidence overwhelmingly shows that reflexes from the contracting muscles are of equivalent importance. At the onset of muscle contraction group 111 mechanoreceptors inhibit cardiac vagal tone and prevent baroreceptor excitation, so ensuring there is an immediate increase in heart rate. As contraction proceeds muscle metabolic products activate metaboreceptors, which increase sympathetic cardiovascular activity, which further increases cardiac output and, most importantly, channels this towards the working muscles, by vasoconstriction in non-essential vascular beds. AL-ANI, M., ROBINS, K., AL-KHALIDI, A. H., VAILE, J., TOWNEND, J. N. & COOTE, J. H. (1997). Isometric contraction of arm flexor muscles as a method of evaluating cardiac vagal tone in man. Clinical Science 92, BAUM, K., ESSFELD, D. & STEGEMANN J. (1990). 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