News Physiol Sci 15: 241-245, 2000;
1548-9213/00 $5.00
News in Physiological Sciences, Vol. 15, No. 5, 241-245,
October 2000
© 2000 Int. Union Physiol. Sci./Am. Physiol. Soc.
Stopping Exercise: Role of Pulmonary C Fibers and Inhibition Of Motoneurons
Simon C. Gandevia,
Janet L. Taylor and
Jane E. Butler
S. C. Gandevia, J. L. Taylor, and J. E. Butler are at the Prince of Wales Medical Research Institute and University of New South Wales, Sydney, 2031 Australia.
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Abstract
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In animals, the J reflex evoked by pulmonary C fibers provides potent inhibition of limb muscles and would act to limit exercise. However, recent work shows that although activation of these fibers causes severe respiratory discomfort, it does not impair the output of limb motoneurons to voluntary, reflex, or locomotor drives in awake humans.
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Introduction
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In human subjects, intermittent or sustained contraction of skeletal muscle constitutes exercise, an activity accompanied by increases in blood pressure, heart rate, ventilation, and by a host of local and central neuroendocrine responses. The initiation and continuation of exercise usually requires a voluntary decision (for example, to walk to the shop or to cycle for recreation). However, exercise physiologists have long sought to identify a particular cardiovascular, respiratory, or metabolic variable directly associated with the termination of exercise at the point commonly called exhaustion (15). Severe muscle fatigue may be present at this point. During exercise, many factors change at an intracellular level within muscle, and its perfusion and metabolic regulation also change, but identification of a factor or combination of them that stops conventional human exercise has proven difficult.
An alternative approach, which has historically received less attention, is to identify neural factors that limit exercise. One intriguing possibility is that afferents from tissues and organs whose activity is increased during exercise act reflexively to limit the activity of somatic muscles. This concept of viscerosomatic inhibition with exercise has been best developed for a class of pulmonary afferent fibers whose reflex actions include a marked reduction in muscle activity (7). This J reflex, as named by Paintal (11), has been considered a feedback mechanism to limit exercise when pulmonary blood flow and capillary pressure increase sufficiently to activate pulmonary C fibers or J receptors. (The terms pulmonary C fiber and J receptor are used synonymously in this text, although the former term is now used more commonly. The term J reflex has been retained because it denotes the viscerosomatic component of the pulmonary C fiber reflex.) This brief review considers the mechanisms underlying this reflex and its relevance to human exercise and provides speculation on other limits to exercise performance and their evolution.
The lungs (both bronchi and parenchyma) and the heart (at least the left ventricle and right atrium) are richly innervated with unmyelinated afferents (conduction velocities < 2.5 ms–1) capable of signaling the mechanical and chemical status of their local surroundings (3, 12). J receptors, so named because of their position ("juxta" pulmonary capillaries), respond to increased pulmonary blood flow and pressure, local edema, and a variety of chemicals, including phenylbiguanide, lobeline, and capsaicin (Fig. 1A
). (Note that there has been some confusion in the use of phenylbiguanide and phenyldiguanide; see Ref. 10.) These receptors also discharge when pulmonary capillary pressure rises, as in left ventricular failure or in lung pathologies such as pulmonary embolism. Moderate to severe aerobic exercise in humans increases pulmonary capillary pressure by 5–20 cm H2O (15), a level sufficient, on the basis of animal studies, to activate the endings.
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FIGURE 1. Data obtained in the cat with right atrial injections of phenyl diguanide to activate pulmonary C fibers (or J receptors). A, top: J receptor firing. A, bottom: tendon jerk depression for same dose as top ( , derived from data in Ref. 1) and monosynaptic H reflex (•, data in Ref. 4 ). B: abolition of ankle flexor and extensor electromyogram in a walking decerebrate cat after an injection into the right atrium of phenyl diguanide (based on Ref. 14, with permission).
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J receptors have no, or a very low, background discharge rate (<1 Hz). Their rate and duration of discharge increases in a dose-dependent manner with chemical excitants. When activated, their reflex cardiovascular effects, also known as the Bezhold-Jarisch reflex, include severe bradycardia with a consequent hypotension beginning a few seconds after right atrial injections of phenylbiguanide in the dog, cat, rabbit, rat, and mouse. Respiration stops briefly and is followed by a period of rapid shallow breathing that varies in different species. Additional components of the pulmonary chemoreflex include bronchoconstriction and increased airway secretion, responses that would not be appropriate during exercise. Reflex effects can occur even in fish in which there is bradycardia and a reduction in perfusion of the gills. This presumably serves a protective function because it would minimize contact with toxic substances.
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Viscerosomatic effects
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What changes occur in motoneurons and muscles? Injection of chemicals that activate pulmonary C fibers causes the intact cat to slump to the ground (9). In decerebrate cats that walk with stimulation of the mesencephalic locomotor region, Pickar and colleagues (13) have shown that not only do right atrial injections of phenylbiguanide stop rhythmic bursts of muscle activity in locomotor muscles (Fig. 1B
) but so do transient increases in pulmonary capillary pressure (induced by a left atrial balloon). The mechanisms for this cessation of activity in limb motoneurons are likely to be multifactorial. Possible mechanisms include direct inhibition of skeletomotor (
) motoneurons, inhibition of fusimotor (
) motoneurons with a consequent reflex disfacilitation of -motoneurons, and gating out of central and peripheral excitatory input to motoneurons. In the anesthetized cat, right atrial injections of phenylbiguanide abolish the tendon jerk of a leg muscle and also reduce the monosynaptic reflex of both flexor and extensor muscles (1, 4) (Fig. 1A). The skeletomotor "inhibition," mediated by vagal afferents, constitutes the J reflex (11, 12). The J reflex is present in paralyzed and ventilated animals even when hypotension is prevented. All reflex effects of activation of J receptors appear to show no habituation.
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Possible pathways
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The afferent limb for both the cardiorespiratory and viscerosomatic effects of activation of J receptors is the pulmonary vagus nerves. The projection is to the nucleus of the solitary tract (NTS) and nearby in the medulla (for review see Ref. 2). There the J receptor input may converge with other inputs. Cardiovascular effects are mediated by second-order projections to the caudal ventrolateral medulla. From there an inhibitory connection in the rostral ventrolateral medulla causes a reduction in sympathetic vasoconstrictor outflow. There is also a direct inhibitor of sympathetic outflow at the spinal level. In addition, an output from the NTS inhibits vagal output to the heart. Respiratory effects involve second-order projections into the ventral respiratory group.
Compared with cardiorespiratory effector pathways, those involved in viscerosomatic inhibition are poorly defined. The descending (presumably reticulospinal) projections responsible for the motoneuronal inhibition are unknown, as is the precise mechanism underlying the inhibition. Studies of J receptor stimulation in decerebrate cats have yielded seemingly conflicting results: abolition of extensor tone in limb muscles but some preservation of the tendon jerk and H reflex (4, 7, 9). This may be due to variable sites of decerebration and variable descending effects on different classes of fusimotor neurons. Finally, supramedullary projections are important because bilateral lesions in the caudate abolish the J reflex, as does chronic removal of the cingulate gyri (9).
Ascending projections from the NTS presumably to cortical areas are necessary for the sensations mediated by pulmonary C fibers and other visceral fibers. As argued below, the sensory consequences of excitation of pulmonary C fibers must be considered in evaluation of the human J reflex.
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Sensations from the lungs
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Despite their heavy innervation, the sentience of the lungs is rarely considered except for the sensation of breathlessness. However, many other central and peripheral factors contribute to breathlessness to such an extent that it is preserved in patients exercising after lung transplantation. Intravenous injections of chemicals that evoke the pulmonary chemoreflex produce characteristic noxious sensations of smoke or fumes in the airways in human volunteers (e.g., Refs. 5, 8, and 14) (Fig. 2). Species differences in the peripheral receptors mean that lobeline but not phenylbiguanide activates pulmonary C fibers in humans. At threshold doses of lobeline (~10 µg/kg), the sensation is referred mostly to the throat. At higher doses, the sensation spreads to involve the upper chest. Even in carefully informed subjects, the sensation evokes an element of fear. The duration and intensity of this respiratory discomfort increase in proportion to the size of the intravenous bolus dose, with no attenuation of symptoms on repeated testing in one experimental session. The latency for the "threshold" sensations with injections into an antecubital vein is ~10 s, and this diminishes slightly with larger doses. This is consistent with activation of pulmonary endings because it takes ~3 s for the injectate to reach the right atrium, with a few seconds required to reach the juxtapulmonary capillary receptor and activate it.
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FIGURE 2. Data from a human volunteer. An injection of lobeline was made into the right antecubital vein at the time indicated by the arrow. The subject used a potentiometer to signal ongoing sensations, which were also quantified using psychological scales. Note the onset of perceived burning in the chest and throat, accompanied by apnea followed by a cough (based on Ref. 5). BP, blood pressure; HR, heart rate.
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Coughing may occur at the peak of the discomfort and, provided that the dose is not too high, it can be suppressed voluntarily. It is unlikely that the coughing is simply a behaviorally appropriate response to the evoked sensation because the noxious sensations of fumes and smoke in the throat occur at lower doses, which do not evoke a cough. Because the dose required to cause coughing is unaffected by concurrent inflation or deflation of the lungs, Raj and colleagues (14) have argued that the cough is a primary reflex effect of the J receptors and that it is not due to sensitization of rapidly adapting airway receptors. However, a contribution of these receptors to the later phases of the sensation has not been eliminated. The overall sensory response has been likened to that reported in subclinical cases of pulmonary congestion due to altitude sickness.
Consistent with data from other species, activation of the pulmonary chemoreflex in humans produces bradycardia (a decrease of 10–15 beats/min), with the accompanying hypotension (a decrease of ~40 mmHg) being exacerbated by coughing. The initial effects on ventilation are variable, but commonly there is a brief apnea or hypopnea followed by rapid shallow breathing. There is also a late hyperventilation, which is likely to reflect activation of arterial chemoreceptors.
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The J reflex in humans
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We recently assessed whether the motor output from limb muscles was affected during the sensations evoked by lobeline injections (5). The doses were selected to give severe respiratory discomfort lasting ~30 s. Injections of lobeline or saline were given at unpredictable times, and motor output was assessed in several ways. The soleus H reflex, a largely monosynaptic reflex, and the responses of upper limb muscles to transcranial magnetic stimulation of the motor cortex were measured. In addition, maximal and submaximal forces were generated voluntarily, and one subject was studied when walking.
Surprisingly, no inhibition of motor performance occurred, although, as indicated above, ventilation changed. In contrast to the cat, in humans the motoneuronal responses to soleus muscle afferents and to corticospinal inputs increased above control levels during lobeline-evoked sensations (Fig. 3). This increase in both responses is not unexpected given the strong arousal created by the visceral sensation. Arousal stimuli are known to increase spinal excitability in humans. The studies do not rule out the possibility that there is a concomitant increase in excitability of the motor cortex. However, given the reflex changes and the preservation of maximal voluntary forces, it is unlikely that - and -motoneurons received significant postsynaptic inhibition. Given the surprising lack of the J reflex affecting the limb muscles of conscious subjects, it would be useful to determine whether a classic J reflex is unmasked under different conditions, for example during sleep or general anesthesia.
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Possible implications
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These results have implications not only for exercise termination but also for the sensory role of small-diameter pulmonary afferents. Why might the J reflex not be expressed in conscious humans? One explanation is that with evolution, particularly of the neocortex, humans have acquired the capacity to evaluate the consequences of sensory stimuli, both visceral and somatic. To fall to the ground through potent inhibition of limb motoneurons in the face of incipient pulmonary edema is inappropriate. It is better to reach the other side of the street and to seek medical help. Given the presence of the pulmonary chemoreflex in species as primitive as fish, and its potency, one solution may be to place the viscerosomatic component of the reflex under supramedullary control. Many primitive motor reflexes in humans are modulated by supraspinal sites and become unmasked after cortical damage. For example, the Babinski (or extensor plantar) response that would inappropriately lift the toe off the ground during walking and standing disappears about the time an infant begins to walk but reappears following a stroke. However, the absence of a J reflex in awake human subjects does not rule out the possibility that vagal afferents (both pulmonary and subdiaphragmatic in origin) contribute in other ways to the central nervous system adaptations that accompany exercise.
One of the subjective responses to lobeline injections is the sensation of smoke or noxious fumes in the throat and upper airways. Furthermore, if smoke is actually introduced into the airways, it rapidly increases the discharge of pulmonary C fibers (in 1–2 s in the rat) (10). Thus a major function of this class of afferents may be to generate sensations and reflex responses that protect the airway and, ultimately, ventilation and circulation. Here the overall response will depend particularly on the behavior of small-diameter afferents innervating the nose, the portal of entry for the smoke. Interestingly, smoke in the nose evokes reflex responses at concentrations that are inactive when supplied directly to the lungs.
Finally, although the J reflex does not act to terminate human exercise, the search for it has emphasized the sensory consequences of exercise. At the end of moderate to severe exercise in all but the elite athlete, the respiratory discomfort and the discomfort of the exercising limbs may dictate the point of stopping at a time when the lungs, heart, and muscles could still do more (Fig. 4). The role of the input from the exercising limb has been examined in sustained maximal isometric exercise. Muscle force declines with fatigue, and some of this decline is due to a decline in voluntary activation of the muscle. On the basis of the increasingly large twitch forces evoked by transcranial magnetic stimulation of the motor cortex during maximal efforts, at least some of the decline in voluntary activation occurs because voluntary drive becomes unable to get the optimal output from the motor cortex (6). If, instead of being allowed to recover at the end of the contraction, the muscle is maintained ischemic and increasingly uncomfortable by using a sphygmomanometer cuff to block blood flow, it is well known that peripheral force fails to improve. However, the ability to drive the muscle voluntarily also remains depressed. The failure of voluntary drive to recover when the muscle is maintained ischemic occurs despite electrophysiological evidence for recovery of inhibition within the motor cortex. This suggests that signals dependent on inputs from the ischemically sensitive group III and IV muscle afferents acting at sites upstream of the motor cortex are involved in the decline in voluntary performance during exercise (6).
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FIGURE 4. Summary of factors associated with pulmonary C fibers and their possible role in stopping exercise. Cardiorespiratory effects of stimulation of pulmonary C fibers are mediated via medullary circuits, with supramedullary projections involved in noxious sensations and in generation of motoneuronal "inhibition" (in animals). NTS, nucleus of the solitary tract; HR, heart rate; BP, blood pressure. Closed circles indicate inhibitory effects at limb motoneurons.
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A future challenge is to determine how and where upstream of the motor cortex the neural inputs not only from the limbs but also from the heart and lungs interact to provide a neural "stop" to human exercise. Further information is required about the tonic levels of activation of the small-diameter afferents innervating viscera, muscles, and joints and about their reflex effects during exercise and their long-term effects on muscle performance.
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Acknowledgments
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We are grateful to W. Blessing and E. McLachlan for comments on the manuscript.
Our laboratories are supported by the National Health and Medical Research Council of Australia and have also received assistance from the Australian Brain Foundation and the Asthma Foundation of New South Wales.
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References
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Introduction
Viscerosomatic effects
