Marc P. Kaufman

The exercise pressor reflex

Abstract. The exercise pressor reflex is believed to play a role in causing the cardiovascular and ventilatory responses to exercise. This review will discuss the evidence that the reflex is active in both humans abd animals. In addition, this review will discuss the nature of the mechanical and metabolic stimuli that evoke the exercise pressor reflex. Particular attention will be paid to the discharge properties of the thin fiber sensory nerves (i. e., group III and IV muscle afferents) whose activation by these mechanical and metabolic stimuli is responsible for evoking the reflex. Finally, some current findings and controversies will be discussed.

Effects of capsaicin and bradykinin on afferent fibers with ending in skeletal muscle.

Capsaicin, injected into the arterial supply of the skinned hindlimb of dogs, evokes reflex increases in cardiovascular function. Moreover, the cardiovascular reflexes evoked by capsaicin are very similar to those evoked by static exercise. The afferent fibers initiating these reflex increases have not been identified electrophysiologically, although their endings are believed to be located in skeletal muscle. We have, therefore, attempted to determine which afferent fibers are stimulated by capsaicin. In anesthetized dogs, we recorded impulses from afferent fibers with endings in either the gastrocnemius or gracilis muscles and injected capsaicin (10–30 μg/kg) into the abdominal aorta. Capsaicin stimulated 24 of 34 group IV (C fiber) endings, but only 5 of 19 group III (Aδ fiber) endings. By contrast, bradykinin (0.5–1.5 μg/kg) stimulated 17 of 33 group IV endings and 9 of 19 group III endings. Impulse activity for the 24 group IV afferents stimulated by capsaicin increased from 0.7 ± 0.1 to a peak of 9.3 ± 1.4 imp/sec. Firing started 6 ± 1 seconds after injection and remained above control levels for 24 ± 5 seconds. Capsaicin had no significant effect on the firing rate of 30 group I and II muscle afferents. Our results suggest that group IV muscle afferents are primarily responsible for causing the reflex increases in cardiovascular function evoked by injecting capsaicin into the arterial supply of the skinned hindlimb of dogs. Moreover, capsaicin is likely to be a useful pharmacological tool with which to determine the reflex autonomic effects caused by stimulation of group IV muscle afferents.

Stimulation of renal sympathetic activity by static contraction: evidence for mechanoreceptor-induced reflexes from skeletal muscle.

Static muscular contraction in anesthetized animals has been firmly established to reflexly increase arterial pressure. Although group III and IV muscle afferents are known to be responsible for this reflex pressor response, there is no evidence that the stimulation of muscle mechanoreceptors, many of which are supplied by group III fibers, plays a role in causing this contraction-induced reflex effect. To provide this evidence, we recorded renal sympathetic nerve activity in chloralose-anesthetized cats while contracting the triceps surae muscles. We found that static contraction tripled renal nerve activity within three seconds of its onset, an increase that was abolished by cutting the L6 and S2 dorsal roots. On average, the contraction-induced increase in renal nerve activity was observed 0.8±0.1 seconds after the onset of this maneuver. In addition, intermittent tetanic contractions synchronized renal nerve discharge so that a burst of activity was evoked by each contraction. A similarly synchronized renal nerve discharge was evoked in paralyzed cats by electrical stimulation of the tibial nerve at five times motor threshold, a current intensity that activates group III afferents. We conclude that, in anesthetized animal preparations, mechanoreceptors with group III afferents contribute to the reflex stimulation of renal sympathetic outflow evoked by muscular contraction.

Operational sensitivity and acute resetting of aortic baroreceptors in dogs.

Stimulus-response curves of aortic baroreceptors constructed by alternately increasing and decreasing pressure from a normal baseline or set-point differ from curves constructed by varying pressure in one direction only from an abnormally high or low pressure. In anesthetized dogs we recorded impulses from aortic baroreceptors with myelinated fibers, using a pressurized reservoir to control mean aortic blood pressure (MABP). After setting MABP to a baseline of 100 mm Hg (normal MABP in unanesthetized dogs), we constructed baroreceptor response curves by alternately decreasing MABP from 100 to 30 mm Hg, and increasing it from 100 to 180 mm Hg, in each case returning MABP to the baseline to obtain hysteresis loops. All baroreceptors were active at 100 mm Hg, their discharge averaging 15–16 impulses/sec. At all pressures above threshold, baroreceptors fired more when pressure was increasing than when pressure was decreasing. This hysteresis caused the steepest part of the response curve constructed in this manner to span the baseline value, demonstrating that, contrary to previous views, aortic baroreceptors signal decreases in pressure below the normal level, as well as increases above it. We also constructed response curves after holding MABP at a “hyperten- sive” baseline of 125 mm Hg for 20 minutes. “Hypertensive” curves demonstrated reversible resetting, shifting significantly to the right of “normotensive” curves so that baroreceptor threshold increased on average by 7 mm Hg (P < 0.01). Both hysteresis and short-term resetting probably result from the viscoelastic behavior of wall elements with which baroreceptors are coupled.

Stimulation by bradykinin of afferent vagal C-fibers with chemosensitive endings in the heart and aorta of the dog.

Bradykinin applied directly to the epicardium evokes a reflex increase in blood pressure by stimulating sympathetic afferent nerve endings in the heart, but injected into the coronary artery it evokes vagally mediated reflex decreases in heart rate and blood pressure. The afferents initiating these latter depressor effects have not been identified. We have attempted to determine which vagal sensory nerve endings in the heart are stimulated by bradykinin. In anesthetized dogs, we recorded impulses from afferent vagal fibers with endings in the heart and aorta and injected bradykinin (0.3-1.0 /ig/kg) into the left atrium. Neither Anor C-fiber mechanoreceptors nor aortic body chemoreceptors were stimulated directly by bradykinin, any changes in firing of a trial or ventricular mechanoreceptors, or of aortic baroreceptors or chemoreceptors, being secondary to the cardiovascular effects of bradykinin. However, 16 of 20 irregularly discharging vagal C-fibers with chemosensitive endings in the left ventricle, left atrium, and aorta were stimulated by bradykinin; firing increased from 0.2 ± 0.1 to 7.8 ± 1.4 (mean ± SE) impulses/sec and usually remained above control for about 30 seconds. These chemosensitive endings were not stimulated by ventilating the lungs with 5% O2 in N2, but they were stimulated by injecting capsaicin or phenyl diguanide into the left atrium. Four chemosensitive endings in the ventricular epicardium were also stimulated by dripping bradykinin (1 pg/ml) onto the heart. We suggest that these chemosensitive vagal C-fibers are responsible for the reflex decreases in heart rate and blood pressure elicited by bradykinin. Circ Res 46: 476-484, 1980

The exercise pressor reflex in animals

This report summarizes work concerning the exercise pressor reflex performed in my laboratory over the past 20 years or so. It is part of a symposium held to celebrate the 40th anniversary of two publications by Dr Jere Mitchell that appeared in The Journal of Physiology. For the most part, this report concerns itself with the discharge properties of group III and IV muscle afferents. Particular attention has been paid to their responses to arterial injection of putative metabolic byproducts of muscular contraction as well as their responses to both static contraction and dynamic exercise.

Responses to inflation of vagal afferents with endings in the lung of dogs.

In dogs, inflating the lungs to pressures of 9 cm H2O or less reflexly increases heart rate, whereas inflating the lungs to pressures of 10–30 cm H2O reflexly decreases heart rate. The afferent fibers responsible for the cardioacceleration travel in the vagus nerves and are believed to be pulmonary stretch receptors, whereas the afferents responsible for the deceleration also travel in the vagus nerves, but are believed to be lung C-fibers. To identify the afferents responsible for these effects, we recorded the impulse activity of vagal afferents with endings in the left lung, while we slowly inflated that lung to 30–45 cm H2O. We found that 12 slowly adapting receptors fired at significantly lower inflation pressures than did 10 rapidly adapting receptors (5.8 ± 1.5 vs. 13.5 ± 2.2 cm H2O, respectively). We also found that 13 pulmonary C-fibers fired at significantly lower inflation pressures than did 10 bronchial C-fibers (16.4 ± 1.8 vs. 26.5 ± 2.9 cm H2O, respectively). We conclude that slowly adapting receptors are likely to be responsible for the cardioacceleration evoked by low levels of inflation, and that both pulmonary and bronchial C-fibers are likely to be responsible for the cardiodeceleration evoked by high levels of inflation.

Discharge Properties of Group III and IV Muscle Afferents

Stimulation of group III and IV muscle afferents has been shown to have important reflex effects on both the somatic and autonomic nervous systems. These include an inhibitory effect on alpha motoneurones, an excitatory effect on gamma motoneurones and an excitatory effect on the sympathetic nervous system. The purpose of this review is to describe the mechanical and metabolic stimuli that discharge group III and IV muscle afferents. Particular attention will be paid to the responses of these afferents to dynamic exercise induced by electrical stimulation of the mesencephalic locomotor region.

Blockade of acid sensing ion channels attenuates the exercise pressor reflex in cats

Although thin fibre muscle afferents possess acid sensing ion channels (ASICs), their contribution to the exercise pressor reflex is not known. This lack of information is partly attributable to the fact that there is no known selective in vivo antagonist for ASICs. Although amiloride has been shown to antagonize ASICs, it also has been shown to antagonize voltage‐gated sodium channels, thereby impairing impulse conduction in sensory nerves. Our aim was to test the hypothesis that lactic acid accumulation in exercising muscle acted on ASICs located on thin fibre muscle afferents to evoke the metabolic component of the exercise pressor reflex. To test this hypothesis, we determined in decerebrate cats if amiloride attenuated the pressor and cardioaccelerator responses to static contraction, to tendon stretch and to arterial injections of lactic acid and capsaicin. We found a dose of amiloride (0.5 μg kg−1; i.a.) that attenuated the pressor and cardioaccelerator responses to both contraction and lactic acid injection, but had no effect on the responses to stretch and capsaicin. A higher dose of amiloride (5 μg kg−1, i.a.) not only blocked the pressor and cardioaccelerator responses to lactic acid and contraction, but also attenuated the responses to stretch and to capsaicin, manoeuvers in which ASICs probably play no significant role. In addition, we found that the low dose of amiloride (0.5 μg kg−1) had no effect on the responses of muscle spindles to tendon stretch and to succinylcholine, whereas the high dose (5 μg kg−1) attenuated the responses to both. Our data suggest the low dose of amiloride used in our experiments selectively blocked ASICs, whereas the high dose blocked ASICs and impulse conduction in muscle afferents. We conclude that ASICs play a role in the metabolic component of the exercise pressor reflex.

Pressor reflex response to static muscular contraction: Its afferent arm and possible neurotransmitters

Static muscular contraction has been shown to increase cardiovascular and ventilatory function in reflex manner. The sensory arm of this reflex arc is comprised of group III and IV muscle afferents. The discharge properties of these muscle afferents whose activation causes the pressor reflex response to contraction were investigated. Group III afferents were more responsive to mechanical stimuli, such as tendon stretch and probing their receptive fields than were group IV afferents. In contrast, group III afferents were less responsive to ischemic contraction than were group IV afferents. Equal percentages of group III and IV afferents were stimulated by potassium, lactic acid and arachidonic acid, each of which are metabolic products of contraction. Adenosine, phosphate and lactate, however, had no effect on the discharge of the afferents. Intrathecal injection of antagonists or antibodies to substance P and somatostatin attenuated the pressor response to contraction by about half, a finding that suggests a role for these 2 peptides in the spinal transmission of the reflex.