12.1. INTRODUCTION

Exercise is well known to increase mean arterial pressure, heart rate, and ventilation, effects caused, in part, by a reflex arising from contracting skeletal muscles. This phenomenon has been named the exercise pressor reflex (Mitchell, Kaufman, and Iwamoto 1983) and is thought to relay information to the central nervous system regarding the metabolic state and the mechanical activity of the exercising muscles (Hayes and Kaufman 2001; Kaufman and Forster 1996). The afferent arm of the exercise pressor reflex arc is composed of thinly myelinated group III and non-myelinated group IV muscle afferents. Group III afferents primarily transmit information about mechanical stimuli arising in the exercising muscles, whereas the group IV afferents primarily transmit information about metabolic stimuli (Hayes and Kaufman 2001; Kaufman and Forster 1996). Group III and IV muscle afferents are also thought to be activated by nociceptive stimuli and are likely the sole source of pain from skeletal and cardiac muscle. The aim of this account is to correlate what is known about the afferent arm of the exercise pressor reflex and to what extent it is evoked by nociceptive versus non-nociceptive stimulation of skeletal muscle.

12.2. MUSCLE AFFERENTS

Before discussing the role played by muscle afferents in evoking the sensation of pain, we need to provide some basic information about the sensory innervation of limb skeletal muscles and the discharge properties of their afferents. Limb skeletal muscle is innervated by five types of afferents. Group I is subdivided into Ia and Ib. These afferents are thickly myelinated and conduct impulses between 72 and 120 m/s in cats and dogs. Group II afferents are also thickly myelinated and conduct impulses between 31 and 71 m/s in cats and dogs. Group Ia and II afferents innervate muscle spindles, and group Ib afferent innervate Golgi tendon organs. Group III afferents, also known as Aδ fibers, are thinly myelinated and conduct impulses between 2.5 and 30.0 m/s in cats and dogs. Group IV afferents, also known as C-fibers, are unmyelinated and conduct impulses at less than 2.5 m/s in cats and dogs. Group III and IV afferents have free nerve endings often within the connective tissue of skeletal muscle, whereas group IV afferents have free nerve endings often within small vessels of muscle (von During and Andres 1990).

Group Ia and Ib as well as group II afferents do not contribute to cardiovascular response to exercise, nor are they responsible for the evoking the sensation of pain. McCloskey and Mitchell (1972) found that the reflex ventilatory and cardiovascular increases evoked by static contraction were caused by stimulation of group III and IV muscle afferents. Specifically, anodal blockade of the dorsal roots prevented impulses from group I and II afferents from reaching the spinal cord, but did not prevent the contraction-induced increases in ventilatory and cardiovascular function. On the other hand, topical application of a local anesthetic (which blocks group III and IV fibers before blocking group I and II fibers) to the dorsal roots did not block impulse conduction in group I and II afferents, but did block the contraction-induced cardiovascular increases and reduced the ventilatory increases. In subsequent studies in dogs, Tibes (1977), using cold blockade, also reported that group III and IV muscle afferents, but not group I and II afferents, were responsible for evoking the exercise pressor reflex.

There is additional evidence that groups III and IV, but not groups I or II, cause the reflex cardiovascular and ventilatory increases evoked by contraction of hindlimb skeletal muscle. For example, electrical stimulation of the central cut end of the medial and lateral gastrocnemius nerves did not increase either ventilation or arterial pressure until the current intensity recruited group III fibers (Mizumura and Kumazawa 1976; Sato, Sato, and Schmidt 1981; Tibes 1977). Also, activation of group Ia and II spindle afferents by longitudinal vibration, a strong stimulus for these afferents, had almost no effect on ventilation, arterial pressure, or heart rate (Hodgson and Matthews 1968; McCloskey, Matthews, and Mitchell 1972). On the other hand, chemical activation of group Ia and II afferents has been shown to increase ventilation, arterial pressure, and heart rate (Crayton, Mitchell, and Payne, III 1981; Kaufman and Forster 1996; Tibes 1977), whereas chemical activation of group la and II afferents had no effect on these variables (Hodgson and Matthews 1968; Waldrop, Rybicki, and Kaufman 1984).

Group III and IV afferents, not group I or II, are also the afferents that are responsible for evoking the sensation of pain. Close arterial injections of bradykinin into the triceps surae muscle, in concentrations that were considered painful in man and animals, increased only the activity of group III and IV muscle afferents. In fact, group I and II afferents exhibited no change and even decreased their firing rates. On the other hand, the injections of bradykinin increased the firing rate of over two-thirds of the group III afferents tested and over 50% of group IV afferents tested (Mense 1977). In agreement with this animal study, a human study also found that group III and IV muscle afferents were responsible for evoking the sensation of pain within skeletal muscle (Graven-Nielsen, Mense, and rendt-Nielsen 2004). When these authors anesthetized skin as well as differentially nerve-blocked group I and II afferents within skeletal muscle, the subjects could still feel a painful pressure stimulus.

12.3. DISCHARGE PROPERTIES OF GROUP III AND IV AFFERENTS

One of the first to investigate the discharge properties of group III afferents was Paintal, who found that group III endings located in the hindlimb muscles of dogs responded to pressure applied to the muscle (Paintal 1960). Since then several investigators have independently reached similar conclusions about the discharge properties of these thinly myelinated afferents. These are (1) that about half responded to contraction, be it intermittent tetanic or maintained tetanic (static) contraction ( Ellaway, Murphy, and Tripathi 1982; Kaufman et al. 1983; Mense and Stahnke 1983; Paintal 1960); (2) that about half responded to intra-arterial injection of bradykinin, a potent algesic agent (Kaufman et al. 1983; Kumazawa and Mizumura 1977; Mense 1977); (3) that many responded to non-noxious punctate pressure applied to their receptive fields ( Hayward, Wesselmann, and Rymer 1991; Kaufman et al. 1983, 1984a; Kumazawa and Mizumura 1977; Mense and Stahnke 1983; Paintal 1960); and (4) that their responses to tendon stretch was variable, some investigators finding a frequent effect (Abrahams, Lynn, and Richmond 1984), others finding a moderate effect ( Hayward, Wesselmann, and Rymer 1991; Kaufman et al. 1983; Kaufman and Rybicki 1987; Mense and Stahnke 1983), and still another finding an infrequent effect (Paintal 1960).

Group III muscle afferents are believed to possess polymodal discharge properties because they respond to both chemical and mechanical stimuli (Kumazawa and Mizumura 1977). This belief, however, is controversial because it is based on the responses of group III afferents to large and possibly unphysiological doses of bradykinin (Mense and Meyer 1985). Nevertheless, the mechanical sensitivity of group III afferents might be their most relevant discharge property when assessing their contribution to evoking reflex autonomic adjustments to exercise. Group III muscle afferents, for example, respond vigorously at the onset of tetanic contraction, with the first impulse often being discharged within 200 milliseconds of the start of this maneuver (Kaufman et al. 1983). Moreover, group III afferents increase their responses to tetanic contractions as the peak tension developed by the working muscle increases ( Hayward, Wesselmann, and Rymer 1991; Kaufman et al. 1983; Mense and Stahnke 1983). In addition, group III afferents usually decrease their discharge rate during a static contraction as the working muscle fatigues ( Hayward, Wesselmann, and Rymer 1991; Kaufman et al. 1983). Further, group III afferents are capable of synchronizing their discharge with a constantly oscillating stimulus, be it either 5 Hz twitch contraction (Kaufman et al. 1984b), intermittent tetanic contraction (Mense and Stahnke 1983), or a true form of dynamic exercise evoked by stimulation of the mesencephalic locomotor region ( Adreani, Hill, and Kaufman 1997; Pickar, Hill, and Kaufman 1994). Lastly, gadolinium has been shown to block the mechanical sensitivity of group III afferents (Hayes et al. 2009; Hayes and Kaufman 2001) in the triceps surae muscles of cats.

Group III afferents respond to the metabolic stimuli possibly through direct stimulation or sensitization of their endings. For example, they are stimulated by bradykinin (Kaufman et al. 1983; Kumazawa and Mizumura 1977; Mense 1977), potassium (Hník et al. 1986; Kumazawa and Mizumura 1977; Mense 1977; Rybicki, Waldrop, and Kaufman 1985; Thimm and Baum 1987), arachidonic acid (Rotto and Kaufman 1988), and lactic acid (Rotto and Kaufman 1988; Sinoway et al. 1993; Thimm and Baum 1987). In addition, bradykinin and arachidonic acid increased the responsiveness of group III fibers to contraction of the triceps surae muscles (Mense and Meyer 1988; Rotto et al. 1990).

Group IV afferents respond minimally to mechanical stimuli compared with group III afferents and are much more responsive to metabolic stimuli. In fact, these afferents possess different discharge properties than do group III muscle afferents. These differences are (1) group IV afferents usually display obvious responses to contraction with latencies of 5–30 seconds, whereas group III afferents often respond vigorously within 30–200 milliseconds (Kaufman et al. 1983; Kaufman et al. 1984b; Mense and Stahnke 1983); (2) their responses to dynamic exercise are not attenuated by gadolinium, a mechanogated channel blocker, whereas the responses of group III afferents are blocked by this agent (Hayes et al. 2008a); (3) when compared to contraction while the muscle was freely perfused, contraction while the muscle was ischemic increased the responses of almost half the group IV afferents tested but increased the responses of only 12% of group III afferents tested, indicating responsiveness to metabolites in the former, but much less in the later group (Kaufman et al. 1984a); (4) about half responded to static contraction while the muscles were ischemic but did not respond to a static contraction of equal magnitude when the muscles were freely perfused (Kaufman et al. 1984a; Mense and Stahnke 1983); (5) group IV afferents are much less sensitive than are group III afferents to mechanical stimuli (either probing their receptive fields or to tendon stretch). In contrast to group III afferents, group IV afferents most often require noxious pinching of their receptive fields to discharge them, and frequently do not respond to noxious tendon stretch (Kaufman et al. 1984a; Kaufman and Rybicki 1987; Kniffki, Mense, and Schmidt 1978; Mense and Stahnke 1983).

Group IV afferents are stimulated by the same substances that have been shown to stimulate and/or sensitize group III afferents to other stimuli, such as contraction or probing of their receptive fields. Hence, intra-arterial injection of bradykinin (Kaufman et al. 1983; Mense 1977; Mense and Schmidt 1974), potassium (Hník et al. 1969; Kaufman and Rybicki 1987; Mense 1977), lactic acid (Graham et al. 1986; Rotto and Kaufman 1988; Thimm and Baum 1987), and arachidonic acid (Rotto and Kaufman 1988) have been shown to stimulate at least half of the group IV afferents tested. In addition, other substances stimulate group IV afferents, such as prostaglandin E2 (Mense 1981) and ATP ( Hanna, Hayes, and Kaufman 2002; Hanna and Kaufman 2004; Reinöhl et al. 2003). Histamine and serotonin stimulated only a few group IV afferents and the threshold doses appeared to be quite high ( Kniffki, Mense, and Schmidt 1978; Mense 1977).

12.4. METABOLITES RELEASED DURING MUSCULAR CONTRACTION AND PAIN

The evidence concerning ATP, working through purinergic 2 (P2) receptors, as a substance that evokes the exercise pressor reflex is strong. Specifically, injection of P2 agonists into the arterial supply or directly into the gastrocnemius muscle stimulated over two-thirds of the group IV afferents tested in cats (Hanna and Kaufman 2004) and rats (Reinöhl et al. 2003). In addition, close arterial injection of P2 agonists into the vascular supply of feline hindlimb muscle has been shown to evoke a reflex pressor response (Hanna, Hayes, and Kaufman 2002). Perhaps even more compelling evidence is that the pressor response to static exercise was attenuated by injection of PPADS, a P2 receptor antagonist (Hanna and Kaufman 2003; Kindig, Hayes, and Kaufman 2007). Further, blockade of P2 receptors by PPADS attenuated the responses of both group III and IV afferents to static contraction, both while the muscles were freely perfused and while they were ischemic. Likewise, PPADS attenuated the responses of group IV afferents to post contraction ischemia (Kindig et al. 2006; Kindig, Hayes, and Kaufman 2007). All these findings suggest that ATP activates P2 receptors on the endings of group III and IV thin fiber afferents during exercise and that these receptors contribute to the exercise pressor reflex by sensitizing group III mechanoreceptors and stimulating group IV metaboreceptors.

Of the P2 receptor subtypes, the P2X receptor on group IV afferents is thought to evoke the muscle chemoreflex (Chen et al. 1995; Cook et al. 1997; Hayes, McCord, and Kaufman 2008; Lewis et al. 1995). In addition, these receptors respond to levels of ATP that are released in muscle in response to stress (Cook and McCleskey 2002). Lastly, injections of ATP and a P2X receptor agonist, alpha, beta-methylene ATP, into the rat hindpaw increased behavioral indexes of pain (i.e., hindpaw licking, lifting, and flinching) (Bland-Ward and Humphrey 1997; Sawynok and Reid 1997), effects that were prevented by P2X receptor blockade (Bland-Ward and Humphrey 1997; Sawynok and Reid 1997). Therefore, it seems likely that ATP plays a role in the pressor response and the sensation of muscle pain.

Arachidonic acid and its cyclooxygenase products appear to play a role in evoking the exercise pressor reflex. Concentrations of arachidonic acid and PGE2 in the freely perfused gastrocnemius muscles of cats increased significantly when these muscles were contracted. When the muscles were contracted under ischemic conditions, arachidonic acid and PGE2 concentrations rose to an even higher level (Rotto et al. 1989; Symons et al. 1991). Most importantly, the pressor, cardioaccelerator, and cardiac contractility responses to static contraction of the hindlimb muscles of anesthetized cats were significantly attenuated by indomethacin as well as by sodium meclofenamate, agents that block the activity of cyclooxygenase. Further, blood flow to the hindlimb muscles during static contraction was found to be almost the same both before and after indomethacin (Stebbins, Maruoka, and Longhurst 1988). These findings led to the speculation that prostaglandins must be acting on the endings of thin fiber afferents instead of through a regional vascular effect. In a subsequent study, the responses of group III and IV afferents to dynamic exercise, performed under both freely perfused and ischemic conditions, were attenuated by blockade of cyclooxygenase. In addition, during a postexercise ischemic period, cyclooxyge-nase blockade decreased the discharge of group IV afferents (Hayes, Kindig, and Kaufman 2006).

Nonsteroidal anti-inflammatory agents (NSAIDs) may have actions on acid-sensing ion channels (ASICs) that are independent of their cyclooxygenase activity. For example, arachidonic acid has been shown to potentiate currents passed through ASICs in dorsal root ganglion neurons (Smith, Cadiou, and McNaughton 2007). Moreover, the potentiation is not prevented by inhibition of arachidonic acid metabolism (Smith, Cadiou, and McNaughton 2007). Additional studies would need to determine if the activation of group III and IV afferents by arachidonic acid metabolites during exercise work through prostaglandin receptors or through effects on ASICs. Nonetheless, the attenuation of the pressor response (Stebbins, Maruoka, and Longhurst 1988) and discharge rate of group III and IV afferents (Hayes, Kindig, and Kaufman 2006) during exercise was achieved by cycolooxygenase blockade with indomethacin, an agent, unlike other NSAIDs, that did not inhibit current passing through ASICs (Voilley et al. 2001). This evidence suggests that cyclooxygenase products activate group III and IV afferents during exercise, and prostaglandin receptors contribute to the stimulation of mechanoreceptors and metaboreceptors evoking the exercise pressor reflex.

Bradykinin has also been suggested to play a role in the exercise pressor reflex. Muscle contraction increased levels of bradykinin within skeletal muscle (Stebbins et al. 1990). Moreover, bradykinin injected into the arterial supply of muscle reflexly increased mean arterial pressure, a response that was attenuated by a bradykinin 2 receptor antagonist. A bradykinin 1 receptor agonist did not evoke a reflex pressor response (Pan, Stebbins, and Longhurst 1993). Inflammation and trauma can increase the concentrations of cyclooxygenase products of arachidonic acid, such as PGE2, and bradykinin in skeletal muscle. PGE2 not only stimulated group IV afferents but in concentrations less than that needed for stimulation, PGE2 enhanced the excitatory action of bradykinin on thin fiber afferents (Mense 1981). Bradykinin is also released by noxious stimulation and in greater amounts during an ischemic than in a freely perfused contraction (Stebbins et al. 1990).

Several lines of evidence suggest that lactic acid plays a role in the exercise pressor reflex. First, lactic acid injected into the arterial supply of muscle stimulates groups III and IV afferents as well as evokes a reflex pressor response (Rotto and Kaufman 1988; Rotto, Stebbins, and Kaufman 1989; Sinoway et al. 1993). Second, lactic acid concentrations in the muscle interstitium are increased by contraction (MacLean et al. 1998). Third, blunting lactic acid production by either dichloroacetate or glycogen depletion decreased the exercise pressor reflex (Ettinger et al. 1991; Sinoway et al. 1992). Blockade of receptors to lactic acid provided additional evidence for lactic acid’s involvement in evoking the exercise pressor reflex. Lactic acid activates two receptors, transient receptor potential vanilloid type 1 channels (TRPV1) and acid sensing ion channels (ASICs). Whereas TRPV1 receptors were found not to play a role in the exercise pressor reflex (Kindig, Heller, and Kaufman 2005), two structurally different ASIC antagonists (amiloride and A-317567) attenuated the reflex (Hayes et al. 2008; Hayes, Kindig, and Kaufman 2007; McCord, Hayes, and Kaufman 2008). All this evidence suggests that lactic acid, working through ASICs, plays a role in the exercise pressor reflex.

A strong role for lactic acid working through ASICs has also been found in the sensation of pain, especially that caused by ischemia. Of the four ASICs, ASIC3 seems to be the most likely channel responding to muscle stress (e.g., exercise) and pain. First, ASIC3 was found to be expressed almost exclusively in dorsal root ganglion neurons ( Krishtal, Marchenko, and Pidoplichko 1983; Waldmann et al. 1997, 1999) and in very high levels on metaboreceptors ( Benson, Eckert, and McCleskey 1999; Molliver et al. 2005; Sutherland et al. 2001). In addition, ASIC3 knockout mice did not respond to noxious stimuli, whereas their wild type counterparts did (Price et al. 2001). Moreover, ASIC3 channels open when the pH drops from 7.4 to 7.0 (Sutherland et al. 2001) and can pass a sustained current at a pH of 7.0 (Yagi et al. 2006); this pH is consistent with that found during ischemic exercise (Cornett et al. 2000; Sinoway et al. 1989) and ischemic pain (Cobbe and Poole-Wilson 1980; Remme et al. 1986). Further, the responsiveness of this channel was greatly enhanced when lactate and/or ATP were present, two molecules that are released during exercise and pain (Immke and McCleskey 2001).

During pain, lactic acid has been suggested to stimulate TRPV1. However, pH must reach a level of less than 6.0 to activate TRPV1, a value that is below that occurring during exercise or ischemic pain except in extreme circumstances. Not surprisingly, during an infusion of a solution with a pH of 6.0 directly into human skin, the intensity of the pain was not diminished by blockade of TRPV1 receptors (Ugawa et al. 2002), suggesting that another receptor such as ASICs were responsible of the sensation of pain at this pH level. Nonetheless, TRPV1 receptors were found to work synergistically along with ASICs and P2X receptors to respond to the metabolites produced during muscle contraction and pain (Light et al. 2008).

The data presented thus far suggests that blockade of either the receptor or the production of a metabolite reduces the exercise pressor reflex by half. One wonders how all of these substances can be responsible for the reflex when adding the individual magnitudes of the reduction in the reflex far exceeds 100%. An answer to this question comes from two lines of evidence suggesting that the combination of metabolites is the key to activation of group III and IV afferents during exercise and nociceptive stimulation of muscle. The first line of evidence offered by McCleskey and colleagues found that lactate and ATP greatly potentiated the effect of an acidic pH (~7.0–6.8) on the activation of ASIC3. When ASIC3 was activated by a pH of 7.0 the current was 80% greater in the presence of physiological levels of lactate than when lactate was not present (Immke and McCleskey 2001). Further, it was found that not only does lactate act immediately but it must be present in the inter-stitium for the ASIC current to be augmented because lactate acts by chelating calcium, allowing the ASIC channel react to protons (Immke and McCleskey 2003). In addition, ATP, in concentrations seen in an ischemic contraction, increased current through ASIC3; moreover, the current through the channel was still high for minutes after the ATP was removed (Naves and McCleskey 2005). The enhanced current from ATP required 15s—1 minute after ATP application for peak effect (Naves and McCleskey 2005).

The second line of evidence by Light and colleagues found that combinations of protons, lactate, and ATP were needed to activate cultured dorsal root ganglion cells. When the cells were exposed to just one of the metabolites, only a small stimulatory effect was measured, whereas the combination of all three metabolites had an effect that exceeded the summation of each one individually (Light et al. 2008). This finding also explains why half of the exercise pressor reflex was attenuated by blockade of one receptor. The conclusion from these investigations provides evidence that not just one metabolite or receptors can be the sole contributor to the reflex, but combinations of metabolites act synergistically on two or more receptors for the full expression of the reflex.

12.5. AFFERENT PATHWAY

The prior sections have described the discharge properties of group III and IV affer-ents and the metabolites that stimulate them during exercise and pain. The findings show that stimulation of the same afferents can evoke two effects, one resulting in cardiovascular reflex adjustments during exercise and one resulting in the sensation of pain. How can the same afferent endings cause both effects? It is possible that group III and IV receptors are separated into subclasses; that is, some afferents respond to non-noxious stimuli while other afferents respond to noxious stimuli (Mense and Meyer 1985). In agreement, Light et al. (2008) found two populations of metaboreceptors in dorsal root ganglion neurons. They found one population of neurons responded best to low metabolite levels, in concentrations that would be considered consistent with non-painful contractions. The second population of neurons responded best to high levels of metabolites that would be consistent with either ischemic contractions or tissue damage. Thus, during ischemic contraction two different populations of metaboreceptors would respond, one population to contraction and the other to ischemia.

Noxious stimuli can increase the number of dorsal horn cells responding to electrical stimulation. Following a noxious lesion to the gastrocnemius muscle in anesthetized rats, only two hours were needed to see an expansion of the spinal input from the inflamed area. The result was that 30% of neurons within the L3 spinal segment, which receives little input from the gastrocnemius muscles of control rats, responded to electrical stimulation of nerves supplying inflamed muscle, whereas no neurons in the L3 region of rats without inflamed muscles responded to this stimulation (Hoheisel, Koch, and Mense 1994).

Group III and IV afferents synapse onto laminae I and V neurons in the dorsal horn of the spinal cord (Mense and Craig 1988; Willis, Jr. et al. 2001), with the majority terminating in lamina 1 ( Craig, Heppelmann, and Schaible 1988; Craig and Mense 1983). Lamina I neurons transmit information from group III and IV afferents to the brain through three relevant pathways. First, projections have been found from lamina I neurons to the posterior part of the ventromedial nucleus of the thalamus, a center for pain and temperature sensation (Craig et al. 1994). Second, projections have been found from lamina I neurons to the rostral ventrolateral medulla, an area that contains sympathetic premotor neurons (Craig 1995). Third, lamina I neurons project to the nucleus tractus solitarius, an area that receives baroreceptor information (Craig 1995).

Iwamoto et al. (1985) completed serial sectioning of the neuraxis to determine what neural structures were necessary to evoke the exercise pressor reflex. Their critical finding was that an intact medulla was needed to evoke the exercise pressor reflex. Further, it has been shown that input from skeletal muscle can excite neurons within the nucleus tractus solitarius, rostral ventrolateral medulla, caudal ventrolateral medulla, the lateral tegmental field, and the ventromedial region of the rostral periaqueductal grey (Ciriello and Calaresu 1977; Iwamoto et al. 1982; Iwamoto and Kaufman 1987; Li et al. 1997; Li and Mitchell 2000; Person 1989).

12.6. SYMPATHETIC ACTIVATION

The sympathetic nervous system is a two-neuron chain and is comprised of a preganglionic neuron, whose axon is usually myelinated, and an unmyelinated postganglionic neuron. The terminal ending of the preganglionic axon releases acetylcholine, which in turn activates a nicotinic receptor on the postganglionic dendrites or cell body. The postganglionic terminal usually releases norepinephrine onto the end organ. In the limbs, stimulation of sympathetic postganglionic fibers has vasomotor, pilomotor, and sudomotor functions. In the kidneys, stimulation of sympathetic postganglionic fibers evokes renin secretion, vasoconstriction, and sodium reabsorption. Likewise in the heart, stimulation of sympathetic postganglionic fibers increases cardiac rate and contractility (via β1-adrenergic receptors) and causes coronary vascular smooth muscle to constrict (via α1-adrenergic receptors).

In humans, the exercise pressor reflex has been shown to increase sympathetic nerve activity to non-exercising muscle ( Hill, Adreani, and Kaufman 1996; Mark et al. 1985; Saito 1995; Saito, Naito, and Mano 1990). For example, Victor and colleagues found that attempted exercise in humans that were paralyzed partially by curare yielded a trivial increase in muscle sympathetic nerve activity to non-exercising muscles compared with the increase that was evoked by actual handgrip performed before curare (Victor et al. 1989a). In addition, the exercise pressor reflex has been shown to play a key role in causing renal vasoconstriction, a sympathetically mediated effect that was attributed to group III mechanoreceptors (Momen et al. 2003).

The exercise pressor reflex has been shown to increase whole renal nerve activity in both chloralose-anesthetized and decerebrated cats. Static contraction of the hindlimb muscles tripled renal nerve discharge, an increase that was shown to be reflex in origin because it was prevented by section of the dorsal roots innervating the hindlimb (Victor et al. 1989b). The reflex increase in renal nerve discharge was in part due to the stimulation of group III mechanoreceptors. Static contraction reflexly increased renal nerve activity with an onset latency that averaged less than one second (Matsukawa et al. 1990; Victor et al. 1989b). This brief latency appears to be too short to allow for the activation of group IV metaboreceptors in the contracting muscles. In addition, intermittent static contraction synchronized renal nerve discharge so that a burst of activity was evoked by each contraction. This synchronization appears best explained by activation of group III mechanoreceptors. In addition, the increase in renal sympathetic nerve activity during exercise was attenuated by blockade of group III mechanoreceptors with gadolinium (Kim et al. 2007).

While the list of substances that activate and/or sensitize mechanoreceptors is a work in progress, it does include P2 receptors (Kindig, Hayes, and Kaufman 2007) but does not normally include lactic acid working through ASICs (McCord, Hayes, and Kaufman 2008). Even though it is likely that metaboreceptors do not play a role in the first few seconds of the increased renal sympathetic nerve activity at the onset of exercise, metaboreceptors are thought to provide a continuous signal to keep sympathetic activity increased for the duration of exercise (Matsukawa et al. 1990).

The exercise pressor reflex has also been shown to play a role in the increase of sympathetic nerve activity to the heart. Specifically, the onset latency of the cardiac sympathetic nerve activity response to static contraction was found to always be less than one second and as a consequence was attributed to the stimulation of group III mechanoreceptors in contracting skeletal muscle (Matsukawa et al. 1994; Tsuchimochi et al. 2009).

Activation of the sympathetic nervous system by the exercise pressor reflex has important physiological effects in humans. In static exercise, sympathetically induced vasoconstriction in both the viscera (Middlekauff et al. 1997; Momen et al. 2003) and resting skeletal muscles (Victor et al. 1989a) shunts arterial blood to contracting muscles as well as maintains their perfusion pressure. There is ample evidence that muscle performance is directly related to its perfusion pressure in both humans and animals (Eiken 1987; Fitzpatrick, Taylor, and McCloskey 1996; Hobbs and McCloskey 1987). In dynamic exercise, sympathetic restraint of vasodilation in rhythmically contracting muscles is necessary to maintain arterial pressure during large muscle mass dynamic exercise (Pryor et al. 1990). For example, the vasodilation occurring in 20 kilograms of exercising muscle in humans would require a cardiac output of 50 liters per minute for arterial pressure to be maintained. The human heart is not capable of generating this output. Consequently, the maintenance of arterial pressure by sympathetic vasoconstriction assures the brain and the heart of adequate perfusion during dynamic exercise.

During static exercise the reflex sympathetic activation arising from the contraction-induced stimulation of group III and IV afferents is believed to increase arterial blood pressure to counter the mechanical compression of vessels in contracting muscles. Any vasodilation occurring in contracting muscles is believed to be caused by the production of metabolites, which act directly to relax vascular smooth muscle. An alternative view, however, is also possible. This view is that the vasodilation seen in exercising skeletal muscles is caused by vasodilator peptides, including substance P and CGRP, which are released by group IV afferents (Kruger et al. 1989), whose endings are located in small vessels (von During and Andres 1990). These unmyelinated afferents are stimulated by contraction and send impulses in two directions, the first being toward the dorsal horn where they synapse, and second in a retrograde fashion, where they relax vascular smooth muscle. This mechanism, which is often called the axon reflex, would only oppose sympathetic restraint of blood flow in exercising muscle. As a consequence, the combination of sympathetic restraint which would occur in all muscles, and the axon reflex, which would occur only in exercising muscles, could function to shunt blood flow to the muscles in need of an increased blood flow.

12.7. TRANSLATION TO HEART FAILURE

Patients with heart failure display augmented sympathetic nerve activity, vascular resistance, and blood pressure in response to exercise when compared to their healthy counterparts (Middlekauff et al. 2000, 2001; Ponikowski et al. 2001; Sterns et al. 1991). This exaggerated response is thought to be due to alterations in the exercise pressor reflex rather than to alterations in central command (Middlekauff et al. 2001). Further, involuntary biceps contraction, a maneuver that selectively stimulates mechanoreceptors, produced an augmented renal vasoconstrictor response in heart failure patients, suggesting that mechanoreceptors were sensitized (Middlekauff et al. 2001). In contrast, studies using post-contraction ischemia determined that metaboreceptors were not sensitized in humans (Middlekauff et al. 2000; Sterns et al. 1991). Therefore, evidence in humans indirectly suggests that the exaggerated sympathoexcitation of heart failure patients is due to sensitization of mechanoreceptors leading to an exaggerated exercise pressor reflex.

Heart failure studies in rats have shown that group III afferents are responsible for the exaggerated exercise pressor reflex. To determine the contribution of the mechan-oreflex to the exercise pressor reflex, gadolinium, which blocks mechanogated channels, was injected into healthy control rats, heart failure rats, and healthy rats that had their group IV afferent neurons destroyed (Smith et al. 2005a). Healthy rats that have selective destruction of group IV afferent neurons exhibited the exaggerated exercise pressor reflex observed in heart failure (Smith et al. 2005b). Gadolinium reduced the pressor response to exercise in all three groups, but the magnitude of the reduction was greater in the heart failure and the group IV afferent-destroyed rats than in the healthy control rats (Smith et al. 2005a). These findings suggest that if group IV afferents are not present or desensitized, group III afferents will overcompensate, thus accounting for the augmented exercise pressor in the heart failure population.

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