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Experimental Physiology 91.1 pp 89-102
DOI: 10.1113/expphysiol.2005.032367
© The Physiological Society 2006
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The mammalian exercise pressor reflex in health and disease

Scott A Smith1, Jere H Mitchell2,3 and Mary G Garry2

Departments of 1 Physical Therapy2 Internal Medicine3 Physiology, Harry S. Moss Heart Center, University of Texas Southwestern Medical Center, Dallas, TX, USA


   Abstract
Top
 Abstract
Introduction
 References
 
The exercise pressor reflex (a peripheral neural reflex originating in skeletal muscle) contributes significantly to the regulation of the cardiovascular system during exercise. Exercise-induced signals that comprise the afferent arm of the reflex are generated by activation of mechanically (muscle mechanoreflex) and chemically sensitive (muscle metaboreflex) skeletal muscle receptors. Activation of these receptors and their associated afferent fibres reflexively adjusts sympathetic and parasympathetic nerve activity during exercise. In heart failure, the cardiovascular response to exercise is augmented. Owing to the peripheral skeletal myopathy that develops in heart failure (e.g. muscle atrophy, decreased peripheral blood flow, fibre-type transformation and reduced oxidative capacity), the exercise pressor reflex has been implicated as a possible mechanism by which the cardiovascular response to physical activity is exaggerated in this disease. Accumulating evidence supports this conclusion. This review therefore focuses on the role of the exercise pressor reflex in regulating the cardiovascular system during exercise in both health and disease. Updates on our current understanding of the exercise pressor reflex neural pathway as well as experimental models used to study this reflex are presented. In addition, special emphasis is placed on the changes in exercise pressor reflex activity that develop in heart failure, including the contributions of the muscle mechanoreflex and metaboreflex to this pressor reflex dysfunction.

(Received 28 September 2005; accepted after revision 18 October 2005; first published online 10 November 2005)
Corresponding author M. G. Garry: University of Texas Southwestern Medical Center, Harry S. Moss Heart Center, Department of Internal Medicine, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9174 USA. Email: mary.garry{at}utsouthwestern.edu


   Introduction
Top
 Abstract
 Introduction
References
 
The cardiovascular response to dynamic exercise is characterized by large increases in heart rate (HR), stroke volume (SV) and cardiac output (CO) (Gallagher et al. 1999). These haemodynamic changes support an increase in blood flow to active skeletal muscle. In contrast, owing to large increases in intramuscular pressure, blood flow to active skeletal muscle is greatly decreased during static exercise (Gallagher et al. 1999). In an attempt to maintain adequate perfusion of exercising muscle under these conditions, large elevations in sympathetic tone (evoking systemic vasoconstriction) and small HR-induced increases in CO manifest. As a result of these cardiovascular adjustments, marked increases in blood pressure accompany static exercise.

Three distinct neural control mechanisms contribute to the regulation of these cardiovascular responses to dynamic and static exercise: the arterial baroreflex, central command and the exercise pressor reflex (Fig. 1). The arterial baroreflex, the afferent fibres of which originate from the carotid sinus and aortic arch, regulates blood pressure on a beat-to-beat basis by continually adjusting HR, SV and peripheral resistance (Mancia & Mark, 1983). During exercise, baroreflex function is reset to operate around the higher blood pressures established during physical activity (Potts et al. 1993). Central command is a mechanism whereby signals from the motor cortex or subcortical nuclei, responsible for recruiting motor units, activate cardiovascular control areas in the brainstem to modulate sympathetic and parasympathetic activity during exercise (Goodwin et al. 1972). These autonomic adjustments elicit changes in HR and blood pressure proportional to the intensity of exercise. Lastly, the exercise pressor reflex is a peripheral neural drive originating in skeletal muscle that likewise activates brainstem cardiovascular control areas during physical activity (McCloskey & Mitchell, 1972). During exercise, activation of this reflex is mediated by stimulation of group III (predominantly mechanically sensitive A{delta} fibres) and IV (predominantly metabolically sensitive C fibres) primary afferent neurones, which reflexively augment blood pressure and HR, primarily via increases in sympathetic nerve activity and reductions in parasympathetic nerve activity (Kaufman & Forster, 1996).



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  		Figure 1.  Neural cardiovascular control during exercise
Neural signals originating from the brain (central command), the aorta and carotid arteries (arterial baroreflex), and skeletal muscle (exercise pressor reflex) are known to modulate sympathetic and parasympathetic nerve activity during exercise. The alterations in autonomic outflow induce changes in heart rate and contractility, changes in the diameter of resistance and capacitance vessels within peripheral tissue beds and release of adrenaline from the medulla of the adrenal gland. As a result, changes in heart rate, stroke volume and systemic vascular resistance mediate alterations in mean arterial pressure appropriate for the intensity and modality of exercise. ACh, acetylcholine; NA, noradrenaline.

 
It has been clearly established that the cardiovascular response to exercise is altered in heart failure (Hammond et al. 2000; Middlekauff et al. 2000; Negrao et al. 2001; Notarius et al. 2001; Kim et al. 2004). Of the three neural mechanisms contributing to cardiovascular regulation during exercise, considerable attention has recently been given to the role of the exercise pressor reflex in mediating the abnormal response to physical activity in heart failure. Therefore, this review will focus upon not only the normal function of the exercise pressor reflex during physical activity but also the changes that occur in this reflex with the manifestation of heart failure.

The exercise pressor reflex neural pathway

Afferent limb.  Exercise-induced signals which comprise the afferent arm of the exercise pressor reflex are generated by activation of mechanically (muscle mechanoreflex) and chemically sensitive (muscle metaboreflex) skeletal muscle receptors (Kaufman et al. 1983). Mechanical stimuli predominantly activate group III afferent neurones and include stretch and pressure (Stebbins et al. 1988; Williamson et al. 1994; Hayes et al. 2005). Chemical stimuli primarily activate group IV afferent neurones and include the byproducts of skeletal myocyte metabolism (Kaufman et al. 1983). These metabolites are particularly important to exercise pressor reflex activity during periods of ischaemia (Stebbins & Longhurst, 1989). It should be noted, however, that these afferent fibres exhibit a degree of polymorphism, since some group III fibres respond to metabolic changes within the muscle while a minority of group IV fibres respond to mechanical distortion (Kaufman & Forster, 1996). The extent to which mechanically and metabolically sensitive fibres contribute to exercise pressor reflex activity is controversial. For example, it has been shown that the pressor response to static exercise in large muscle groups is equally attributable to mechanical and metabolic stimulation of afferent nerves (Williamson et al. 1994). In contrast, it has been shown that mechanically sensitive fibres dominate activation of the exercise pressor reflex in response to submaximal dynamic exercise (Gallagher et al. 2001). Yet others have shown the cardiovascular response to dynamic exercise to be predominantly mediated by the metabolic component of the reflex (Victor & Seals, 1989; Rowell & O'Leary, 1990). Alternatively, it has also been suggested that the exercise pressor reflex-evoked cardiovascular response to exercise is dependent upon the total amount of sensory input from skeletal muscle rather than the modality of afferent fibre activation (i.e. mechanical versus metabolic stimuli) (Leshnower et al. 2001). As such, the contribution of the muscle mechanoreflex and metaboreflex to exercise pressor reflex activity continues to be an area of intense investigation.

The chemical stimuli and receptors mediating the excitation of small diameter afferent neurones in vivo during exercise is also an area of great interest. Several studies, expertly reviewed by Kaufman & Forster (1996), have reported that lactic acid, H+, bradykinin, K+, arachadonic acid, adenosine, analogues of ATP, diprotonated phosphate and prostaglandins activate these nerve endings in muscle and blood vessels. The ATP-gated ion-channel receptor, P2X3, is known to be exclusively localized to small diameter afferent neurones (Chen et al. 1995; Lewis et al. 1995). In cats, it has recently been determined that intra-arterial injection of {alpha},ß-methylene ATP (a P2X1 and P2X3 agonist) elevates mean arterial pressure (MAP) and HR via activation of the P2X3 receptor localized, primarily, on group IV afferent neurones (Hanna et al. 2002). Presumably, {alpha},ß-methylene ATP activates primary afferent neurones within skeletal muscle. However, data in the rat demonstrate that primary afferent neurones expressing the P2X3 receptor rarely project to skeletal muscle (Bradbury et al. 1998). More recently, it has been determined that, in the cat, only 30% of neurones within the dorsal root ganglia express the P2X3 receptor (Ruan et al. 2005). Future studies designed to determine species differences between the rat and cat, with regard to the expression of the P2X3 receptor, will be required to clarify these issues.

It is well established that injection of capsaicin into the arterial supply of skeletal muscle causes an increase in blood pressure and HR in dogs (Kaufman et al. 1982), cats (Hayes & Kaufman, 2001) and rats (Li et al. 2004; Smith et al. 2005c). Further, it has been shown that these haemodynamic changes occur via activation of the transient receptor potential vanilloid 1 (TRPv1) receptor localized on group IV afferent neurones (Smith et al. 2005c). Yet, it is currently a subject of debate as to whether stimulation of the TRPv1 receptor mediates the metaboreflex contribution to exercise pressor reflex activity during muscle contraction. Recent studies in the cat suggest that TRPv1 receptor activation does not contribute to the cardiovascular response elicited by activation of the exercise pressor reflex (Kindig et al. 2005). In contrast, studies in humans indicate that activation of this receptor is necessary to elicit the normal cardiovascular response to exercise (Dawson et al. 2004). Additional studies are needed to definitively determine the chemical substances and receptors essential to the peripheral afferent arm of the exercise pressor reflex.

Spinal cord.  In general, group III and IV primary afferent neurones project to the dorsal horn of the spinal cord, specifically to Rexed's laminae I, II, V and X. Early studies demonstrated that muscle afferents projected to laminae I–V, although the diameter of these afferents could not be determined (Kalia et al. 1981). In a recent study, fine diameter muscle afferents (group III and IV) from the gastrocnemius were observed to project predominately to laminae I, II (inner medial aspect) and V within the lumbar spinal cord (Panneton et al. 2005). Lamina VI, in the rostral portion of the sacral cord, also has dense projections from the gastrocnemius and these continue into Clarke's column (Panneton et al. 2005). These afferent neurones impinge upon both ascending neurones and interneurones within the dorsal horn of the spinal cord. In response to static muscle contraction, spinal neurone activation has been observed primarily in the superficial laminae of the dorsal horn by evaluating c-fos immunoreactivity (Li & Mitchell, 2002).

In response to static muscle contraction, levels of several neurotransmitters and neuropeptides, such as glutamate, aspartate and substance P, are increased in the spinal cord (Wilson et al. 1993; Hand et al. 1996). In many studies, it is presumed that these neuroactive substances are released from primary afferent neurones activated by static muscle contraction. It is also feasible, however, that some substances are released from second order neurones within the dorsal horn. For example, nitric oxide production in cells of the superficial laminae of the dorsal horn, those which are activated by static muscle contraction, have been shown to modulate exercise pressor reflex activity at the level of the spinal cord (Wilson et al. 1999; Li & Mitchell, 2002).

As presented in a recent review (Wilson, 2000), the activation of several receptors within the spinal cord has been shown to modulate exercise pressor reflex activity, including NMDA receptors, non-NMDA receptors (AMPA receptors), NK-1 receptors and the ATP-sensitive P2X receptors. In addition, it has been reported that bradykinin receptor activation facilitates exercise pressor reflex activity at the level of the spinal cord (Stebbins & Bonigut, 1996). In contrast, activation of oxytocin and {alpha}2-adrenergic receptors in the spinal cord attenuates the rise in blood pressure and HR in response to static muscle contraction (Hill & Kaufman, 1991; Stebbins & Ortiz-Acevedo, 1994). Similarly, blockade of angiotensin II receptors reduces exercise pressor reflex activity. However, it is not clear whether this blunting effect is due to the interruption of afferent nerve traffic or the inhibition of the sympathetic efferent arm of the reflex (Stebbins & Bonigut, 1995).

Mapping of the spinal pathways via which signals from group III and IV primary afferents project to the brainstem is incomplete, although it is known that patients with Brown–Sequard syndrome (hemisected spinal cord) or syringomylia (expanding central canal lesion) exhibit a blunted or absent blood pressure and HR response to muscle contraction (Lind et al. 1968; Winchester et al. 2000). In addition, lesioning studies in the dog indicate that ascending spinal pathways mediating cardiovascular responses to ischaemic exercise are located in the lateral funiculus, including the dorsolateral sulcus area and dorsolateral funiculus (Kozelka et al. 1987). More recently, using the anterograde tracer biotinylated dextran amine in rats, neurones in the superficial laminae of the cervical spinal cord (including group III, A{delta} and group IV, C fibres) were shown to project to the cuneate nucleus, the nucleus of the solitary tract and the lateral reticular nucleus, as well as the caudal and rostral ventrolateral medulla within the medulla oblongata (Potts et al. 2002). These findings support the existence of a spinomedullary pathway that transmits group III and IV sensory information to the brainstem.

Brainstem.  By performing a series of brainstem lesions, Iwamoto et al. (1985) determined that regions within the medulla were essential for the expression of the exercise pressor reflex. Importantly, studies have shown that peripheral input from skeletal muscle is capable of modulating the excitability of neurones within the nucleus tractus solitarii (NTS), which raises the possibility that the NTS represents a central site of integration for the exercise pressor reflex (Person, 1989). In addition, cells responding to muscle contraction have been described in the rostral ventral medulla (RVLM), specifically, in the region of the laterolateral reticular nucleus of the inferior olive (medial accessory olive), the caudal ventrolateral medulla (CVLM), the lateral tegmental field (adjacent to the lateral reticular nucleus) and the ventromedial region of the rostral periaqueductal grey (Ciriello & Calaresu, 1977; Iwamoto et al. 1982; Iwamoto & Kaufman, 1987; Li et al. 1997; Li & Mitchell, 2000). Further, cells in the nucleus ambiguus are inhibited during muscle contraction (Iwamoto & Kaufman, 1987).

The neurochemicals and receptors involved with the transmission and processing of exercise pressor reflex sensory signals in the brainstem currently represent an area of intense investigation. For example, within the NTS, increasing nitric oxide (NO) production has been shown to attenuate the elevation in blood pressure elicited by activation of the exercise pressor reflex (Smith et al. 2005a). Within the RVLM, it has been observed that inhibition of glutaminergic systems by non-selective opioid agonists can attenuate responses to muscle contraction (Ishide et al. 2000b). It is further proposed that production of NO contributes to elevated glutamate levels in the RVLM in response to contraction (Ishide et al. 2000a). Similarly, activation of serotonin 5-HT1A receptors within the RVLM attenuates cardiovascular responses to static exercise (Chaiyakul et al. 2001). It has also been suggested that the cardiovascular responses to static muscle contraction are mediated via changes in extracellular concentrations of monoamines (noradrenaline, dopamine and serotonin). It has been demonstrated that AMPA receptor blockade attenuates the blood pressure and HR response to contraction, as well as reducing the levels of monoamines in the RVLM (Ishide et al. 2004). Further, GABAergic neurones within the RVLM are believed to be inhibitory to the exercise pressor reflex (Ishide et al. 2003). Within the CVLM, chemical lesioning of neurones with kynurenic acid (a non-specific inotropic excitatory amino acid receptor antagonist) has been shown to attenuate the pressor response to static muscle contraction in cats (Bauer et al. 1989). Collectively, these examples illustrate the complexity of the neural mechanisms responsible for processing skeletal muscle somatosensory signals centrally. The findings further suggest that numerous neurochemicals and receptors acting within several areas of the brainstem are involved in this process.

Efferent limb.  The exercise pressor reflex induces cardiovascular adjustments to exercise predominately via increases in sympathetic nerve activity and by withdrawal of parasympathetic nerve activity (Kaufman & Forster, 1996). As previously described, in the exercise pressor reflex arc sensory signals from skeletal muscle are transmitted to the spinal cord by group III and IV afferent fibres and subsequently to the brainstem for central processing. Autonomic parasympathetic outflow is mediated primarily through cardiac vagal motor neurones travelling via central preganglionic neurones originating in the nucleus ambiguus to postganglionic cardiac neurones next to or in the walls of the heart (Mendelowitz, 1999). From the brainstem, activated sympathetic premotor neurones project to preganglionic sympathetic neurones in the intermediolateral cell columns of the spinal cord and subsequently to the paravertebral sympathetic chain ganglia (Dampney et al. 2003). From these ganglia, sympathetic transmission continues along postganglionic neurones innervating the heart and vasculature. Through these pathways, the exercise pressor reflex contributes to haemodynamic regulation during physical activity.

Experimental models of the exercise pressor reflex

The exercise pressor reflex in humans and large animals.  Previous investigations have established that the exercise pressor reflex contributes significantly to cardiovascular control in larger mammalian species, such as cats and dogs as well as humans (Kaufman & Forster, 1996). Two recent reviews outline these studies and their importance to our understanding of cardiovascular regulation during exercise in both health and disease (Kaufman & Hayes, 2002; Sinoway & Li, 2005). As a result, findings regarding exercise pressor reflex function in humans, cats and dogs will not be discussed extensively within the context of this review.

The exercise pressor reflex in rodent models.  Although invaluable to our understanding of exercise pressor reflex function during physical activity, experimentation in humans and larger animals is not without limitations. In humans, it is difficult to experimentally isolate the exercise pressor reflex from other neural mechanisms known to influence cardiovascular control during exercise (i.e. the arterial baroreflex and central command). This limitation can be, for the most part, circumvented using invasive large animal preparations. As such, dogs and cats have traditionally been the animal models of choice for studying the exercise pressor reflex. However, as mechanistic physiological research moves further into the realm of cellular and molecular biology, use of larger animal models is hampered by the current lack of biological tools needed to conduct such research. Further, as evidence accumulates indicating that alterations in circulatory haemodynamics during exercise contribute to deleterious vascular and cardiac events in individuals with cardiovascular disease (Ponikowski et al. 2001), a need for animal models in which cardiovascular disease can be readily produced has developed. In many larger animals, models of cardiovascular disease either do not exist or are no longer cost effective. As a result, alternative animal models, such as rodents, have been generated to study neural cardiovascular regulation during exercise in both health and disease. This includes rodent models designed to investigate exercise pressor reflex function.

Several attempts have been made to develop a rat model in an anaesthetized preparation. However, the development of a rat model that consistently and reliably mimics exercise pressor reflex activity in humans and larger animals has encountered obstacles. For example, activation of the exercise pressor reflex during muscle contraction in anaesthetized rats has been shown to elicit an increase (Freda et al. 1999), a decrease (Overton & Stremel, 1992; Toney & Mifflin, 1996), or no change (Vissing et al. 1991) in arterial blood pressure and HR (Table 1). The reasons for these discrepant results are not readily clear, although the most obvious differences between these studies were: (i) the method used to evoke muscle contraction; and (ii) the method used to induce anaesthesia. Noting these differences, our laboratory has recently attempted to develop a reliable rat model for the study of the exercise pressor reflex (Smith et al. 2001).


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  		Table 1. The effects of anaesthesia on the cardiovascular response to exercise in rats
 
Previously, a majority of investigators used electrical stimulation of either the sciatic or the tibial nerve to evoke muscle contraction in the rat (Vissing et al. 1991; Toney & Mifflin, 1996; Freda et al. 1999). Since these are mixed nerves (i.e. nerves containing both afferent and efferent neurones), electrical stimulation potentially activates both motor neurones as well as group III and IV sensory neurones. Under these conditions, cardiovascular responses elicited by muscle contraction may be attributable to direct activation of afferent fibres rather than to physiological stimulation of the exercise pressor reflex. To circumvent this problem, we surgically isolated the spinal ventral roots innervating the triceps surae muscles of the hindlimb (Fig. 2). By directly stimulating the cut, distal end of the ventral root, controlled static contraction of the triceps surae muscle was induced without direct activation of afferent neurones. In rats anaesthetized with halothane, however, static contraction via ventral root stimulation elicited a marked depressor and bradycardic response (Fig. 3A), opposite to that demonstrated in humans and larger mammals. This was anticipated, given the variable responses to muscle contraction previously noted under inhalant and injectable anaesthetics. To address this problem, animals were rendered insentient by precollicular decerebration, thereby obviating the need for inhalant anaesthesia. Following decerebration, in the absence of anaesthesia, static contraction via ventral root stimulation elicited significant increases in both blood pressure and HR (Fig. 3B). Neuromuscular blockade prevented these increases, indicating that the responses were not due to direct stimulation of afferent fibres. Importantly, these responses were due to a neural reflex originating in the triceps surae, since transection of the dorsal roots transmitting sensory information from the muscle abolished the increases in blood pressure and HR in response to contraction. Interestingly, when the sciatic nerve (a mixed nerve) was stimulated in the decerebrate preparation, a pressor response was observed, but one that could not be attributed to activation of the exercise pressor reflex because the response was not abolished by neuromuscular blockade (Fig. 4). These data indicate that, in a decerebrate animal, stimulation of a peripheral nerve innervating skeletal muscle can elicit a pressor response to contraction. However, this response is induced by artificially stimulating somatosensory afferent fibres rather than by physiological activation of the exercise pressor reflex. Therefore, use of the ventral root technique to contract skeletal muscle is preferable in order to activate the exercise pressor reflex physiologically.



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  		Figure 2.  Surgical preparation used to activate the exercise pressor reflex in rats
Electrically induced static hindlimb contraction is evoked by stimulating the ventral roots of the fourth and fifth lumbar vertebrae. Contraction under these conditions has been shown to activate the exercise pressor reflex. In this same preparation, activation of the mechanically sensitive component of the exercise pressor reflex can be achieved by passively stretching the hindlimb skeletal muscle.

 


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  		Figure 3.  Changes in MAP, HR and tension development in response to static contraction (evoked by electrical stimulation of ventral spinal roots) and passive stretch of the triceps surae muscles of the hindlimb in halothane-anaesthetized (A) and decerebrate rats (B)
The contraction- and stretch-induced decreases in MAP and HR in the halothane-anaesthetized animals were reversed in the decerebrate rats. Denervation (via dorsal rhizotomy) or neuromuscular blockade abolished the responses to static contraction and passive stretch in both animal preparations. The reintroduction of halothane in decerebrate rats attenuated the increase in MAP and HR induced by both contraction and stretch. The number of rats tested in each protocol is shown in parentheses. *Significantly different from control cindition; {dagger}significantly different from control contraction; {ddagger}significantly different from decerebrate-halothane anaesthesia condition (P < 0.01). Reproduced with permission from Smith et al. (2001).

 


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  		Figure 4.  Changes MAP, HR and tension development in response to static contraction evoked by electrical stimulation of the sciatic nerve in halothane-anaesthetized and decerebrate rats
The large pressor and tachycardic responses elicited by electrical stimulation in the decerebrate animal could not be abolished by neuromuscular blockade, indicating that direct activation of somatosensory afferent fibres occurred. This finding may also explain the increases in MAP and HR produced in halothane-anaesthetized rats. *Significanly different from control stimulation in halothane-anaesthetized rats; {dagger}significantly different from control stimulation in decerebrate animals (P < 0.01). Reproduced with permission from Smith et al. (2001).

 
The advantages to using the rat model to study the exercise pressor reflex are numerous. To begin, the reflex can be studied without the influence of central command and the arterial baroreflex (Smith et al. 2001). For example, the combination of decerebration and electrical induction of muscle contraction eliminates input from central command. Input from the arterial baroreflex can be prevented by chemical or surgical barodenervation. Further, much of the genome of the rat has been determined, which allows the use of cellular and molecular techniques that are unavailable in larger mammalian species. Importantly, models of human cardiovascular disease are readily produced in the rat, which presents the opportunity to study the function of this reflex in disease. Similar rodent preparations have been developed in situ (Potts et al. 2000) and in vivo (Hayashi, 2003) in other laboratories. Finally, it is important to note that a mouse model for the study of the exercise pressor reflex has also been described (Kramer et al. 2001). Expanded use of the mouse model could extend the advantages of rodents in the study of the exercise pressor reflex because a variety of transgenic and genetically manipulated models are available in this species.

The exercise pressor reflex in heart failure

Studies in humans.  Cardiovascular regulation during physical activity is clearly altered in heart failure, since studies using dynamic and static forms of exercise have demonstrated augmentations in sympathetic nerve activity, vascular resistance, HR and blood pressure (Piepoli et al. 1999; Middlekauff et al. 2000, 2001; Negrao et al. 2001; Notarius et al. 2001; Ponikowski et al. 2001). Accumulating evidence in humans supports a significant involvement of the exercise pressor reflex in mediating this exaggerated cardiovascular responsiveness to physical activity (Piepoli et al. 1999; Middlekauff et al. 2000; Negrao et al. 2001). While there is general agreement that the exercise pressor reflex is overactive in heart failure, the mechanism(s) of this reflex dysfunction is not clear. For example, several reports suggest that the muscle mechanoreflex mediates these abnormal cardiovascular responses to exercise (McClain et al. 1993; Middlekauff et al. 2001), while others report that mechanically sensitive group III afferent neurones contribute little to exercise pressor reflex activity in heart failure (Carrington et al. 2001). With regard to the muscle metaboreflex, it has been reported that the contribution of chemically sensitive group IV afferent fibres to the exercise pressor reflex is blunted in heart failure (Sterns et al. 1991; Middlekauff et al. 2000), while other data suggest that the metaboreflex contribution is exaggerated (Piepoli et al. 1996; Ponikowski et al. 2001). Various factors are likely to contribute to these discrepancies among studies. The difficulty in isolating either the metaboreflex or the mechanoreflex in humans is likely to contribute to the conflicting results obtained in heart failure patients.

Studies in cardiomyopathic rats.  In order to circumvent some of the limitations inherent to human research, we have recently conducted a series of experiments in rats designed specifically to examine exercise pressor reflex function in heart failure and to determine the contribution of the muscle mechanoreflex and metaboreflex to the exercise pressor reflex in this disease (Smith et al. 2003, 2005b,c). In these experiments, heart failure was induced by ischaemic injury (i.e. ligation of the left anterior descending coronary artery). Significant changes in cardiac muscle morphology, histology and function resulted from the induction of myocardial infarction (Table 2 and Fig. 5). Using the decerebrate rat model previously described (Smith et al. 2001), it was demonstrated that activation of the exercise pressor reflex by electrically induced static muscle contraction evoked elevations in blood pressure and HR that were significantly larger in animals with heart failure than in healthy control rats (Fig. 6). These cardiovascular responses were augmented over a wide range of contraction intensities. The findings suggest that the potentiated cardiovascular response to exercise in heart failure is mediated, in part, by an exaggerated exercise pressor reflex (Smith et al. 2003). The augmented cardiovascular responses to exercise elicited in this rat model are similar to those reported in humans with heart failure. Therefore, this rat preparation represents a valid model for the study of the exercise pressor reflex in this disease.


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  		Table 2. Morphometric characteristics of rats with (dilated cardiomyopathic, DCM) and without (control, sham) ischaemic heart injury
 


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  		Figure 5.  Morphological and physiological assessment of hearts in rats with (dilated cardiomyopathic, DCM) or without (control and sham) ischaemic injury
A, photomicrographs of control and DCM hearts after coronary artery ligation. Masson's Trichrome Blue identified fibrotic tissue in cross-sections from base to apex. B, M-mode echocardiographic images from control and DCM hearts. Arrows demarcate left ventricular end diastolic dimension (LVEDD) and left ventricular end systolic dimension (LVESD). C, echocardiographic analysis determined that both LVEDD and LVESD were significantly larger in animals in which the left anterior descending coronary artery had been ligated, indicative of ventricular dilation. Left ventricular systolic function, assessed by fractional shortening (FS), was impaired in DCM animals. *Significantly different from control and sham (P < 0.05). Reproduced with permission from Smith et al. (2003).

 


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  		Figure 6.  Changes in MAP, HR and tension development in response to static contraction (evoked by electrical stimulation of ventral spinal roots) and passive stretch of the triceps surae muscles
These procedures were performed in healthy rats (normal, untreated), dilated cardiomyopathic rats (DCM, heart failure induced by ligation of the left anterior descending coronary artery), sham-treated control rats (sham; a thoracotomy was performed but heart failure was not induced), neonatal capsaicin-treated rats (NNCAP, treated with capsaicin as neonates for the selective destruction of group IV afferent neurones) and vehicle-treated control rats (NNVEH, treated with the vehicle for capsaicin as neonates, leaving group IV afferent neurones intact). In adult animals, contraction and stretch induced increases in MAP and HR that were significantly larger in DCM than normal, sham and NNVEH. These exaggerated cardiovascular responses to contraction and stretch were recapitulated in healthy animals in which group IV afferent neurones had been ablated (i.e. NNCAP). *Significantly different from normal, sham and NNVEH; **significantly different from normal, sham, NNVEH and DCM (P < 0.05). Reproduced with permission from Smith et al. (2005c).

 
Using the decerebrate rat model, we have further demonstrated that the cardiovascular response to selective activation of metabolically sensitive group IV afferent neurones is reduced in heart failure (Smith et al. 2005c). In these studies, capsaicin was injected into the arterial supply of hindlimb skeletal muscle. It is well established that capsaicin selectively stimulates group IV afferent fibres because its receptor, TRPv1, is localized on these neurones (Guo et al. 1999; Michael & Priestly, 1999). Therefore, stimulation of the TRPv1 receptor activates the neuronal population known to primarily mediate metaboreflex activity. In this study, dose-related increases in blood pressure and HR were observed in response to capsaicin in both healthy control rats and those with heart failure. However, in animals with heart failure, these cardiovascular responses were significantly less than those elicited in control rats (Fig. 7). Similar observations have been reported by other laboratories (Li et al. 2004). Moreover, expression of mRNA for TRPv1 receptor protein, a marker of group IV afferent fibres, was downregulated in the dorsal root ganglia and soleus muscle of animals with heart failure, indicating a possible reduction in group IV fibre density and/or sensitivity (Fig. 8). These findings indicate that the muscle metaboreflex is blunted in heart failure despite an overall exaggeration in exercise pressor reflex activity. Interestingly, it was also demonstrated that selective ablation of group IV afferent fibres in healthy rats recapitulates the exaggerations in exercise pressor reflex activity observed in heart failure (Fig. 6). Likewise, the cardiovascular response to intra-arterial injection of capsaicin within the hindlimb was blunted in group IV deficient rats in a manner similar to that reported in animals with heart failure. Collectively, these findings suggest that the withdrawal or decreased sensitivity of group IV afferent neurones (the primary mediators of the muscle metaboreflex) is important to the development of exercise pressor reflex overactivity but that these neurones do not, themselves, drive this overactivity.



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  		Figure 7.  Changes in MAP and HR in response to injection of capsaicin within the arterial supply of hindlimb skeletal muscle
These procedures were performed in healthy rats (normal, untreated), dilated cardiomyopathic rats (DCM, heart failure induced by ligation of the left anterior descending coronary artery), and sham-treated control rats (sham; a thoracotomy was performed but heart failure was not induced). An additional subset of sham-treated control animals received an intra-arterial injection of capsaicin in the presence of the selective TRPv1 antagonist, capsazepine (Capz; 100 µg (100 µl)–1). Injection of capsaicin induced increases in MAP and HR that were significantly less in DCM than in normal and sham animals. *Significanntly different from normal and sham; **significantly different from normal, sham and DCM; {dagger}significantly different from saline within normal, sham and DCM groups; {dagger}{dagger}significantly different from saline within sham + Capz group; #significantly different from saline within normal and sham groups (P < 0.05). Reproduced with permission from Smith et al. (2005c).

 


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  		Figure 8.  Semiquantitative RT-PCR expression of TRPv1 mRNA with the use of RNA isolated from dorsal root ganglia (DRG) L4–L6 and soleus muscle of sham-treated control rats (sham) and dilated cardiomyopathic (DCM) rats
Note the decreased expression of TRPv1 transcripts (a marker of metabolically sensitive group IV fibres) in the DRG and skeletal muscle from animals in heart failure. Rn18s (18s ribosomal RNA) was used as a loading control. (–)RT indicates reverse transcriptase control. Reproduced with permission from Smith et al. (2005c).

 
In the decerebrate rat preparation, it was also determined that the mechanoreflex contribution to the exercise pressor reflex is enhanced in heart failure (Smith et al. 2003, 2005b). For example, passively stretching skeletal muscle (a stimulus which preferentially activates mechanically sensitive afferent neurones) elicits a greater increase in blood pressure and HR in animals with heart failure than in healthy control rats (Fig. 6; Smith et al. 2003). Similar findings have been reported by other laboratories (Li et al. 2004). More recently, we have confirmed these findings during the physiological contraction of skeletal muscle (Smith et al. 2005b). In these studies, hindlimb muscle contractions were performed before and after pharmacological blockade of mechanically sensitive skeletal muscle receptors using the trivalent lanthanide gadolinium. Gadolinium has previously been shown to significantly attenuate the activity of mechanically sensitive group III afferent neurones (Hayes & Kaufman, 2001). In healthy control rats and those with heart failure, gadolinium significantly reduced the blood pressure and HR response to muscle contraction. However, the magnitude of this reduction was greater in rats with heart failure compared to control animals. In addition, it was also determined that selective ablation of group IV afferent fibres in healthy rats recapitulates the exaggerations in mechanoreflex activity observed in heart failure (Fig. 6; Smith et al. 2005b,c). Collectively, these studies indicate that the mechanoreflex mediates the exaggerated exercise pressor reflex activity observed in heart failure and, further, suggest that this may be a compensatory response for the loss or desensitization of group IV afferent neurones in this disease.

Does exercise pressor reflex overactivity contribute to exercise intolerance?

Exercise intolerance is a hallmark of congestive heart failure. While the neural mechanisms regulating the cardiovascular responses to exercise are known, their potential contributions to exercise tolerance are unclear. We have evaluated exercise tolerance in rats with heart failure and have observed, as anticipated, that animals in heart failure fatigue more rapidly in a run-to-fatigue protocol than do healthy control animals (Smith et al. 2005c). We have also evaluated exercise tolerance in animals in which group IV afferent fibres have been ablated. As stated previously, these animals exhibit mechanoreflex-mediated exercise pressor reflex overactivity much like rats with heart failure. However, unlike rats with heart failure, these animals have normal cardiac function. Male rats deficient in group IV fibres did not exhibit a decrease in exercise tolerance compared to their healthy male control counterparts (Smith et al. 2005c). In contrast, others have observed a decrease in exercise tolerance in group IV deficient female rats when compared to healthy controls (Dousset et al. 2004). The reason for the discrepancy between males and females in these two studies is not readily apparent. However, these findings do raise the possibility that the development of exercise pressor reflex dysfunction in heart failure affects exercise tolerance differently in males than in females.

Nociceptors versus ergoreceptors

Primary afferent neurones innervate skin, joints and skeletal muscle. The fine afferent neurones that are localized in skeletal muscle are capable of responding to both noxious and innocuous stimulation (Kehl & Fairbanks, 2003). These fibres are classified as nociceptors and ergoreceptors, respectively. Because of the known polymodal characteristics of nociceptive fibres (Kaufman et al. 1983), it is unclear whether some primary afferent neurones can contribute to both the cardiovascular response to exercise and the perception of painful stimuli. Patients in whom the exercise pressor reflex is activated either by static hand grip or dynamic exercise do not report the exercise bout to be painful. As a result, it may be assumed that the exercise pressor reflex does not involve nociceptive neurones and is activated only by stimulation of ergoreceptors. In contrast, our data demonstrate that the abolition of capsaicin-sensitive fibres (group IV, C fibres), known to be nociceptors, causes significant abnormalities in the exercise pressor reflex response to both muscle contraction and stretch. These data support the concept that nociceptors contribute to exercise pressor reflex activity in normal rats and/or that capsaicin-sensitive afferent neurones are both nociceptors and ergoreceptors.

Perspectives

Figure 9 proposes a model of exercise pressor reflex activity in both health and disease. Based on the evidence accumulating from our laboratory and those of others, it is clear that both the metaboreflex and the mechanoreflex contribute to exercise pressor reflex activity in normal, healthy individuals. In heart failure, however, alterations in group IV afferent fibres render the metaboreflex less sensitive to stimulation. In response to this desensitization, we hypothesize that group III mechanically sensitive afferent neurones undergo functional changes that may be induced by alterations in gene expression to compensate for the reductions in metaboreflex activity. While these compensatory changes in mechanoreflex function are intended to preserve exercise pressor reflex function in heart failure, they are not precise and result in exaggerations in cardiovascular responsiveness during exercise. Theoretically, exaggerations in exercise pressor reflex activity may promote chronic increases in peripheral vascular resistance, end organ damage and premature muscle fatigue during physical activity. Questions as to what causes reduced responsiveness or withdrawal of group IV afferent neurones and what molecular events facilitate overactivity in group III afferent fibres remain to be answered. Clearly, additional experimentation will be required to address these issues.



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  		Figure 9.  Theoretical model of exercise pressor reflex activity in health and disease
In healthy individuals, exercise pressor reflex (EPR) activity is mediated by input from the muscle mechanoreflex and metaboreflex. In heart failure, however, metaboreflex activity is blunted. In an attempt to compensate for this reduction in activity, muscle mechanoreflex activity is augmented. While these compensatory changes are intended to preserve exercise pressor reflex function, they are imperfect, resulting in exercise pressor reflex overactivity.

 


   References
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