The exercise pressor reflex (EPR) is a mechanism whereby signals from the exercising muscle, propagated via group III (predominately mechanically sensitive) and group IV (predominately metabolically sensitive) skeletal muscle afferent fibers (10,16), elevate the mean arterial pressure (MAP) and heart rate (HR). This reflex is essential for the maintenance of adequate blood perfusion to the exercising muscle, thereby matching the metabolic demands that exercise creates. Historically, it was believed that abnormal cardiovascular responses to exercise in patients with heart failure were due to increased filling pressures and decreases in cardiac output. An understanding of the mechanisms that underlie these abnormalities, however, has been advanced by the "muscle hypothesis" (1). This hypothesis states that the abnormal responses to exercise originate in the skeletal muscle and, ultimately, in the primary afferent neurons that innervate the muscle. In this review, we will present our data that support this hypothesis (26,29,30) and that advance this hypothesis by revealing the mechanisms (25,26,29,30,37) via which these abnormal reflexes are initiated and maintained in heart failure.
The EPR is exaggerated in heart failure patients. Previous studies have suggested that the exaggerated increases in blood pressure, sympathetic nerve activity, and vascular resistance to exercise in patients with cardiovascular disease are due, in part, to an overactive EPR. There is general agreement that the EPR is exaggerated in humans with heart failure (15,19,20,22,23,31) and that these exaggerations correlate with morbidity and mortality as well as with decreased left ventricular (LV) function (4). Therefore, the clinical relevance of an abnormal EPR is well established. Despite this, defining the mechanisms that mediate the abnormal EPR in heart failure patients has proven to be difficult, and the literature surrounding this issue is conflicted (18). For example, in human subjects, studies have not been able to clearly discern whether peripheral primary afferent neurons or central areas that process the EPR are responsible for the exaggerated EPR that is observed in heart failure. Most studies in humans are focused on the peripheral neurons that regulate the EPR (mechanosensitive and metabosensitive primary afferent fibers). A great deal of controversy exists regarding the contribution of the metabolic component of the EPR because its activity has been reported to be both enhanced (22,23) and reduced (20,31) in response to exercise in heart failure patients. At the same time, other groups have demonstrated that the mechanosensitive afferent neurons are responsible for the exaggerations in the EPR that occur in heart failure (19,20,23). Based on these contradictory findings, there was a need for more direct investigations that required an animal model.
The EPR is exaggerated in a rodent model of heart failure. In an attempt to reveal the mechanisms that contribute to the EPR in heart failure, we have developed a rat model in which static muscle contraction reliably elicits an increase in both HR and MAP in decerebrate rats in the absence of anesthesia (27). This model has since been used by other laboratories (32,36). The value of this model resides in the fact that it provides a way to study mechanisms that underlie the exaggerated EPR because the mechanisms controlling these cardiovascular responses are not studied easily in disease in cats and dogs (the major species being used to study the EPR), and mechanistic studies in humans have encountered feasibility problems. Additionally, more genomic information currently is available for rodents compared with larger mammals presenting the opportunity to study the mechanisms of this reflex at the level of cellular and molecular physiology. With this model, we have been able to study the mechanisms that mediate the abnormal responses to exercise in heart failure. Previously, we published a complete characterization of our rodent model for the study of the EPR (27) and an extensive review of other models that are available for the study of these reflexes (28). We have combined this model with a model of cardiac ischemia (left anterior descending (LAD)) artery ligation originally described by Pfeffer et al. (21). In these animals, we first evaluated LV dysfunction and morphological indices of heart failure. After LAD ligation, we observed that rats develop a dilated cardiomyopathy (DCM) (26), and morphometric indices of heart failure are elevated (26). In addition, we evaluated the MAP and HR responses to exercise in animals with confirmed heart failure. Exercise was stimulated in one of two ways in our studies: 1) ventral root stimulation, which activates motor neurons and, in turn, produces a static muscle contraction; or 2) passive stretch. It should be noted that, in this model to study the EPR, the animal is decerebrate. This eliminates input from the central command, which is another reflex that controls MAP and HR in response to exercise. Generally, it is believed, however, that the central command is activated only during high-intensity exercise under both physiological and pathological conditions (12,33), whereas stimulation of the EPR has been demonstrated to occur with mild-to-moderate forms of exercise (8).
At various times after LAD ligation, we performed ventral root stimulation and passive stretch in healthy, sham-treated, and cardiomyopathic animals. We observed a significant rise in both blood pressure and HR in response to these stimuli in all groups of animals (Fig. 1). However, the cardiovascular responses to static muscle contraction were exaggerated in cardiomyopathic rats, when compared with sham-treated or healthy controls. We also observed that this exaggerated response was present, albeit weaker, upon passive stretching of the muscle. Moreover, the exaggerated responses were evident at all intensity levels of electrical stimulation. We also have observed that the exaggeration in the EPR correlates with LV dysfunction (Fig. 2). In addition, the exaggeration in the EPR progresses temporally after LAD ligation (26). All of these data indicate that this rat model, designed to study the abnormalities of the EPR in heart failure, is valid as it closely mimics the course of patients in heart failure.
Mechanisms Controlling the Exaggerated EPR in Heart Failure
In an attempt to determine what neuronal population was responsible for the exaggerated EPR in heart failure, we elected to examine specific arms of the reflex loop. The reflex arc that comprises the EPR is shown in Figure 3. It has been demonstrated the skeletal muscle contraction results in activation of groups III and IV afferent fibers that innervate the skeletal muscle. Passive stretch, in contrast, predominately activates group III afferent neurons (6). These activated afferent neurons send signals through the brainstem where sympathetic and parasympathetic efferent neurons are engaged and the physiological result is an increase in both blood pressure (BP) and HR.
Role of the TRPv1 receptor under physiological conditions
Although it is well established that the activation of groups III and IV afferent neurons by muscle contraction stimulates the EPR (8,16), the exact receptors that mediate these responses currently are being explored (13,36). Recently, we demonstrated that the transient receptor potential vanniloid 1 (TRPv1) is a mediator of the EPR in the rat as responses to skeletal muscle contraction were reduced significantly in the presence of specific TRPv1 antagonists. In contrast, responses to passive stretch, which primarily stimulate group III afferent neurons were not affected by these antagonists (25). We also observed similar effects with iodo-resinaferatoxin and Ruthenium Red as well (25). These data indicate that the TRPv1 receptor contributes to the activation of the EPR during skeletal muscle contraction in the rat. This is similar to observations in humans (2) where it has been suggested that the EPR is mediated by the TRPv1. However, reports in the cat indicate that TRPv1 does not appear to affect the EPR (11). These data also support the concept that the TRPv1 is localized predominately to group IV afferent neurons that are activated by metabolic stimulation (static muscle contraction) and that group III afferent neurons contribute to the EPR in response to mechanical deformation (i.e., passive stretch) and metabolic stimulation. Therefore, the afferent neurons mediating the EPR do not appear to be polymodal in nature.
Role of the TRPv1 receptor in heart failure
Because much of the controversy in the human literature surrounded the metabolically sensitive afferent neurons, we chose to begin our evaluation by stimulating the group IV afferent neurons in this reflex loop. To do this, we used the neurotoxin, capsaicin. Intra-arterial injection of capsaicin into the circulation of the hind limb is a tool for the selective activation of group IV afferent neurons (9). Capsaicin selectively activates the TRPv1 receptor, a nonselective cation channel, that is localized on, and serves as a marker for, the group IV afferent neuron (5,17). We injected capsaicin into the intra-arterial supply of the hind limb of healthy, sham, and cardiomyopathic rats. We observed that there was a dose-related increase in MAP and HR in healthy and sham-treated animals in response to increasing doses of capsaicin (Fig. 4). We also observed that this increase was reduced significantly when capsaicin was administered together with capsazepine, a selective TRPv1 antagonist. Taken together, these data indicate that capsaicin causes a significant, dose-related increase in MAP and HR by activating the TRPv1 receptor on metabosensitive (group IV) afferent neurons in this rat model. When we administered capsaicin to animals with heart failure, however, we observed a significantly blunted MAP and HR response when compared with healthy and sham-treated controls (Figure 4). These data indicate that the metabosensitive, group IV afferent neurons are less responsive to TRPv1 activation in heart failure when compared with healthy or sham-treated conditions. To evaluate the putative reasons for these blunted responses to capsaicin, we determined the levels of TRPv1 mRNA on neurons innervating the skeletal muscle using reverse transcriptase-polymerase chain reaction analysis. We observed a significant decrease in the TRPv1 mRNA levels in the sensory neurons innervating the skeletal muscle in animals with heart failure when compared with sham-treated animals (Fig. 5).
Finally, we evaluated the responses to contraction and stretch in the absence of group IV, capsaicin-sensitive, TRPv1-expressing afferent neurons. To do this, we treated neonatal rat pups (2 d old) with a single, subcutaneous injection of capsaicin. Neonatal capsaicin treatment is a well-established model for the selective and permanent destruction of group IV primary afferent neurons (7). We confirmed the destruction of group IV afferent neurons by evaluating the protein levels of the TRPv1 receptor (Fig. 6A and B) and by determining the number of eye wipes in response to a dilute solution of capsaicin delivered to the cornea in adult animals (Fig. 6C). We also evaluated cardiac function in these animals and observed no significant difference in LV function when compared with healthy and vehicle-treated controls (data not shown). We observed that neonatal capsaicin treatment resulted in an exaggerated EPR in response to contraction and passive stretch similar to that which we observed after heart failure (Fig. 6D). In other words, destruction of group IV afferent neurons in animals with normal LV function serves to exaggerate the EPR (30).
Collectively, this body of data indicates that the TRPv1 receptor is downregulated in heart failure. This downregulation causes a decreased responsiveness in the TRPv1-expressing sensory neuron that, ultimately, results in an exaggeration of the EPR and not in a dampening of the EPR. This conclusion is supported by our observations of an exaggerated EPR after neonatal capsaicin treatment. These data support the findings of Sterns et al. (31) and Middlekauff et al. (20), as they reported that the metabosensitive afferent neurons are blunted in patients with heart failure. Additionally, these observations further advance the muscle hypothesis as we have demonstrated that ablation of a population of peripheral neurons can create an abnormal EPR in an animal with normal cardiac function.
We next attempted to answer the following questions: 1) what causes the downregulation of TRPv1 in heart failure; 2) if the group IV metabosensitive afferents yield a blunted response to exercise, what neuronal population accounts for the overall exaggeration of the EPR that is observed in heart failure; and 3) is TRPv1 the sole receptor involved in the blunted responses to exercise?
What Causes the Downregulation of the TRPv1 in Heart Failure?
Evaluation of cell death
Because destruction of group IV afferent neurons resulted in an exaggerated EPR similar to that which we observed in heart failure, we considered the possibility that group IV afferent neurons were dying in heart failure. To determine whether cell death occurs in the primary afferent neurons during heart failure, we used terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL) assay to evaluate programmed cell death in the dorsal root ganglia (location of the cell bodies of the primary afferent neurons) in normal and ligated rats. We observed no TUNEL-positive neurons in sections from either normal (Fig. 7A) or ligated (Fig. 7B) rats. Positive (arrowheads in Fig. 7C) and negative controls (Fig. 7D) were performed in the dorsal root ganglia from healthy rats to ensure the quality of the assay. Additionally, we observed no indication of necrosis in these tissue sections when evaluated with hematoxylin and eosin staining (data not shown). From these data, we conclude that cell death is unlikely to account for the reduced responsiveness of the TRPv1 receptor and/or the downregulation of TRPv1 mRNA that we observe in heart failure.
Evaluation of nerve growth factor
Nerve growth factor (NGF) is a target-derived trophic factor, and its gene is a highly conserved molecule with a high interspecies homology. The biological activity of NGF is regulated by two structurally unrelated receptors: a low-affinity receptor (p75) and a high-affinity tyrosine kinase receptor known as trkA. Approximately two thirds of small diameter (<30 μm), capsaicin-sensitive primary afferent neurons express a functional trkA receptor (24), and approximately 50%-65% of neurons expressing TRPv1 mRNA also expressed trkA mRNA in rat dorsal root ganglia (14,17). Nerve growth factor binds to trkA receptors on the presynaptic terminals of afferent neurons and is transported back to the cell body located in the dorsal root ganglia. Consistent with these observations, NGF positively regulates TRPv1 expression (38,39) and promotes TRPv1 sensitization by enhanced cell surface expression (40).
We hypothesized that muscle-derived NGF levels may be decreased in heart failure because of the atrophy and metabolic changes that are known to occur in skeletal muscle in heart failure. We further hypothesized that a reduction in NGF levels could contribute to the downregulation in TRPv1 expression that we observed in heart failure. In these studies, we evaluated the levels of NGF in the dorsal root ganglia. We observed that there are detectable levels of NGF in the dorsal root ganglia from healthy animals. However, when we compared NGF levels in healthy animals versus heart failure animals, we observed significant decreases in the levels of NGF (37). We observed no significant differences in the levels of NGF in the brain stem or ganglia unrelated to the EPR. Therefore, these data indicate that NGF levels are reduced in heart failure in regions that are involved in the processing of the EPR. Additionally, the dysregulation of NGF seems to be limited to peripheral sites that mediate the EPR and not the central regions. These data are consistent with our observations of a downregulation/desensitization of the TRPv1 receptor as NGF is essential for the maintenance and proper function of the TRPv1 receptor. Again, these data further promote the muscle hypothesis as the dysregulation of NGF occurs in peripheral sites involved in the EPR.
What Neuronal Population Accounts for the Overall Exaggeration of the EPR That Is Observed in Heart Failure?
We have demonstrated clearly that the group IV metabosensitive afferent neuron population is impaired in heart failure. Therefore, although important, this population of neurons does not mediate directly the exaggeration in the EPR that is observed in heart failure. As a result, we chose to evaluate the contribution of the group III mechanosensitive afferent population of neurons in our rat preparation. It has been shown previously that gadolinium significantly attenuates the activity of mechanically sensitive group III afferent neurons, whereas the group IV afferent neurons are unaffected (8). Therefore, in this preparation, gadolinium can block specifically the firing of group III afferent neurons. To make these determinations, hind limb muscle contractions were performed before and after pharmacological blockade of mechanically sensitive skeletal muscle receptors with the trivalent lanthanide gadolinium in sham, control, and heart failure rats. Furthermore, in an attempt to understand the evolution of EPR overactivity, additional studies were conducted to determine the contribution of the muscle mechanoreflex to the exaggerated EPR that we observed in animals deficient in group IV afferent fibers. We hypothesized that gadolinium would attenuate the reflex cardiovascular response to muscle contraction to a greater degree in cardiomyopathic rats compared with sham control animals. Likewise, we hypothesized that gadolinium would have a greater effect on the EPR in animals treated with neonatal capsaicin when compared with vehicle-treated controls.
Consistent with our previous observations (26,29), baseline cardiovascular responses to static muscle contraction before administration of gadolinium were exaggerated in both DCM and neonatally capsaicinized (NNCAP) animals when compared with sham rats. Sixty minutes after administration of gadolinium, MAP and HR responses to contraction were reduced significantly in sham, DCM, and NNCAP animals. At 120 min after gadolinium administration, the cardiovascular response to contraction began to return to baseline levels in all groups. Similar results were observed in response to passive stretch (29). In contrast to gadolinium, isotonic saline had no effect on the cardiovascular response to either muscle contraction or stretch.
Effects of Gadolinium Are More Pronounced in DCM and NNCAP When Compared With Sham
To determine the relative contribution of group III afferent neurons to the cardiovascular response elicited by contraction and stretch in all animal groups, we calculated both absolute and percentage changes in MAP and HR responses to these maneuvers before and after administration of gadolinium. First, we plotted the absolute differences in MAP and HR responses to contraction and stretch after administration of gadolinium from those obtained before administration of gadolinium (Fig. 8). Although gadolinium reduced MAP and HR responses to both contraction and stretch in sham controls, the effect of gadolinium was more pronounced in DCM and NNCAP animals. Second, we calculated the contraction- and stretch-induced percentage increases in MAP and HR from baseline MAP and HR values, respectively, before and after administration of gadolinium. Again, although gadolinium significantly reduced the percentage increase in both MAP and HR in response to contraction and stretch, the difference between the pre-gadolinium percentage increase and the post-gadolinium percentage increase consistently was larger in DCM and NNCAP than in sham animals. However, it should be noted that when expressed as a percentage change from baseline, changes in MAP markedly were larger than changes in HR in all groups (29).
These data suggest that group III afferent neurons are hyperactive in heart failure and after neonatal capsaicin treatment. This hyperactivity contributes to the exaggerated EPR that is observed in these states as administration of gadolinium can normalize the reflexive responses to exercise. These data lend further support to the muscle hypothesis as the blocking of peripheral nerve traffic (group III afferent neurons with gadolinium) can normalize the EPR in heart failure and after neonatal capsaicin treatment. Our observations are supported by the recent findings of Wang et al. (34) where direct recordings of afferent neurons demonstrate that group III afferent neurons are sensitized, whereas group IV afferent neurons are desensitized in heart failure. Finally, these data support the certain findings in the human literature as an increased activity in mechanosensitive afferent neurons in patients with heart failure has been reported previously (19,20,23).
Role of Cannabinoid Receptors
To determine whether the TRPv1 alone was abnormal in heart failure or whether other receptors contribute to the abnormal responses to exercise, we evaluated the cannabinoid-1 (CB-1) receptor in heart failure. CB-1 receptors are colocalized heavily with TRPv1 receptors on group IV afferent neurons and activation of the CB-1 by the endogenous ligand anandamide (AEA) has been shown to affect MAP and HR. In these studies, we administered AEA into the intra-arterial hind limb in the same fashion that we administered capsaicin. After AEA administration, we observed a dose-related increase in MAP and HR to AEA in healthy and sham-treated animals, similar to the responses to capsaicin (Fig. 9). We also observed a blunted response to AEA in animals with heart failure, again similar to the responses to capsaicin (37). Based on these data, several interpretations are possible. First, it is feasible that both the TRPv1 and the CB1 receptor individually are affected by heart failure in a manner that results in the blunted responses of both receptors. It seems likely, in this case, that downstream targets of both of these receptors (such as protein kinase C) may be affected by the abnormalities in both of these receptors. Another possibility is that the primary defect in heart failure animals exists in the CB1 receptor, which, in turn, affects the function of the TRPv1 receptor. In support of this concept, it has determined recently that the constitutive activity of the CB1 receptor was essential for the normal responses to TRPv1 activation (3). We have studies underway to unravel the mechanisms that contribute to the blunting of the CB1 receptor in heart failure.
It is well established that patients with heart failure experience abnormal increases in BP and HR in response to mild forms of exercise. Although such abnormalities contribute to a poor clinical prognosis, the mechanisms controlling these cardiovascular responses are understood incompletely. Increased sympathetic activation is a hallmark of heart failure. The EPR is a multisynaptic reflex involving the following: 1) primary afferent neurons, 2) second-order spinal neurons, 3) neurons in medullary centers, and 4) sympathetic and parasympathetic efferent neurons. The exaggerated EPR result in increased sympathetic activation during exercise. Although the benefit of sympathetic blockade has been established in heart failure patients, some physicians remain hesitant to prescribe such therapy for treatment of heart failure, particularly in high-risk patients, because it is believed that long-term activation of the sympathetic nervous system provides compensatory support for the failing heart. Our findings suggest that selective blockade of the mechanoreflex may hold potential as a novel therapy in the treatment of heart failure. Recently, it has been determined that long-term exercise training improves EPR function and decreases mechanoreflexive activity in rats with heart failure (35). Therapies focused on normalizing the mechanoreflex selectively could prevent sympathetic overactivation in response to exercise while avoiding the potentially negative effects associated with chronic sympathetic inhibition.
There is general agreement that the EPR is exaggerated in humans with heart failure (15,19,20,22,23,31) and that these exaggerations correlate with morbidity and mortality, as well as with decreased LV function (4). Therefore, the clinical relevance of an abnormal EPR is well established. Despite this, defining the mechanisms that mediate the abnormal EPR in heart failure patients has proven to be difficult, and the literature surrounding this issue is conflicted (18). A great deal of controversy exists regarding the contribution of the metabolic component of the EPR because its activity has been reported to be both enhanced (22,23) and reduced (19,31) in response to exercise in heart failure patients. Likewise, it has been reported that the mechanosensitive afferents are hyperactive in humans with heart failure (19,23).
In this review, we have discussed studies by our laboratory and those of others to highlight our current understanding of the pathophysiology of the EPR in heart failure. Using our novel rat model, we have revealed mechanisms that are important in controlling the EPR in heart failure. Although human studies have indicated that there is abnormality that exists in either the metabolically sensitive afferent neurons or the mechanically sensitive afferent neurons, we have determined that abnormalities exist in both of these neuronal populations. Moreover, we have advanced our knowledge of the abnormal EPR in heart failure by proposing that blunting of the group IV afferent neurons precedes the hyperexcitability that is observed in the group III afferent neurons. We have presented evidence to support that the blunting of the group IV afferent neurons initiates the abnormal EPR, whereas the hyperexcitability of the group III afferent neurons mediates the exaggerated EPR. We hypothesize that the following sequence of events leads to the development of an exaggerated EPR in heart failure (Fig. 10). Levels of NGF are decreased in skeletal muscle during heart failure. Decreases in NGF levels cause a decrease in the expression of TRPv1 in metabolically sensitive afferent neurons that innervate the skeletal muscle. Decreases in the expression of TRPv1 causes decreased responsiveness of group IV afferent neurons and create an imbalance between metabolically and mechanically sensitive afferent neurons. This imbalance results in a compensatory hyperexcitability of group III afferent neurons, which, ultimately, results in an exaggerated EPR. Many questions remain with regard to the pathways that regulate this neuroplasticity.
Funding for this work is supported by the American Heart Association (Texas Affiliate, BGIA) and the NIH (2R01HL070242-07A2).
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