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Department of Medicine (Cardiology), David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California
Submitted 6 November 2007 ; accepted in final form 19 February 2008
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ABSTRACT |
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exercise; sympathetic nerve activity
The following two major reflex systems control the circulatory responses to exercise: 1) central command, a central neural system closely linked to perceived effort during exercise; and 2) sensory nerve fibers located in the skeletal muscle itself, including the muscle mechanoreceptors, sensitive to stretch during contraction, and the muscle metaboreceptors, sensitive to ischemic metabolites generated during exercise (12, 14, 27). In healthy humans, the muscle metaboreceptors exert the greatest control over reflex increases in sympathetic nerve activity during static exercise (14, 15, 27). Central command plays a supporting role, underlying increases in muscle sympathetic nerve activity (MSNA) only during extreme, or near maximal, effort (33). Recent reports support the notion that the muscle mechanoreceptors also underlie the increase in MSNA during exercise, especially rhythmic exercise, in healthy humans (3, 11). We (19, 20) reported that cyclooxygenase products, but not lactic acid or adenosine, sensitize muscle mechanoreceptors in healthy humans. These data in healthy humans, and data in animals (1, 12–14, 28, 30), strongly support the concept that that the group III mechanosensory neurons are sensitized by specific metabolic by-products.
In HF patients, reflex control of MSNA during exercise is different from that of healthy humans. Unlike in healthy humans, in HF patients, muscle metaboreceptor reflex control of MSNA during exercise has been shown to be markedly blunted (31). In its place, the muscle mechanoreceptors contribute importantly to the reflex control of the circulation during exercise in HF patients (16, 18, 29). Basal muscle mechanoreceptor control of MSNA in HF patients is increased compared with that in healthy humans (18, 19). It is unknown whether cyclooxygenase products or adenosine sensitizes the muscle mechanoreceptors in patients with HF, underlying their augmented muscle mechanoreceptor control of sympathetic nerve activity. The purpose of the present study is to test the hypothesis that ischemic metabolites, including cyclooxygenase products and adenosine, do sensitize the muscle mechanoreceptors during exercise in patients with HF.
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METHODS |
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After giving written informed consent on University of California Los Angeles (UCLA) Internal Review Board-approved protocols, 24 patients with advanced HF participated in these studies. Patient characteristics are shown in Table 1. Advanced HF patients were recruited consecutively from the UCLA-Ahmanson Cardiomyopathy Center. All HF patients met the following inclusion criteria: clinically stable, without change in cardiac medications for 3 mo before the study, not involved in a formal exercise program, and no significant liver or renal disease, autonomic neuropathy, myopathy, untreated thyroid disease, or peripheral vascular disease. All patients were New York Heart Association class II and III, with a left ventricular ejection fraction 
35%, with chronic (>12 mo duration) HF, and under consideration for heart transplantation. Medications were not discontinued for study purposes, although furosemide was withheld the morning of the experimental protocol.
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Sympathetic nerve activity directed to muscle MSNA was recorded from the peroneal nerve using the technique of microneurography (7). Briefly, multiunit postganglionic muscle sympathetic nerve recordings were made using a tungsten microelectrode. Signals were amplified by a factor of 50,000 to 100,000 and band-passed filtered (700 to 2,000 Hz). Nerve activity was rectified and integrated (0.1-s time constant) to obtain a mean voltage display of sympathetic nerve activity that was recorded on paper. All recordings of MSNA met previously established and described criteria (15, 32). Muscle sympathetic bursts were identified by visual inspection by a single investigator (H. R. Middlekauff) blinded to the intervention and expressed as burst frequency (bursts per minute) and total activity (units per minute). Total activity per minute was determined by the sum of the heights of individual bursts per minute. The interobserver and intraobserver variabilities in identifying bursts are <10% and <5%, respectively (15, 17).
Rhythmic Handgrip Exercise
A short course of low-level rhythmic exercise was used to principally engage the muscle mechanoreceptors without simultaneously activating the metaboreceptors. Maximum voluntary contraction (MVC) was determined by having the subject briefly squeeze a handgrip dynamometer (Stoelting) at maximal levels. The greater of two maximal contractions was selected as the MVC. Rhythmic handgrip (RHG) was performed at 20% of the subject's MVC at a rate of 30 contractions/min (1 contraction/s) for 3 min. A metronome was used to optimize the uniformity of the contraction rate.
Posthandgrip Circulatory Arrest
To assess whether the muscle metaboreceptors had been inadvertently engaged, posthandgrip circulatory arrest (PHG-CA) was performed (2). Five seconds before the conclusion of exercise, a blood pressure cuff was rapidly inflated to suprasystolic blood pressure levels (220 mmHg) using an automatic inflation device (University of Iowa). Exercise was then terminated so that muscle mechanoreceptors and central command were no longer engaged. This maneuver is a well-accepted means to trap ischemic metabolites in the exercising muscle bed, thereby isolating the muscle metaboreflex contribution to the activation of MSNA. The cuff was deflated after 2 min.
Pharmacological Inhibition of Ischemic Metabolites
Intrabrachial arterial indomethacin was used to inhibit the forearm production of prostaglandins during exercise. The dose (0.3 mg/100 ml, forearm volume infused over 20 min immediately before exercise) has been shown to virtually eliminate forearm prostaglandin release during static handgrip exercise in healthy humans (34). Following a 5-min rest period, rhythmic exercise was begun.
Intrabrachial arterial aminophylline, a nonselective adenosine receptor antagonist, was administered at a rate of 1 µg/ml forearm volume/min beginning 10 min before exercise and continuing through recovery. This dose has been shown to significantly blunt the increase in MSNA during static handgrip exercise in healthy humans (5).
Miscellaneous
Blood pressure was monitored noninvasively with an automatic blood pressure cuff (Press-Mate 8800; Colin Medical Instrument, San Antonio, TX). The monitor was cycled continuously during the exercise protocol, resulting in the measurement of systolic, diastolic, and mean blood pressure every 20–30 s. Heart rate (HR) was monitored continuously through lead II of the ECG.
Experimental Protocols
Two different drugs were tested in two different groups of HF patients. Time lines for each protocol are shown in Fig. 1. Following an unblinded saline infusion administered in the same volume and rate as the study drug, the exercise protocol (as described in Rhythmic Handgrip Exercise) was performed. Following a 45-min rest period for recovery, study drug or saline was administered in a double-blind, randomized fashion, and the exercise protocol was repeated. Subjects were invited to return to repeat the entire protocol on a different day, during which the study drug or saline that they did not receive the first day was administered in a double-blind fashion on the second day (e.g., blinded aminophylline on day 1 and blinded saline on day 2). With this design, unblinded saline served as a control for the drug effect. The double-blind saline served as a control for an order or time effect. The half-life of the drugs prohibited a design in which both saline and drug were only administered in a double-blind manner on the same day, since a subject receiving a drug during the first exercise session of the day may have a spillover effect during the second session.
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Data are presented as means ± SE. Repeated-measures ANOVA was used for the comparison of between- and within-group means and to compute the P values. A paired t-test, which is a special case of repeated-measures ANOVA when only two time points are used, was also used in some of the analyses. P values <0.05 were considered significant.
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RESULTS |
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Twelve HF patients participated in these indomethacin studies; nine patients completed the indomethacin protocol, nine patients completed the blinded saline protocol, and six patients completed both protocols.
Hemodynamic responses. Resting mean arterial pressure (MAP) and HR are shown in Table 2. MAP and HR increased similarly during exercise during saline and during blinded saline runs (Table 3). Intra-arterial indomethacin had no effect on resting MAP or HR (data not shown). The increase in MAP, but not HR during exercise, was blunted following indomethacin infusion (Table 3).
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Twelve different patients were enrolled in this study; nine patients completed the blinded aminophylline protocol, nine patients completed the blinded saline protocol, and six patients completed both protocols.
Hemodynamic responses. Resting MAP and HR are shown in Table 2. MAP and HR increased similarly during exercise during saline and during blinded saline runs (Table 3). Intra-arterial aminophylline had no effect on resting MAP or HR (data not shown). The increases in MAP and HR during exercise were not blunted following aminophylline infusion (Table 3).
MSNA. Following unblinded saline control and blinded saline infusion, MSNA increased significantly and similarly during RHG (drug, P = NS; time, P = 0.001; and drug-time interaction, P = NS; Fig. 2). Thus there was no order effect. MSNA increased steadily during exercise, and following blinded aminophylline, this increase of MSNA was not blunted (drug, P = NS; time, P = 0.0006; and drug-time interaction, P = NS; Fig. 2).
Once again, to investigate whether the muscle metaboreceptors were activated during exercise, PHG-CA was performed (2). During saline infusion, MSNA levels during PHG-CA were not elevated compared with those during recovery (Fig. 3), eliminating the possibility that sympathetic activation was mediated by muscle metaboreceptors.
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DISCUSSION |
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According to the muscle hypothesis, abnormalities of the skeletal muscle, including a skeletal myopathy, abnormal muscle metabolism, and abnormal reflex control of the circulation during exercise in HF patients, all contribute to the subnormal exercise capacity in patients with HF (4, 9, 22, 23). Piepoli and colleagues (22, 24, 25) have recognized a hyperventilatory response to exercise in patients with HF, which presumably leads to premature fatigue and early exercise termination. They have evidence consistent with the concept that hyperventilation during exercise is attributable to abnormal reflex control of the circulation by the muscle ergoreceptors, nerve endings that are sensitive to ischemic metabolites generated during exercise. In an effort to identify the ischemic metabolite(s) contributing to the abnormal ergoreflex control of the ventilatory drive during exercise in HF, local muscle blood effluent concentrations of metabolic mediators were assessed, including prostaglandins (PGF1-
and PGE2), bradykinin, phosphate, K+, H+, and lactate (25). These metabolites were collected and measured in 16 HF patients and 10 controls. Interestingly, the HF patients developed higher levels of prostaglandins, bradykinin, and lactate compared with those of the healthy controls, but only prostaglandins were correlated with the exaggerated ventilatory response. In a follow-up study (26), these investigators confirmed these findings in a different group of HF patients and found that ketoprofen infusion, which inhibits prostaglandin and bradykinin production, attenuated the ergoreflex hyperreactivity. These experimental protocols differed from those in the present study in an important way, since in the present study, only the muscle mechanoreceptor, and not the muscle metaboreceptor, contribution to reflex responses during exercise was engaged and investigated. Nonetheless, these prior studies identify a role during exercise for prostaglandins in sensitizing the muscle metaboreceptor control of ventilation in HF patients but not in healthy humans.
Notarius and colleagues (21) investigated the role of endogenous adenosine in mediating the heightened sympathetic responses during exercise in patients with HF. Caffeine, an adenosine receptor blocker, was infused intravenously in 12 HF patients and 10 controls during isometric and isotonic handgrip exercise. Caffeine abolished the MSNA response during the posthandgrip ischemic arrest maneuver, but not during the exercise itself, consistent with a role for adenosine in stimulating muscle metaboreceptors but not mechanoreceptors in patients with HF. Since the caffeine was administered intravenously, a central nervous system effect cannot be completely excluded. Interestingly, but not commented on in the discussion by the investigators, intravenous caffeine did abolish the sympathetic activation during 10% RHG exercise in HF patients but not in healthy controls. This type and level of exercise, 10% RHG exercise, predominantly engages the muscle mechanoreceptors. This finding that caffeine abolished sympathetic responses to low-level rhythmic exercise is consistent with the adenosine sensitization of muscle mechanoreceptors in HF patients. In contrast, in our study, we did not find a role for adenosine in sensitizing the muscle mechanoreceptors. This discrepancy warrants further investigation.
Our findings in HF patients are similar, with one important exception discussed below, to our previous findings in healthy humans. Using the identical protocol as utilized in the current study (20), we previously reported that in healthy humans, cyclooxygenase products abolished the MSNA response to low-level rhythmic exercise, whereas aminophylline had no effect. In a study of fatiguing handgrip exercise in healthy volunteers, Cui and colleagues (6) found that the MSNA response was attenuated during the infusion of the cyclooxygenase blocker ketorolac. Unfortunately, the effect of ketorolac on the muscle mechanoreceptor contribution to the increase in MSNA was not isolated in these studies.
The situation in HF patients differs from that in healthy humans in one apparently important way. We have previously reported, and once again observed in the present data, that MSNA increases immediately in HF patients, within the first minute of low-level rhythmic exercise. We have previously demonstrated that basal muscle mechanoreceptor sensitivity is increased in HF patients, since during a passive exercise maneuver that does not engage central command or generate ischemic metabolites, MSNA increased in HF patients but not in controls (19). In the current study, somewhat surprisingly, even the immediate increase in MSNA during low-level exercise is abolished by indomethacin, consistent with the concept that cyclooxgenase products are present earlier in patients with HF compared with healthy humans. Whether cyclooxygenase products are generated sooner, and/or in greater quantity compared with healthy humans, or whether the muscle mechanoreceptors in HF patients are more sensitive to cyclooxygenase products remains to be investigated.
Limitations
It would be ideal to be able to measure prostaglandin and adenosine levels in the vicinity of the muscle mechanoreceptors during this exercise paradigm. However, these nerve endings are in the interstitial space. Other investigators have substituted venous effluent levels of prostaglandins (25) or performed microdialysis of the interstitial space to estimate adenosine levels (10). Unfortunately, the former is just an estimate of interstitial levels, since it is unlikely that these metabolites are in a steady state of metabolism and transport. Furthermore, the half-life of adenosine in the blood stream is seconds, thus blood levels are meaningless. The latter technique mandates several minutes to perform and a larger muscle bed than the forearm; thus it is not feasible in these protocols. Although study drugs were administered into the brachial artery, it is likely there was spillover to the systemic circulation. Baseline hemodynamics and sympathetic nerve activity levels were not altered by intrabrachial infusion of either study drug, but we cannot completely exclude that the sympathetic nerve attenuation during exercise was mediated by spinal cord or brain stem drug effects. Finally, blood pressure was monitored noninvasively; the reproducibility of our noninvasive blood pressure monitor to measure the smallest changes under these experimental conditions is unknown.
In conclusion, muscle mechanoreceptors are sensitized by cyclooxygenase products, but not adenosine, in patients with HF. This sensitization appears to play a role in the immediate (minute 1) muscle mechanoreceptor-mediated increase in MSNA during RHG. Whether this reflects a heightened sensitivity to prostaglandins, and/or the premature and augmented release of prostaglandins in HF compared with healthy controls, remains unknown.
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GRANTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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