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Attenuation of Muscle Metaboreflex in Chronic BRUNO T. ROSEGUINI1, CRISTIANO N. ALVES1, GASPAR R. CHIAPPA1, RICARDO STEIN1,2, MARLI M. KNORST3,4,and JORGE P. RIBEIRO1,2,4 1Exercise Pathophysiology Research Laboratory, 2Cardiology and 3Pulmonary Divisions, Hospital of Clinics of Porto Alegre,Porto Alegre, BRAZIL; and 4Department of Medicine, Faculty of Medicine, Federal University of Rio Grande Sul, PortoAlegre, BRAZIL ROSEGUINI, B. T., C. N. ALVES, G. R. CHIAPPA, R. STEIN, M. M. KNORST, and J. P. RIBEIRO. Attenuation of Muscle Metaboreflex in Chronic Obstructive Pulmonary Disease. Med. Sci. Sports Exerc., Vol. 40, No. 1, pp. 1–6, 2008. Purpose: Abnormal skeletal muscle function is well documented in chronic obstructive pulmonary disease, but there is no information about the activity of muscle metabosensitive afferents. In this study, we tested the hypothesis that patients with chronic obstructive pulmonary disease would have abnormal reflex responses to stimulation of metabosensitive afferents in skeletal muscle when compared with healthy, matched subjects. Methods: In 16 patients with moderate to severe chronic obstructive pulmonary disease and 13 healthy, age-matched control subjects, we evaluated heart rate, mean blood pressure, calf blood flow, and calf vascular resistance responses to static handgrip exercise at 30% of maximal voluntary contraction, followed by recovery with or without circulatory occlusion. Muscle metaboreflex control of calf vascular resistance was estimated by subtracting the area under the curve with circulatory occlusion from the area under the curve without circulatory occlusion. Results: Mean blood pressure and heart rate responses were not significantly different in patients and controls during exercise and recovery. In the control group, calf vascular resistance increased significantly during exercise and remained elevated above baseline during circulatory occlusion, whereas in patients changes from rest were not significantly different in both trials. Estimated muscle metaboreflex control of calf vascular resistance was significantly reduced in the patients (controls: 31 T 22units, patients: 8 T 31 units, P G 0.05). Conclusion: Patients with chronic obstructive pulmonary disease have a reduced calf vascularresistance response to handgrip exercise and to selective activation of muscle metaboreflex when compared with healthy subjects. Key Words: BLOOD FLOW, STATIC EXERCISE, METABORECEPTORS, HEMODYNAMIC CONTROL Itiswellrecognizedthatcardiovascularadjustmentsto In this technique, interruption of perfusion immediately static exercise are partially mediated by activation of before the termination of exercise is thought to trap mechanosensitive and metabosensitive afferents within metabolites within the formerly active muscle, thus stim- the active skeletal muscle. Specifically, stimulation of metab- ulating chemosensitive fibers (12). Although the specific osensitive afferents by products of muscle contraction evokes chemical products that activate these metabosensitive a powerful increase in sympathetic nervous system activity afferents remain controversial, considerable evidence sup- and a consequent pressor response known as the muscle ports the notion that muscle acidosis is strictly linked to metaboreflex (27). It is postulated that the primary function sympathetic vasoconstriction and blood pressure (BP) of this reflex is to correct a mismatch between blood flow and metabolism in ischemic exercising muscle (27).
In patients with chronic obstructive pulmonary disease Static handgrip exercise has been shown to elicit a (COPD), skeletal muscle dysfunction and its contribution to decrease in calf muscle vascular conductance (31), and the pathophysiology of exercise intolerance is a matter of selective activation of muscle metaboreflex in humans can extensive investigation (3). Several studies have shown that be achieved by postexercise circulatory occlusion (PECO+).
patients with COPD have lower percentages of type Imuscle fibers, lower levels of intracellular ATP andphosphocreatine, and reduced activity of oxidative enzymes Address for correspondence: Jorge P. Ribeiro, M.D., ScD, Associate (1,16). The latter may occur in the absence of altered Professor and Chief on Noninvasive Cardiology, Hospital de Clı´nicas de physical activity patterns, as shown by animal experiments Porto Alegre, Rua Ramiro Barcelos 2350, 90035-007, Porto Alegre, RS, (23). During exercise, some studies also have shown that Brazil; E-mail: jpribeiro@cpovo.net.
Submitted for publication July 2007.
these patients develop faster and greater muscular lactic Accepted for publication August 2007.
acidosis (19,20). At present, however, no evidence existsconcerning the activity of muscle metaboreflex in patients 0195-9131/08/4001-0000/0MEDICINE & SCIENCE IN SPORTS & EXERCISEÒ with COPD. Accordingly, the purpose of the present study Copyright Ó 2007 by the American College of Sports Medicine was to test the hypothesis that patients with COPD have abnormal reflex responses to stimulation of metabosensitive Copyright @ 2007 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
afferents in skeletal muscle when compared with healthy- Muscle metaboreflex. Muscle metaboreflex was matched subjects. To accomplish this goal, we evaluated evaluated as described elsewhere (26). In short, after 15 BP, heart rate, and resting limb hemodynamic responses to min of rest, baseline data for HR, BP, and calf blood flow static exercise followed by PECO+ in patients with COPD (CBF) were collected for 3 min. Static handgrip exercise was then performed with the dominant arm, at an intensityof 30% of maximal voluntary contraction, for 3 min. Duringthe last 15 s of exercise, a pneumatic cuff on the upper arm was inflated to suprasystolic pressure for 3 min (PECO+).
Subjects. Sixteen patients (11 men) with moderate to In addition, in a crossover design, subjects performed the severe COPD (Global Initiative for Chronic Obstructive same protocol without circulatory occlusion (PECOj).
Lung Disease classes II–IV) (25) participated in the study.
During the protocol, HR was monitored by lead II of the COPD diagnosis was based on a previous smoking history electrocardiogram, and BP was measured, using a standard and pulmonary function testing showing irreversible airflow auscultatory technique, by the same observer. Mean BP obstruction (postbronchodilatator FEV1 G 80% and FEV1/ (MBP) was calculated as diastolic + 1/3(systolic j diastolic).
FVC G 70% of predicted). Exclusion criteria were exacer- CBF was measured by venous occlusion plethysmography bation or infection in the past 4 wk; severe or unstable (Hokanson, TL-400, Bellevue, WA) (33). The limb was cardiac disease revealed by medical history, physical positioned above heart level and was supported in the thigh examination, and resting, as well as exercise electrocar- and ankle to ensure proper venous drainage. A strain gauge diogram; and locomotor or neurological disease, diabetes was positioned on the right calf at the point of maximum mellitus, or uncontrolled hypertension. The control group circumference. During the entire protocol, a BP cuff on the consisted of 13 (8 men) healthy, age-matched subjects, who thigh was alternately inflated to 60 mm Hg and deflated in also participated in a previously reported study (26). The 7.5-s cycles. Additionally, another cuff was placed on the research protocol was approved by the institutional ethics ankle and inflated to suprasystolic levels (240 mm Hg) to committee, and signed informed consent was obtained from occlude foot circulation. CBF (mLIminj1I100 mLj1) was determined manually on the basis of a minimum of four Protocol. Subjects came to the laboratory for two visits.
separate readings. Reproducibility of CBF measurements in On day 1, after individuals had spent 20 min of quiet rest in our laboratory present coefficients of variations of 5.7% and the supine position, venous blood samples were drawn for 5.9% for short-term (same day) and medium-term (different plasma norepinephrine determination by high-pressure liquid chromatography and electrochemical detection. In addi- Data analysis. Values are reported as means T SD.
tion, arterial blood was drawn from the radial artery for Subjects_ characteristics and baseline data were compared blood gas analysis (Rapidlab 865, Chiron Diagnostics, East by Student_s t-test. Hemodynamic responses to exercise and Walpole, MA). Later, pulmonary function tests and to PECO+/PECOj were compared by analysis of variance symptom-limited cardiopulmonary exercise tests were per- for repeated measures and Tukey–Kramer_s post hoc for formed. In the second visit, at least 72 h after the tests, pairwise comparisons. Correlations were evaluated with the subjects performed the protocol for the evaluation of mus- Pearson correlation coefficient. Significance was accepted cle metaboreflex activity. On both days, patients with COPD were asked to withdraw from inhaled short-actingA2-agonists and short-acting anticholinergic agents for 8 h, as well as long-acting A2-agonists and theophylline for 12 h.
Pulmonary function and cardiopulmonary exercise As shown in Table 1, groups had similar age and body T1 tests. Measurements of forced vital capacity and forced mass index. Patients had severe ventilatory obstruction and expiratory volume in 1 s were obtained with a computerized mild reduction in resting PaO2 and SaO2, but normal PaCO2.
spirometer (Eric Jaeger, GmbH, Wu¨erzburg, Germany), as As expected, exercise tolerance was markedly reduced in recommended by the American Thoracic Society (2), and COPD patients. Baseline MBP, CBF, and calf vascular AQ1 results were expressed as percent predicted (17). A resistance (CVR) were similar between the two groups.
symptom-limited incremental exercise test was performed Maximal voluntary contraction (Table 1) and absolute on an electrically braked cycle ergometer (ER-900, handgrip force were not significantly different in COPD Ergoline, Jaeger, Wu¨erzburg, Germany), with minute patients and controls. Plasma norepinephrine was signifi- increments of 5–10 W for COPD patients and 10–15 W cantly higher in COPD patients (414 T 163 pgImLj1) when for healthy controls. During the test, gas exchange was compared with controls (203 T 101 pgImLj1; P G 0.05).
measured breath-by-breath by a previously validated system MBP, HR, CBF, and CVR responses to handgrip exercise, (Metalyzer 3B, CPX System, Cortex, Leipzig, Germany) PECO+/PECOj, and recovery are shown in Figure 1. MBP F1 (22). Heart rate (HR) was determined from a 12-lead and HR increased significantly during exercise and re- electrocardiogram. Salbutamol (spray, 400 Kg) was inhaled mained elevated during circulatory occlusion (PECO+) when 20 min before the tests in patients with COPD.
compared with the control trial (PECOj) (Fig. 1). Changes Official Journal of the American College of Sports Medicine Copyright @ 2007 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
increase in CVR during handgrip exercise and postexercise circulatory occlusion when compared with healthy, matched controls. Overall, these findings provide the first evidence for an attenuated contribution of the muscle metaboreflex to the calf hemodynamic control in COPD.
It is well known that during static handgrip exercise, there is a time-dependent increase in muscle sympathetic nerve activity to inactive calf muscles that is tightly coupled with a reduction in CBF and a pronounced increase in CVR (29,31). This sympathetic, mediated vasoconstriction acts to redistribute blood flow toward exercising muscles (27). In our study, CVR increased, on average, by approximately 38% in healthy controls at the end of exercise, whereas in patients with COPD it increased by only about 20%, thus demonstrating a blunted CBF response to exercise in COPD patients (Fig. 1). Thus, although the mechanisms underlying this response are unclear, they likely involve a reduced sympathetic outflow response to exercise and/or a blunted sympathetic, mediated vasoconstriction in COPD patients.
Available evidence suggests that neurohumoral activation may play a pivotal role in the pathophysiology of COPD (4). Recently, direct evidence of marked sympathetic activation thorough microneurography recordings in patients with COPD when compared with healthy subjects COPD, chronic obstructive pulmonary disease; BMI, body mass index; FEV1, forcedexpired volume in 1 s; % pred, percentage of predicted; FVC, forced vital capacity; was reported (13). In agreement with previous findings CPET, cardiopulmonary exercise test; V˙O2, oxygen uptake; V˙CO2, carbon dioxide (34), our COPD patients had higher basal levels of output; RER, respiratory exchange ratio; V˙E, minute ventilation; SBP, systolic bloodpressure; DBP, diastolic blood pressure; MBP, mean blood pressure; CBF, calf blood norepinephrine than did healthy controls, compatible with flow; CVR, calf vascular resistance. * Significantly different (P G 0.05) from control.
tonic activation of the sympathetic nervous system. In thissetting, it is possible to consider that higher sympathetic from baseline for both variables were similar between activity at rest would limit the incremental response to groups during the entire protocol. CBF did not change exercise because of a ceiling effect, thus resulting in a significantly from baseline in the two trials in both groups.
decreased calf vasoconstriction, as seen in the COPD However, patients with COPD exhibited a distinct response patients. Importantly, however, we did not observe baseline pattern when compared with control subjects. When compar- CVR differences between groups, but only a differential ing both groups, CBF was significantly reduced in healthy CVR response to exercise in the COPD group.
controls at the end of exercise and during the entire The origins of sympathetic activation during exercise are circulatory occlusion period (Fig. 1). CVR increased signifi- not firmly established, but they likely involve the reflex cantly during exercise only in the control group (Fig. 1).
responses to stimulation of metabosensitive afferents within Likewise, during circulatory occlusion (PECO+), CVR the skeletal muscle (27). To gain insight into the potential remained elevated above baseline in the control group, involvement of these chemical-sensitive afferents on the whereas in the COPD patients changes from rest were not hemodynamic adjustments to exercise in patients with significant in either trial. When comparing the estimated COPD, we performed selective activation of the muscle difference in the areas under the curves of CVR between metaboreflex through PECO+ technique. Of note, we also the two trials during PECO+/PECOj periods, patients with observed a reduced calf vasoconstriction during PECO+ in COPD had lower changes (8 T 31 units) compared with the COPD patients when compared with healthy controls.
healthy subjects (31 T 22 units; P G 0.05). There was a Thus, by inference, it is reasonable to suggest that this significant correlation (r = 0.47, P = 0.01) between V impaired sympathetic activation in COPD patients was at and the difference in the area under the curve of CVR.
least partially mediated by an attenuated muscle metabore-flex control of CVR.
Interestingly, despite an evident blunted muscle metabor- eflex control of CVR, COPD patients had only modest In the present study, we evaluated the cardiovascular reductions in the pressor response to PECO+ when com- adjustments to static handgrip exercise and selective pared with healthy subjects. The reasons for this apparent activation of the muscle metaboreflex through PECO+ in discrepancy are unclear, but several hypotheses can be patients with moderate to severe COPD. The major new advanced. Sustained BP elevation during PECO+ is thought finding is that patients with COPD present an attenuated to be mediated by sympathetic, induced vasoconstriction in Medicine & Science in Sports & Exercise Copyright @ 2007 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
FIGURE 1—Mean blood pressure (MBP), heart rate (HR), calf blood flow (CBF), and calf vascular resistance (CVR) changes from baseline duringstatic handgrip exercise, postexercise circulatory occlusion (PECO+), or control (PECOj) periods, and recovery in healthy subjects (left panels) andin patients with COPD (right panels). * P G 0.05 PECO+ vs PECOj.
nonactive vascular beds (12) and enhancement in myocar- and colleagues (8) have demonstrated that, in contrast to dial contractility and cardiac filling (30). Thus, first it is healthy individuals, in which BP elevation during PECO+ relevant to consider that similar BP responses to circulatory is mediated by increases in cardiac output, patients with occlusion do not necessarily mean that the mechanisms heart failure rely mainly on increases in systemic vascular underlying these responses are the same. In fact, Crisafulli resistance to achieve similar BP levels.
Official Journal of the American College of Sports Medicine Copyright @ 2007 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
In our study, patients with COPD had similar BP hypoxia are not sufficient to alter vascular responsiveness to responses but attenuated CVR responses to PECO+. One sympathetic agonists (32). On the basis of these findings, it possible explanation for these findings is that despite blunted seems unlikely that eventual reduction in vascular adrener- vasoconstriction in resting skeletal muscle, these patients gic reactivity may account for the blunted CRV observed would exhibit augmented sympathetic, mediated vasocon- striction in viscera, such as the splanchnic area and the Sympathetic mediated reduction in resting-limb vascular kidneys. Prior reports in patients with chronic heart failure conductance is important for appropriate cardiac output have demonstrated a similar blunted increase in CVR during redistribution during exercise. Thus, the correlation between handgrip exercise (18) associated with exaggerated renal ˙ O2peak and the difference in the area under the curve vasoconstriction (23). Moreover, although controversial, evi- of CVR suggest that the blunted muscle metaboreflex– dence from animal studies suggests that nonuniform changes mediated vasoconstriction in the resting calf would com- in sympathetic nerve activity to different regions may exist promise the distribution of blood flow toward exercising in certain conditions, such as sustained elevations in BP (6) or limbs. Conceivably, however, other mechanisms involved nitric oxide synthase inhibition (15). Together, these findings in sympathoexcitation during exercise, such as the muscle reinforce the notion that a shift in the mechanisms under- mechanoreflex and the respiratory muscle metaboreflex, lying cardiovascular responses to muscle metaboreflex ac- might also be altered in COPD patients. For example, as tivation may also exist in patients with COPD.
indicated by Dempsey et al. (9), augmented respiratory Another potential mechanism involved in the blunted muscle work in these patients can potentially exacerbate CVR responses to exercise and circulatory occlusion in the respiratory muscle metaboreflex and the consequent COPD patients is an attenuated vascular responsiveness to ‘‘stealing’’ of blood flow from locomotor muscles. In this sympathetic stimuli. In general, pathophysiological states scenario, blunted vasoconstriction in inactive areas would associated with tonic activation of the sympathetic nervous also compromise diaphragmatic perfusion, accelerating the system and release of norepinephrine produce an agonist- occurrence of diaphragm fatigue during exercise. However, promoted desensitization of >-adrenergic signaling (29), as the activity of the respiratory muscle metaboreflex remains seen in chronic heart failure (11). In addition, the available to be characterized in this population.
evidence clearly demonstrates that chronic hypoxemia, a The major limitation of the present study is that we did common condition in COPD, impairs reflex responses to not measure muscle sympathetic nerve activity (MSNA) or sympathetic activation. Heistad and colleagues (14) first blood catecholamine responses in our subjects during the demonstrated that patients with chronic severe hypoxemia protocol. It has been suggested that MSNA responses to had a depressed forearm vasoconstriction response to lower- PECO+ provide the major assessment for the muscle body negative pressure. Likewise, animal studies have metaboreflex in humans (24). Accordingly, MSNA mea- shown that chronic, systemic hypoxemia reduces vascular surement could have helped us to explain the mechanisms responsiveness to vasoconstrictor substances (9) and to underlying blunted CVR responses to circulatory occlusion in patients with COPD. Importantly, however, it is well Importantly, patients in the present study experienced known that CVR responses to static handgrip and PECO+ only relatively moderate hypoxia at rest (PaO2 = 71.9 mm Hg), and all were normocapnic (PaCO2 = 40 mm Hg)— In conclusion, this study demonstrates that patients with characteristics that largely differ from those reported in COPD have a reduced calf CVR response to handgrip previous studies that have demonstrated a detrimental effect exercise and to selective activation of muscle metaboreflex, of hypoxemia on vascular responsiveness to sympathetic despite a preserved pressor response. Further studies should stimuli (7,10,13). In contrast to patients with severe be conducted to address the intrinsic causes of this blunted hypoxemia, COPD patients with moderate hypoxemia may muscle metaboreflex control of CVR in COPD and the develop only episodic reductions in arterial oxygenation potential impact of this on the pathophysiology of exercise during the day (5). Thus, it seems reasonable to suggest that intolerance in this clinical condition.
the functional vascular adaptations may differ whencomparing distinct levels and times of exposure to systemic We are grateful to Graziella Aliti, RN, MSc, and Eneida R. Rabelo, RN, ScD, for their careful technical expertise and assistance. This hypoxia. In this regard, there is evidence derived from work was supported in part by grants from CAPES and CNPq, animal studies showing that chronic episodic exposures to Brasilia, Brazil, and FIPE-HCPA, Porto Alegre, Brazil.
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