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00005768-200801000-0000300005768_2008_40_9_roseguini_metaboreflex_1article< 89_0_12_2 >Medicine & Science in Sports & Exercise© 2008 American College of Sports MedicineVolume 40(1)January 2008pp 9-14Attenuation of Muscle Metaboreflex in Chronic Obstructive Pulmonary Disease[CLINICAL SCIENCES: Clinical Investigations]ROSEGUINI, BRUNO T.1; ALVES, CRISTIANO N.1; CHIAPPA, GASPAR R.1; STEIN, RICARDO1,2; KNORST, MARLI M.3,4; RIBEIRO, JORGE P.1,2,41Exercise 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, Porto Alegre, BRAZILAddress for correspondence: Jorge P. Ribeiro, M.D., ScD, Associate Professor and Chief on Noninvasive Cardiology, Hospital de Cli`nicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90035-007, Porto Alegre, RS, Brazil; E-mail: .Submitted for publication July 2007.Accepted for publication August 2007.ABSTRACTPurpose: 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 ± 22 units, patients: 8 ± 31 units, P < 0.05).Conclusion: Patients with chronic obstructive pulmonary disease have a reduced calf vascular resistance response to handgrip exercise and to selective activation of muscle metaboreflex when compared with healthy subjects.It is well recognized that cardiovascular adjustments to static exercise are partially mediated by activation of mechanosensitive and metabosensitive afferents within the active skeletal muscle. Specifically, stimulation of metabosensitive afferents by products of muscle contraction evokes a powerful increase in sympathetic nervous system activity and a consequent pressor response known as the muscle metaboreflex (27). It is postulated that the primary function of this reflex is to correct a mismatch between blood flow and metabolism in ischemic exercising muscle (27).Static handgrip exercise has been shown to elicit a decrease in calf muscle vascular conductance (31), and selective activation of muscle metaboreflex in humans can be achieved by postexercise circulatory occlusion (PECO+). In this technique, interruption of perfusion immediately before the termination of exercise is thought to trap metabolites within the formerly active muscle, thus stimulating chemosensitive fibers (12). Although the specific chemical products that activate these metabosensitive afferents remain controversial, considerable evidence supports the notion that muscle acidosis is strictly linked to sympathetic vasoconstriction and blood pressure (BP) responses during PECO+ (31).In patients with chronic obstructive pulmonary disease (COPD), skeletal muscle dysfunction and its contribution to the pathophysiology of exercise intolerance is a matter of extensive investigation (3). Several studies have shown that patients with COPD have lower percentages of type I muscle fibers, lower levels of intracellular ATP and phosphocreatine, and reduced activity of oxidative enzymes (1,16). The latter may occur in the absence of altered physical activity patterns, as shown by animal experiments (21). During exercise, some studies also have shown that these patients develop faster and greater muscular lactic acidosis (19,20). At present, however, no evidence exists concerning the activity of muscle metaboreflex in patients with COPD. Accordingly, the purpose of the present study was to test the hypothesis that patients with COPD have abnormal reflex responses to stimulation of metabosensitive afferents in skeletal muscle when compared with healthy-matched subjects. To accomplish this goal, we evaluated BP, heart rate, and resting limb hemodynamic responses to static exercise followed by PECO+ in patients with COPD and healthy controls.METHODSSubjects.Sixteen patients (11 men) with moderate to severe COPD (Global Initiative for Chronic Obstructive Lung Disease classes II-IV) (25) participated in the study. COPD diagnosis was based on a previous smoking history and pulmonary function testing showing irreversible airflow obstruction (postbronchodilatator FEV1 < 80% and FEV1/FVC < 70% of predicted). Exclusion criteria were exacerbation or infection in the past 4 wk; severe or unstable cardiac disease revealed by medical history, physical examination, and resting, as well as exercise electrocardiogram; and locomotor or neurological disease, diabetes mellitus, or uncontrolled hypertension. The control group consisted of 13 (8 men) healthy, age-matched subjects, who also participated in a previously reported study (26). The research protocol was approved by the institutional ethics committee, and signed informed consent was obtained from each individual.Protocol.Subjects came to the laboratory for two visits. On day 1, after individuals had spent 20 min of quiet rest in the supine position, venous blood samples were drawn for plasma norepinephrine determination by high-pressure liquid chromatography and electrochemical detection. In addition,arterial blood was drawn from the radial artery for blood gas analysis (Rapidlab 865, Chiron Diagnostics, East Walpole, MA). Later, pulmonary function tests and symptom-limited cardiopulmonary exercise tests were performed. In the second visit, at least 72 h after the tests, subjects performed the protocol for the evaluation of muscle metaboreflex activity. On both days, patients with COPD were asked to withdraw from inhaled short-acting β2-agonists and short-acting anticholinergic agents for 8 h, as well as long-acting β2-agonists and theophylline for 12 h.Pulmonary function and cardiopulmonary exercise tests.Measurements of forced vital capacity and forced expiratory volume in 1 s were obtained with a computerized spirometer (Eric Jaeger, GmbH, Wüerzburg, Germany), as recommended by the American Thoracic Society (2), and results were expressed as percent predicted (17). A symptom-limited incremental exercise test was performed on an electrically braked cycle ergometer (ER-900, Ergoline, Jaeger, Wüerzburg, Germany), with minute increments of 5-10 W for COPD patients and 10-15 W for healthy controls. During the test, gas exchange was measured breath-by-breath by a previously validated system (Metalyzer 3B, CPX System, Cortex, Leipzig, Germany) (22). Heart rate (HR) was determined from a 12-lead electrocardiogram. Salbutamol (spray, 400 μg) was inhaled 20 min before the tests in patients with COPD.Muscle metaboreflex.Muscle metaboreflex was evaluated as described elsewhere (26). In short, after 15 min of rest, baseline data for HR, BP, and calf blood flow (CBF) were collected for 3 min. Static handgrip exercise was then performed with the dominant arm, at an intensity of 30% of maximal voluntary contraction, for 3 min. During the last 15 s of exercise, a pneumatic cuff on the upper arm was inflated to suprasystolic pressure for 3 min (PECO+). In addition, in a crossover design, subjects performed the same protocol without circulatory occlusion (PECO−).During the protocol, HR was monitored by lead II of the electrocardiogram, and BP was measured, using a standard auscultatory technique, by the same observer. Mean BP (MBP) was calculated as diastolic + 1/3 (systolic − diastolic). CBF was measured by venous occlusion plethysmography (Hokanson, TL-400, Bellevue, WA) (33). The limb was positioned above heart level and was supported in the thigh and ankle to ensure proper venous drainage. A strain gauge was positioned on the right calf at the point of maximum circumference. During the entire protocol, a BP cuff on the thigh was alternately inflated to 60 mm Hg and deflated in 7.5-s cycles. Additionally, another cuff was placed on the ankle and inflated to suprasystolic levels (240 mm Hg) to occlude foot circulation. CBF (mL·min−1·100 mL−1) was determined manually on the basis of a minimum of four separate readings. Reproducibility of CBF measurements in our laboratory present coefficients of variations of 5.7% and 5.9% for short-term (same day) and medium-term (different days) measurements, respectively.Data analysis.Values are reported as means ± SD. Subjects‘ characteristics and baseline data were compared by Student‘s t-test. Hemodynamic responses to exercise and to PECO+/PECO− were compared by analysis of variance for repeated measures and Tukey-Kramer‘s post hoc for pairwise comparisons. Correlations were evaluated with the Pearson correlation coefficient. Significance was accepted when P < 0.05.RESULTSAs shown in Table 1, groups had similar age and body mass index. Patients had severe ventilatory obstruction and mild reduction in resting PaO2 and SaO2, but normal PaCO2. As expected, exercise tolerance was markedly reduced in COPD patients. Baseline MBP, CBF, and calf vascular resistance (CVR) were similar between the two groups. Maximal voluntary contraction (Table 1) and absolute handgrip force were not significantly different in COPD patients and controls. Plasma norepinephrine was significantly higher in COPD patients (414 ± 163 pg·mL−1) when compared with controls (203 ± 101 pg·mL−1; P < 0.05).TABLE 1. Subject characteristics.MBP, HR, CBF, and CVR responses to handgrip exercise, PECO+/PECO−, and recovery are shown in Figure 1. MBP and HR increased significantly during exercise and remained elevated during circulatory occlusion (PECO+) when compared with the control trial (PECO−) (Fig. 1). Changes from baseline for both variables were similar between groups during the entire protocol. CBF did not change significantly from baseline in the two trials in both groups. However, patients with COPD exhibited a distinct response pattern when compared with control subjects. When comparing both groups, CBF was significantly reduced in healthy controls at the end of exercise and during the entire circulatory occlusion period (Fig. 1). CVR increased significantly during exercise only in the control group (Fig. 1). Likewise, during circulatory occlusion (PECO+), CVR remained elevated above baseline in the control group, whereas in the COPD patients changes from rest were not significant in either trial. When comparing the estimated difference in the areas under the curves of CVR between the two trials during PECO+/PECO− periods, patients with COPD had lower changes (8 ± 31 units) compared with healthy subjects (31 ± 22 units; P < 0.05). There was a significant correlation (r = 0.47, P = 0.01) between V˙O2peak and the difference in the area under the curve of CVR.FIGURE 1-Mean blood pressure (MBP), heart rate (HR), calf blood flow (CBF), and calf vascular resistance (CVR) changes from baseline during static handgrip exercise, postexercise circulatory occlusion (PECO+), or control (PECO−) periods, and recovery in healthy subjects (left panels) and in patients with COPD (right panels). * P < 0.05 PECO+ vs PECO−.DISCUSSIONIn the present study, we evaluated the cardiovascular adjustments to static handgrip exercise and selective activation of the muscle metaboreflex through PECO+ in patients with moderate to severe COPD. The major new finding is that patients with COPD present an attenuated 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 (28,31). 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 through microneurography recordings in patients with COPD when compared with healthy subjects was reported (13). In agreement with previous findings (34), our COPD patients had higher basal levels of norepinephrine than did healthy controls, compatible with tonic activation of the sympathetic nervous system. In this setting, it is possible to consider that higher sympathetic activity at rest would limit the incremental response to exercise because of a ceiling effect, thus resulting in a decreased calf vasoconstriction, as seen in the COPD patients. Importantly, however, we did not observe baseline CVR differences between groups, but only a differential CVR response to exercise in the COPD group.The origins of sympathetic activation during exercise are not firmly established, but they likely involve the reflex responses to stimulation of metabosensitive afferents within the skeletal muscle (27). To gain insight into the potential involvement of these chemical-sensitive afferents on the hemodynamic adjustments to exercise in patients with COPD, we performed selective activation of the muscle metaboreflex through PECO+ technique. Of note, we also observed a reduced calf vasoconstriction during PECO+ in the COPD patients when compared with healthy controls. Thus, by inference, it is reasonable to suggest that this impaired sympathetic activation in COPD patients was at least partially mediated by an attenuated muscle metaboreflex control of CVR.Interestingly, despite an evident blunted muscle metaboreflex control of CVR, COPD patients had only modest reductions in the pressor response to PECO+ when compared with healthy subjects. The reasons for this apparent discrepancy are unclear, but several hypotheses can be advanced. Sustained BP elevation during PECO+ is thought to be mediated by sympathetic-induced vasoconstriction in nonactive vascular beds (12) and enhancement in myocardial contractility and cardiac filling (30). Thus, first it is relevant to consider that similar BP responses to circulatory occlusion do not necessarily mean that the mechanisms underlying these responses are the same. In fact, Crisafulli and colleagues (8) have demonstrated that, in contrast to healthy individuals, in which BP elevation during PECO+ is mediated by increases in cardiac output, patients with heart failure rely mainly on increases in systemic vascular resistance to achieve similar BP levels.In our study, patients with COPD had similar BP responses but attenuated CVR responses to PECO+. One possible explanation for these findings is that despite blunted vasoconstriction in resting skeletal muscle, these patients would exhibit augmented sympathetic-mediated vasoconstriction in viscera, such as the splanchnic area and the kidneys. Prior reports in patients with chronic heart failure have demonstrated a similar blunted increase in CVR during handgrip exercise (18) associated with exaggerated renal vasoconstriction (23). Moreover, although controversial, evidence from animal studies suggests that nonuniform changes in sympathetic nerve activity to different regions may exist in certain conditions, such as sustained elevations in BP (6) or nitric oxide synthase inhibition (15). Together, these findings reinforce the notion that a shift in the mechanisms underlying cardiovascular responses to muscle metaboreflex activation may also exist in patients with COPD.Another potential mechanism involved in the blunted CVR responses to exercise and circulatory occlusion in COPD patients is an attenuated vascular responsiveness to sympathetic stimuli. In general, pathophysiological states associated with tonic activation of the sympathetic nervous system and release of norepinephrine produce an agonist-promoted desensitization of α-adrenergic signaling (29), as seen in chronic heart failure (11). In addition, the available evidence clearly demonstrates that chronic hypoxemia, a common condition in COPD, impairs reflex responses to sympathetic activation. Heistad and colleagues (14) first demonstrated that patients with chronic severe hypoxemia had a depressed forearm vasoconstriction response to lower-body negative pressure. Likewise, animal studies have shown that chronic, systemic hypoxemia reduces vascular responsiveness to vasoconstrictor substances and to direct sympathetic stimulation (7).Importantly, patients in the present study experienced only relatively moderate hypoxia at rest (PaO2 = 71.9 mm Hg), and all were normocapnic (PaCO2 = 40 mm Hg)-characteristics that largely differ from those reported in previous studies that have demonstrated a detrimental effect of hypoxemia on vascular responsiveness to sympathetic stimuli (7,10). In contrast to patients with severe hypoxemia, COPD patients with moderate hypoxemia may develop only episodic reductions in arterial oxygenation during the day (5). Thus, it seems reasonable to suggest that the functional vascular adaptations may differ when comparing distinct levels and times of exposure to systemic hypoxia. In this regard, there is evidence derived from animal studies showing that chronic episodic exposures to hypoxia are not sufficient to alter vascular responsiveness to sympathetic agonists (32). On the basis of these findings, it seems unlikely that eventual reduction in vascular adrenergic reactivity may account for the blunted CRV observed during exercise in COPD patients.Sympathetic mediated reduction in resting-limb vascular conductance is important for appropriate cardiac output redistribution during exercise. Thus, the correlation between V˙O2peak and the difference in the area under the curve of CVR suggest that the blunted muscle metaboreflex-mediated vasoconstriction in the resting calf would compromise the distribution of blood flow toward exercising limbs. Conceivably, however, other mechanisms involved in sympathoexcitation during exercise, such as the muscle mechanoreflex and the respiratory muscle metaboreflex, might also be altered in COPD patients. For example, as indicated by Dempsey et al. (9), augmented respiratory muscle work in these patients can potentially exacerbate the respiratory muscle metaboreflex and the consequent "stealing" of blood flow from locomotor muscles. In this scenario, blunted vasoconstriction in inactive areas would also compromise diaphragmatic perfusion, accelerating the occurrence of diaphragm fatigue during exercise. However, the activity of the respiratory muscle metaboreflex remains to be characterized in this population.The major limitation of the present study is that we did not measure muscle sympathetic nerve activity (MSNA) or blood catecholamine responses in our subjects during the protocol. It has been suggested that MSNA responses to PECO+ provide the major assessment for the muscle metaboreflex in humans (24). Accordingly, MSNA measurement could have helped us to explain the mechanisms underlying blunted CVR responses to circulatory occlusion in patients with COPD. Importantly, however, it is well known that CVR responses to static handgrip and PECO+ closely mimic MSNA responses (28).In conclusion, this study demonstrates that patients with COPD have a reduced calf CVR response to handgrip exercise and to selective activation of muscle metaboreflex, despite a preserved pressor response. 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Link]|00005768-200801000-00003#xpointer(id(R30-3))|11065405||ovftdb|SL000004611998275h76711065405P80[Medline Link]|00005768-200801000-00003#xpointer(id(R32-3))|11065405||ovftdb|SL00004560200190200711065405P82[Medline Link]|00005768-200801000-00003#xpointer(id(R33-3))|11065213||ovftdb|SL00003111200510815111065213P83[CrossRef]|00005768-200801000-00003#xpointer(id(R33-3))|11065405||ovftdb|SL00003111200510815111065405P83[Medline Link]|00005768-200801000-00003#xpointer(id(R34-3))|11065213||ovftdb|SL00007087200599155511065213P84[CrossRef]|00005768-200801000-00003#xpointer(id(R34-3))|11065405||ovftdb|SL00007087200599155511065405P84[Medline Link]15890510Attenuation of Muscle Metaboreflex in Chronic Obstructive Pulmonary DiseaseROSEGUINI, BRUNO T.; ALVES, CRISTIANO N.; CHIAPPA, GASPAR R.; STEIN, RICARDO; KNORST, MARLI M.; RIBEIRO, JORGE P.CLINICAL SCIENCES: Clinical Investigations140