Exercise testing does not have to be complicated.
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Exercise Test↗
Biomedical subjects
C B Cooper
Publications and source records attributed to C B Cooper.
Recent developments in inhaled therapy in stable chronic obstructive pulmonary disease.
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Administration, Inhalation↗
On issues of confidence in determining the time constant for oxygen uptake kinetics.
BACKGROUND: TauVO(2 )at the onset of constant work rate (CWR) exercise is a variable of aerobic fitness that shortens with physical training and lengthens with cardiopulmonary disease. Determination of tauVO(2) with sufficiently high confidence has typically required multiple exercise transitions limiting its clinical application. OBJECTIVES: To design a protocol to determine tauVO(2) reliably but simply. METHODS: On each of three days, five healthy men performed two CWR tests on a cycle ergometer below the metabolic threshold (VO(2)theta) for blood lactate accumulation as determined by gas exchange measurements followed by an incremental work rate (IWR) test. TauVO(2) was determined (a) from the on-transit (on-tauVO(2)) and off-transit (off-tauVO(2)) of six CWR tests both individually and superimposed, using non-linear regression with a monoexponential model, and (b) by geometric analysis of the IWR tests (ramp-tauVO(2)). RESULTS: Group means (SD) were: VO(2)max 3.84 (0.44) litres/min, VO(2)theta 1.88 (0.23) litres/min, steady state exercise VO(2) 1.67 (0.07) litres/min, on-tauVO(2) 38.0 (5.3) seconds, off-tauVO(2) 39.0 (4.3) seconds, and ramp-tauVO(2) 60.8 (15.4) seconds. On-tauVO(2) correlated with off-tauVO(2) (r = 0.87), VO(2)max (r = -0.73), and VO(2)theta (r = 0.89). The pooled mean tauVO(2) from six superimposed tests agreed with the arithmetic grand mean of the six tests. CONCLUSIONS: The average of on-tauVO(2) and off-tauVO(2) fell within the 95% confidence interval of the pooled mean by the second test. Ramp-tauVO(2) was longer and less reproducible. These findings support the use of both on- and off-transit data for the determination of tauVO(2), an approach that reduces the number of transitions necessary for accurate determination of tauVO(2), potentially enhancing its clinical application.
Adult↗
alpha(4)-integrin mediates neutrophil-induced free radical injury to cardiac myocytes.
Previous work has demonstrated that circulating neutrophils (polymorphonuclear leukocytes [PMNs]) adhere to cardiac myocytes via beta(2)-integrins and cause cellular injury via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme system. Since PMNs induced to leave the vasculature (emigrated PMNs) express the alpha(4)-integrin, we asked whether (a) these PMNs also induce myocyte injury via NADPH oxidase; (b) beta(2)-integrins (CD18) still signal oxidant production, or if this process is now coupled to the alpha(4)-integrin; and (c) dysfunction is superoxide dependent within the myocyte or at the myocyte-PMN interface. Emigrated PMNs exposed to cardiac myocytes quickly induced significant changes in myocyte function. Myocyte shortening was decreased by 30-50% and rates of contraction and relaxation were reduced by 30% within the first 10 min. Both alpha(4)-integrin antibody (Ab)-treated PMNs and NADPH oxidase-deficient PMNs were unable to reduce myocyte shortening. An increased level of oxidative stress was detected in myocytes within 5 min of PMN adhesion. Addition of an anti-alpha(4)-integrin Ab, but not an anti-CD18 Ab, prevented oxidant production, suggesting that in emigrated PMNs the NADPH oxidase system is uncoupled from CD18 and can be activated via the alpha(4)-integrin. Addition of exogenous superoxide dismutase (SOD) inhibited all parameters of dysfunction measured, whereas overexpression of intracellular SOD within the myocytes did not inhibit the oxidative stress or the myocyte dysfunction caused by the emigrated PMNs. These findings demonstrate that profound molecular changes occur within PMNs as they emigrate, such that CD18 and associated intracellular signaling pathways leading to oxidant production are uncoupled and newly expressed alpha(4)-integrin functions as the ligand that signals oxidant production. The results also provide pathological relevance as the emigrated PMNs have the capacity to injure cardiac myocytes through the alpha(4)-integrin-coupled NADPH oxidase pathway that can be inhibited by extracellular, but not intracellular SOD.
Animals↗
Exercise in chronic pulmonary disease: limitations and rehabilitation.
Chronic pulmonary disease is common in the community and increasing in prevalence. Although numerous etiologies exist, chronic obstructive pulmonary disease secondary to tobacco smoking, and asthma constitute the majority of cases. The important impact of these diseases on patients is disabling breathlessness and impairment of functional exercise capacity. The symptoms set up a vicious cycle leading to physical deconditioning and worsening exercise performance. The discipline of pulmonary rehabilitation has been conclusively shown to reverse this process, resulting in improved functional capacity and reduced breathlessness. Pulmonary rehabilitation, therefore, should be viewed as essential secondary preventative care for the majority of patients with chronic pulmonary disease. As such, early disease recognition and implementation of exercise reconditioning is important. In order to be maximally effective, pulmonary rehabilitation must recognize the complex underlying pathophysiology in chronic pulmonary disease and be customized to the individual patient. The chosen mode of exercise training should recognize that in order to be truly beneficial, any physiological responses need to translate readily into improvements in activities of daily living. Therefore, sessions in pulmonary rehabilitation should concentrate on exercises that have proven useful in this regard. Aerobic and resistance exercise prescriptions should be rigorous, scientifically based, and derived from an understanding of the basic principles of the human response to exercise prescription. Each of these exercise prescriptions should encompass the basic principles of intensity, frequency, duration, and progression suitably modified for the individual patient with chronic pulmonary disease.
Exercise Therapy↗
Exercise in chronic pulmonary disease: aerobic exercise prescription.
Endurance exercise training (EXT) is singly the most important aspect of rehabilitation for patients with chronic pulmonary disease. When effective, this modality of physical reconditioning leads to improved functional exercise capacity and reduced breathlessness. Early implementation is desirable to obtain more meaningful responses (e.g., when FEV1 falls below 50% of the predicted value in patients with chronic obstructive disease). Preparation for effective EXT requires optimization of respiratory system mechanics (e.g., using bronchodilator therapy), prevention of gas exchange failure (i.e., using supplemental oxygen), nutritional guidance, and psychological support (e.g., to overcome stigmata of disability, fear, and inclination to panic). EXT should be applied using a rigorous, scientifically based aerobic exercise prescription (AXRx) that recognizes basic principles of the human response to exercise prescription while considering individual pathophysiological limitations and identifying safety thresholds for exercise participation. The mode of aerobic exercise should use large muscle groups of the legs (e.g., treadmill or cycle ergometer). The recommended duration is an accumulation of 30 min of exercise per session at the target intensity, achieved by continuous or interval training. EXT should be supervised with a recommended frequency of at least three times per week for 6--8 wk. Target exercise intensity can be monitored by oxygen uptake, work rate, heart rate, or perceived exertion. Target intensity can be determined initially on the basis of 40% of a reference value for maximum oxygen uptake and linked to other variables through predictable interrelationships. All aspects of the AXRx must be reviewed with regard to progression during training. Pulmonary rehabilitation must recognize the importance of achieving clinically meaningful responses (e.g., increased 6-min walking distance of 54 m) as well as the need for maintenance exercise program to sustain the benefits.
Exercise↗
Cross-talk between G-protein and protein kinase C modulation of N-type calcium channels is dependent on the G-protein beta subunit isoform.
The modulation of N-type calcium current by protein kinases and G-proteins is a factor in the fine tuning of neurotransmitter release. We have previously shown that phosphorylation of threonine 422 in the alpha(1B) calcium channel domain I-II linker region resulted in a dramatic reduction in somatostatin receptor-mediated G-protein inhibition of the channels and that the I-II linker consequently serves as an integration center for cross-talk between protein kinase C (PKC) and G-proteins (Hamid, J., Nelson, D., Spaetgens, R., Dubel, S. J., Snutch, T. P., and Zamponi, G. W. (1999) J. Biol. Chem. 274, 6195-6202). Here we show that opioid receptor-mediated inhibition of N-type channels is affected to a lesser extent compared with that seen with somatostatin receptors, hinting at the possibility that PKC/G-protein cross-talk might be dependent on the G-protein subtype. To address this issue, we have examined the effects of four different types of G-protein beta subunits on both wild type and mutant alpha(1B) calcium channels in which residue 422 has been replaced by glutamate to mimic PKC-dependent phosphorylation and on channels that have been directly phosphorylated by protein kinase C. Our data show that phosphorylation or mutation of residue 422 antagonizes the effect of Gbeta(1) on channel activity, whereas Gbeta(2), Gbeta(3), and Gbeta(4) are not affected. Our data therefore suggest that the observed cross-talk between G-proteins and protein kinase C modulation of N-type channels is a selective feature of the Gbeta(1) subunit.
Calcium Channels, N-Type↗
Minimal domain requirement for cation transport by the potassium-dependent Na/Ca-K exchanger. Comparison with an NCKX paralog from Caenorhabditis elegans.
The retinal rod Na/Ca-K exchanger (NCKX) is a unique calcium extrusion protein utilizing both inward sodium gradient and outward potassium gradient. Three mammalian rod NCKX cDNAs have been cloned to date, but quantitative analysis of NCKX function in heterologous systems has proven difficult. Here, we describe a simple system for quantitative analysis of NCKX function; stable transformation of cultured insect cells with the novel pEA1/153A vector containing NCKX cDNAs was combined with measurements of potassium-dependent (45)Ca uptake in sodium-loaded cells. We carried out structure-function studies on NCKX with the following results: 1) two-thirds of the full-length sequence of bovine NCKX could be deleted without affecting potassium-dependent calcium transport and without affecting key properties of the potassium binding site; 2) the affinity of NCKX for potassium was about 10-fold greater in choline medium when compared with lithium medium; this shift was observed in rod outer segments or in cells expressing full-length rod NCKX, the above deletion mutant, or a distantly related NCKX paralog cloned from Caenorhabditis elegans. We conclude that the potassium binding site is highly conserved among members of the NCKX family and is formed by residues located within the two sets of transmembrane spanning segments in the NCKX sequence.
Amino Acid Sequence↗
Spectrofluorometric detection of Na+/Ca(2+)-K+ exchange.
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Aniline Compounds↗
cDNA cloning and functional expression of the dolphin retinal rod Na-Ca+K exchanger NCKX1: comparison with the functionally silent bovine NCKX1.
cDNAs of human and bovine retinal rod Na+-Ca2++K+ exchanger (NCKX1) have previously been cloned, but potassium-dependent Na-Ca exchange activity upon heterologous expression has not been demonstrated. We have cloned NCKX1 cDNA from dolphin, examined function upon transfection in HEK293 cells, and compared the dolphin sequence encoded by the cDNA with those of human and bovine. The dolphin NCKX1 cDNA encodes 1013 amino acid residues. Comparison to bovine and human NCKX1 revealed strong conservation in the transmembrane domains (>95%), but relatively low conservation in the large extracellular ( approximately 50%) and cytosolic (<50%) domains. The dolphin cytosolic domain differs from the bovine sequence by the absence of a stretch of 114 amino acids. HEK293 cells transfected with dolphin NCKX1 cDNA showed K+-dependent Na-Ca exchange in >95% of the experiments, whereas transfection with bovine NCKX1 yielded no function. The bovine NCKX1 phenotype was imparted on dolphin NCKX1 when the dolphin cytosolic loop was replaced by that from bovine. Conversely, deletion of 114 amino acids from the bovine sequence to match the dolphin sequence resulted in a mutant bovine NCKX1 which performed K+-dependent Na-Ca exchange. These results suggest that domains within the large cytosolic loop of NCKX1 control functional activity when expressed in heterologous systems.
Amino Acid Sequence↗
Treadmill exercise duration and dyspnea recovery time in chronic obstructive pulmonary disease: effects of oxygen breathing and repeated testing.
Oxygen supplementation is known to improve exercise capacity in patients with chronic obstructive pulmonary disease (COPD). Although some COPD patients use oxygen after exercise to relieve dyspnea, the effect of oxygen during recovery from exercise is not clearly understood. Exercise duration and dyspnea recovery time were studied in 18 patients with stable COPD. Patients exercised at a constant submaximal work rate on a treadmill ergometer until they no longer wished to continue. Oxygen, room air and compressed air were randomly administered in three consecutive post-exercise recovery periods. Dyspnea was scored on a 100 mm visual analog scale at 30 s intervals until return to baseline. An additional 20 minute post-recovery resting period was allowed between each test. No significant differences were found in dyspnea recovery time breathing oxygen (271 s), room air (290 s) or compressed air (311 s) When the groups were sorted by sequence of testing, there was a highly significant increase in recovery time (208 s, 307 s and 358 s for the first, second and third tests; P < 0.005) and a non-statistically significant decrease in exercise duration (89 s, 79 s and 76 s). Post-exercise oxygen supplementation had no effect on dyspnea recovery time in these COPD patients. Repeated bouts of exercise increased dyspnea recovery time and tended to decrease exercise duration. These findings suggest that, despite recovery of symptoms, physiological recovery from prior exercise is incomplete.
Aged↗
Exercise and interstitial lung disease.
Interstitial lung disease (ILD) limits exercise capacity through a variety of complex and intriguing mechanisms, including ventilatory limitation, diffusion impairment, and ventilation-perfusion derangement. Resting pulmonary function testing seldom explains the symptoms nor defines the specific pathophysiology of the individual patient. Cardiopulmonary exercise testing can elucidate the relative contributions of these mechanisms and guide therapy. A fundamental problem in ILD is one of inadequate time for lung inflation during intense exercise, resulting in dynamic hypoinflation relative to the ventilatory demand. Pulmonary rehabilitation is underused in ILD. Functional CT imaging may provide insight into the relationship between structural and physiologic abnormalities of regional pulmonary function. Recent advances in nitric oxide research will perhaps further our understanding of the basic pathophysiology of ILD and provide specific treatment for the associated pulmonary vascular disease.
Bronchodilator Agents↗
cDNA cloning of the human retinal rod Na-Ca + K exchanger: comparison with a revised bovine sequence.
PURPOSE: To clone the complementary DNA of the human retinal rod Na-Ca + K exchanger. METHODS: A human retinal cDNA library was screened initially with a radiolabeled probe representing the entire bovine rod Na-Ca + K exchanger cDNA and subsequently with probes from polymerase chain reaction fragments of the human retinal rod Na-Ca + K exchanger obtained after the initial screen. Twelve positive clones were used to obtain the entire coding sequence of the human retinal rod Na-Ca + K exchanger. RESULTS: The cDNA of the human retinal rod Na-Ca + K exchanger codes for a protein of 1081 amino acids, which shows 64.3% overall identity with the bovine retinal rod Na-Ca + K exchanger at the amino acid level. The two sets of putative transmembrane-spanning domains and their short connecting loops showed the highest degree of identity (94%-95%), whereas the extracellular loop at the N terminus showed a 59% identity. The large cytosolic loop that bisects the two sets of transmembrane-spanning domains contained two large deletions in the human exchanger; the first deletion contains 18 amino acids, whereas the second deletion involves a series of repeats that are dominated by acidic amino acid residues observed in the bovine, but not in the human, sequence. The authors observed that the bovine sequence contains a ninth repeat in addition to the eight repeats of the published sequence. CONCLUSIONS: The authors cloned the cDNA of the human retinal rod Na-Ca + K exchanger as a first step in examining the possibility that this gene could be the locus of disease-causing mutations.
Amino Acid Sequence↗
Physiologic benefits of exercise training in rehabilitation of patients with severe chronic obstructive pulmonary disease.
We determined the effect on exercise tolerance and physiological exercise responses of rigorous rehabilitative exercise training in chronic obstructive pulmonary disease (COPD). Fifteen men and 10 women (mean age, 68 +/- 6 yr; FEV1, 0.93 +/- 0.27 L) participated in a rehabilitation program with an exercise component of three per week 45-min sessions of cycle ergometer training for 6 wk with exercise intensity kept near maximal targets. Before and after rehabilitation, patients performed an incremental test and a constant work rate (CWR) test at 80% of the peak work rate in the preprogram incremental test. Ventilation (V(E)) and gas exchange were measured breath by breath; arterialized venous blood was analyzed for blood gas determinations and lactate. Rehabilitation yielded an average increase in peak work rate in the incremental test of 36% (p < 0.001), and in the duration of the CWR test of 77% (p < 0.001). In the CWR test, the kinetics of O2 uptake, CO2 output, V(E), and heart rate were markedly slower than those of healthy subjects. After training, mean response time decrease averaged 17, 22, 34, and 29%, respectively (p < 0.02), evidence of a physiologic training effect. Further, for identical CWR tasks, V(E) was 10% lower (p < 0.02) after training, attributable to altered breathing pattern: tidal volume increased by 8% and respiratory rate decreased by 19%, yielding lower V(D) /V(T) (0.46 versus 0.53 p < 0.005). Rigorous exercise training for patients with severe COPD yields more efficient exercise breathing pattern and lower V(E); this is associated with improved exercise tolerance.
Aged↗
Impact of habitual cocaine smoking on the physiologic response to maximum exercise.
BACKGROUND: Habitual smoking of alkaloidal cocaine (crack) has been reported to be associated with a number of cardiopulmonary complications that may not be clinically obvious but could potentially interfere with normal physiologic responses to exercise and thus impair maximum exercise performance. STUDY OBJECTIVE: To evaluate the impact of regular use of cocaine on maximum exercise. DESIGN: Observational study in crack users and age- and gender-matched control subjects. SUBJECTS: Thirty-five habitual cocaine smokers (21 male and 14 female) and 29 age-matched sedentary control nonsmokers of cocaine (15 male and 14 female), all of whom were in good general health. METHODS: In these subjects, we compared physiologic responses to symptom-limited, incremental maximal exercise performed on a cycle ergometer using a ramp protocol. Comparisons were made for men and women separately. RESULTS: For both men and women, long-term cocaine smokers had a reduced aerobic capacity (maximum oxygen consumption) compared with control nonsmokers but did not show evidence of ventilatory limitation, reduced gas exchange threshold, increased physiologic dead space, or gas exchange abnormality at maximum exercise compared with the healthy control subjects. Although cocaine smokers had reduced maximum heart rates compared with control subjects, the relationship between submaximal heart rate and oxygen uptake was normal, indicating a normal cardiovascular response pattern. However, effort perception was similar between the two groups despite the difference in heart rate at maximum exercise, suggesting the possibility of perceptual dysfunction for effort. Differences in aerobic capacity between the crack users and nonusers could not be explained by differences in physical fitness or altered perception of dyspnea. CONCLUSION: In the subjects we studied, long-term cocaine smoking was associated with reduced maximum exercise performance, probably due to poor motivation or altered effort perception. No other identifiable physiologic abnormality appeared to limit exercise in the habitual crack users.
Adult↗
Muscle substrate utilization from alveolar gas exchange in trained cyclists.
The respiratory exchange ratio (R) during steady-state exercise is equivalent to whole-body respiratory quotient (RQ), but does not represent muscle metabolism alone. If steady-state values of carbon dioxide production (VCO2) and oxygen uptake (VO2) are plotted for different work rates, the slope of the line fitting these points should estimate muscle RQ. Twelve cyclists randomly performed five 8-min, constant work rate tests of 40, 80, 120, 160 and 200 W. Whole-body R, averaged over the final 2 min of each exercise bout, increased with increasing work rate. When VCO2 was plotted as a function of VO2, the regression lines through the five points displayed excellent linearity, had negative y-intercepts, and a slope of 0.915 (0.043) [mean (SD)], which was greater than the whole-body R at any individual work rate [range 0.793 (0.027) at 40 W to 0.875 (0.037) at 200 W]. This slope was comparable to the lower slope of the VCO2 versus VO2 plot of an increasing work rate (ramp) protocol [0.908 (0.054)]. We conclude that, during mild and moderate exercise of relatively short duration, contracting muscle has a high and constant RQ, indicating that carbohydrate is the predominant metabolic substrate. Whole-body R does not accurately reflect muscle substrate utilization and probably underestimates muscle RQ at a given work rate.
Adult↗
Determining the role of exercise in patients with chronic pulmonary disease.
Chronic pulmonary diseases are common in the community and their pathophysiology is complex. The principal symptoms are dyspnea and limited exercise capacity. Some, but not all, patients have true ventilatory limitation where the maximal exercise ventilation (VEmax) equals the measured maximal ventilatory volume (MVV). Those with obstructive disease have impeded expiration requiring an obligatory expiratory time for adequate lung emptying (i.e., a timing constraint). In these patients, increased breathing frequency during exercise tends to lead to hyperinflation and smaller tidal volumes, circumstances that predictably worsen breathing efficiency (i.e., result in high VD/VT). Those with restrictive disease characteristically have limited inspiratory capacity but unimpeded or even accelerated expiration (i.e. tidal volume constraint). These patients characteristically exhibit rapid respiratory rates (e.g., > 50.min-1) at end exercise.
Chronic Disease↗