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The autonomic nervous system may be disturbed in chronic respiratory failure. We tested the hypothesis that there is increased sympathetic activity in patients with chronic hypoxemia. Furthermore, we examined the effect of short-term oxygen on muscle sympathetic nerve activity (MSNA) in these patients. We performed microneurography of the peroneal nerve in 11 patients with hypoxemia due to chronic obstructive pulmonary disease (COPD, n = 6) or lung fibrosis (n = 5) and in 11 healthy subjects matched for age and sex. MSNA was measured during normal breathing in all subjects. In eight patients and in seven control subjects, MSNA was also measured during nasal oxygen (4 L/min). MSNA was higher in the patients with chronic respiratory failure compared with the healthy subjects during normal breathing (61 ± 5 versus 34 ± 2 bursts/min, mean ± SEM; p = 0.0002, paired t test). During oxygen administration, MSNA decreased from 63 ± 6 to 56 ± 6 bursts/min in the patients (p = 0.0004, ANOVA); there was no change in sympathetic activity in the control subjects. For the first time, there is direct evidence of marked sympathetic activation in patients with chronic respiratory failure. This is partly explained by arterial chemoreflex activation and may play an important role in the pathogenesis of the disease.
Keywords: autonomic nervous system; respiration failure; microneurography; oxygen
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Patients with chronic respiratory failure suffer from dyspnea and reduced exercise capacity and show a high mortality rate. Chronic hypoxemia may result in sympathetic activation, but the role of the autonomic nervous system in the pathophysiology of chronic respiratory failure has not been well understood.
Acute hypoxemia is known to increase muscle sympathetic nerve activity (MSNA) by stimulation of arterial chemoreceptors in healthy humans (1, 2). The sympathetic activation evoked by short-term exposure to combined hypoxia and hypercapnia has been shown to persist after return to room air breathing (3).
To our knowledge, the effect of chronic hypoxemia on MSNA in men has not yet been determined and is difficult to predict as chemoreflex sensitivity may change over time. Yet, spectral analyses of heart rate variability suggest autonomic nervous system dysfunction in patients with chronic obstructive pulmonary disease (COPD) (4) as well as in patients with nocturnal hypoventilation due to extrapulmonary restrictive disease (7).
At the moment, long-term oxygen treatment is the only therapeutic option able to improve prognosis in hypoxemic COPD although the mechanism of this effect remains unclear (8, 9). Breathing 100% oxygen has no consistent effect on MSNA in healthy subjects (10). There are no microneurographic recordings of sympathetic activity during oxygen treatment in patients with chronic respiratory failure, and spectral analyses of heart rate variability have shown conflicting results on this question (5, 13).
Our objective was to test the hypothesis that patients with chronic hypoxemia due to COPD or to lung fibrosis show higher MSNA than healthy subjects matched for age and sex. Furthermore, we investigated the effect of short-term nasal oxygen on MSNA in patients with chronic hypoxemia and in healthy subjects.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Subjects
Patients with chronic respiratory failure as well as healthy control subjects of both sexes aged from 19 to 75 yr were included in our study.
Patients with clinically stable lung fibrosis or COPD were eligible if
they showed hypoxemia (PO2 
60 mm Hg) in at least two arterial
blood samples taken within 1 wk prior to the study. General exclusion
criteria were long-term oxygen treatment, chronic heart failure (CHF),
myocardial infarction, or pulmonary edema within 6 mo of entry, renal
or liver disease, or a history of obstructive sleep apnea. We also studied an equal number of healthy control subjects matched for age and
sex. The patients and control subjects were asked to climb 10 stairs and
score the intensity of breathlessness on the modified Borg Scale (14). The study was approved by the local ethics commitee. Informed written consent was obtained from all patients and control subjects.
Measurement of MSNA and Plasma Catecholamines
Sympathetic activity was measured using microneurographic recordings of efferent muscle sympathetic nerve activity (MSNA) in the peroneal nerve as described previously (15). Identification of bursts and measurements were made by a single observer (S.H.) blinded to subject and intervention. Intraobserver variation in identifying bursts was 5% and interobserver variation was 11% when the procedure was repeated by the same or a second investigator (M.L.) on the baseline values. After insertion of an intravenous catheter in an antecubital vein, venous blood samples for catecholamine analysis (16) were obtained without applying a tourniquet after at least 30 min rest.
Monitoring of Respiration and Blood Gases
We registrated respiratory rate and tidal volume by respiratory inductive plethysmography (Respitrace Systems; Ambulatory Monitoring Inc., New York, NY) calibrated in a supine and in a standing position using the least-squares method (17). The transcutaneous O2 and CO2 monitoring system (TINA; Radiometer, Copenhagen, Denmark) was calibrated. Recording began after waiting at least 15 min, until the recording was stable (18) and an arterial blood sample had been taken for in vivo calibration (ABL 3; Radiometer).
Protocol
After a satisfactory nerve signal had been obtained, the protocol started with a 20-min recording period while the patients and control subjects were breathing room air (baseline). Afterward, oxygen 4 L/ min was applied via nasal prongs for 20 min, followed by a 20-min recovery period of room air breathing.
Data Analysis
Data were analyzed and averaged over the last 5 min of each period. All data in the text and tables are given as mean ± standard error of the mean (SEM). We used the two-way repeated measure analysis of variance (ANOVA) with time as within factor to analyze the simple effects of oxygen. When ANOVA revealed significance, we performed the paired Student's t test and the Bonferroni procedure. Significance was accepted at a value of p < 0.05.
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Patients' Characteristics
Eleven patients and 11 healthy subjects were included in the
study. The patients were 62 ± 3 yr old, the body mass index
was 27 ± 2 (kg/m2), the FEV1/vital capacity (VC) was 64 ± 6%. Four patients/control subjects were women. Five patients
had lung fibrosis and six suffered from chronic obstructive
pulmonary disease. On echocardiography, right ventricular diameter was 30 mm in all patients and mean left ventricular
end-diastolic diameter was 44 ± 4 mm. Medications consisted
of systemic prednisolone (mean dose 45 ± 12 mg) in six patients (four patients with lung fibrosis and two patients with COPD), a diuretic in six patients and oral theophylline in four patients with COPD, and inhaled 
2-sympathomimetics in
three patients and systemic 2-sympathomimetics in two patients with COPD.
Comparison of Pulmonary Function Data in the Patients and Control Subjects
The dyspnea level assessed by the modified Borg Scale was higher in the patient group (median 8.0, 10th percentile 5.6, 90th percentile 10.0) compared with the control group (median 2.0, 10th percentile 1.0, 90th percentile 3.0; p < 0.0001, Mann-Whitney test). Both patients with lung fibrosis and COPD showed a lower arterial PO2 and a lower transcutaneous oxygen saturation compared with the corresponding control subjects, but did not differ in the arterial PCO2 and in minute ventilation.
Comparison of Sympathetic Activity in the Patients and Control Subjects
Baseline values of heart rate and MSNA expressed as bursts per minute were higher in the patient group compared with the control group (61 ± 5 versus 34 ± 2 bursts/min, p = 0.0002, paired t test). MSNA was also higher in the patients when expressed as bursts per 100 heart beats (71 ± 5 versus 54 ± 4, p = 0.02). In both subgroups, that is in the five patients with lung fibrosis and in the six patients with COPD, MSNA expressed as bursts per minute was significantly higher compared with the corresponding control subjects.
There was no difference in plasma epinephrine (27 ± 3 versus 34 ± 2 ng/L) and plasma norepinephrine (436 ± 36 versus 498 ± 54 ng/L) in the control subjects and the patients. The two groups did not differ in systolic, diastolic, or mean arterial blood pressure either. There was no significant correlation between MSNA expressed as bursts per minute and the body mass index, the dyspnea level, PO2, PCO2, oxygen saturation (Figure 1), lung function data, or any of the above mentioned drugs.
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Effect of Oxygen on MSNA and Ventilation
Oxygen 4 L/min was administered to seven control subjects and to eight patients (five patients with lung fibrosis and three patients with COPD). Oxygen increased oxygen saturation and the PO2 in both groups, whereas the PCO2 did not change. In the patients, MSNA decreased while on oxygen and returned to baseline values after cessation of oxygen breathing (p = 0.0004 for MSNA expressed as bursts per minute, p = 0.02 for MSNA expressed as bursts per 100 heart beats and as percentage of the baseline total activity (ANOVA)) (Table 1 and Figure 2). In the control group, MSNA did not change during oxygen administration. There was a decrease in heart rate during oxygen breathing and a return to baseline values during the recovery period in both groups (Table 1).
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DISCUSSION |
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For the first time there is direct evidence of markedly increased sympathetic activity in patients with chronic lung disease compared with age- and sex-matched healthy control subjects. Our results extend recently performed spectral analyses of heart rate variability, which suggest the presence of autonomic nervous system dysfunction with an increased vagal tone at rest and a depressed responsiveness to sympathetic and vagal stimulation in patients with COPD with mild evidence of hypoxemia (4).
Chemoreflex Activation of Sympathetic Tone
The most plausible explanation for the high levels of MSNA in patients with chronic lung disease is a chemoreflex activation of sympathetic outflow. As all our patients showed chronic hypoxemia but only two of them were hypercapnic (PCO2 > 45 mm Hg), the underlying mechanism of the observed increase in MSNA would be an activation of the peripheral (arterial) rather than central chemoreceptors.
Elective stimulation of the carotid bodies leads to hyperventilation, bradycardia, and reflex peripheral vasoconstriction. However, in severe and acute systemic hypoxia, bradycardia and vasoconstriction are secondarily modulated by hyperventilation-induced mechanisms or by local vasodilators, consistently resulting in tachycardia and vasodilation (19). However, these findings cannot be transferred to the patients in our study who suffered from chronic and moderate hypoxemia. To our knowledge, the effects of chronic hypoxemia and its correction on the peripheral chemoreceptors have not been examined in patients with lung disease.
Effect of Oxygen on MSNA
Short-term application of nasal oxygen (4 L/min) elicited a
modest decrease in MSNA in our patients with chronic lung
disease but
in accordance with previous studies (11, 12)
not in the healthy control subjects. Sympathetic activity decreased with oxygen in our patients but did not reach the low
levels of MSNA observed in the healthy control subjects. This
suggests either (1) chronic alterations in the effects of chemoreceptor stimulation or (2) other mechanisms than chemoreflex
activation are contributing to sympathetic overactivity in patients with chronic hypoxemia.
Alternative Mechanisms of Increased MSNA in the Patients
Other mechanisms of sympathetic activation are to be considered in patients with chronic hypoxemia. These alternative mechanisms are not exclusive with the chemoreflex mechanism. Ischemic metabolites generated during muscular contraction (e.g., isometric exercise) have been shown to stimulate local receptors and cause increases in heart rate, arterial pressure, and sympathetic activity (20, 21). Therefore, it seems possible that the increased work of breathing in patients with lung disease could lead to sympathetic activation through stimulation of local metaboreceptors. Although we did not measure the work of breathing in our study, it is reasonable to assume that it was increased in the patients as they all suffered from significant restrictive or obstructive pulmonary disease.
Arterial and cardiopulmonary baroreflexes greatly influence sympathetic activity in healthy subjects and are involved in the pathogenesis of CHF, obstructive sleep apnea syndrome (OSAS), and arterial hypertension. Although we cannot think of any plausible mechanism by which baroreflexes increased MSNA in our patients, we cannot entirely rule out the possibility that arterial or cardiopulmonary baroreflexes contribute to the sympathetic overactivity found in chronic hypoxemia.
Lung inflation reflexes mediated by pulmonary vagal afferents may also alter sympathetic activity and have been shown to govern the within-breath modulation of MSNA during normal breathing. The respiratory modulation of MSNA is influenced by the depth and pattern of breathing and by the baseline level of lung inflation in healthy subjects. However, although some forms of altered breathing markedly enhance within-breath modulations of MSNA, they had virtually no effect on total minute MSNA (22). Therefore, we do not believe that the altered breathing pattern (characterized by high respiratory rates and low tidal volumes) observed in the patients of our study contributed to the increased sympathetic activity in chronic respiratory failure. Due to lack of evidence, we can only speculate on possible (sympathoinhibitory) effects of hyperinflation in COPD.
Finally, we have to discuss whether drug effects could have
led to the observed increase in MSNA in our patients. Although the control subjects were not medically treated, the patients with COPD were on potentially sympathoexcitatory
medication (inhaled or systemic 2-sympathomimetics, oral
theophylline, diuretics) until the day before the study was performed (23). For ethical reasons, we did not withhold these
drugs for longer than 12 h in the patients with COPD and
therefore cannot entirely rule out lasting drug action. However, marked sympathetic activation was present not only in
the six patients with COPD, but also in the five patients with
lung fibrosis (compared with their matched control subjects
respectively)none of these five patients being treated with
2-sympathomimetics, methylxanthines, or diuretics. Also,
MSNA was not significantly higher in the patients with COPD compared with the patients with lung fibrosis. Therefore, we
do not believe that the sympathetic activation observed in our
patients results from sympathoexcitatory drug effects.
Possible Consequences of Increased MSNA
Sympathetic activation has been shown to have various deleterious effects in patients with CHF. The decrease in cardiac output due to impaired cardiac function activates the renin- angiotensin as well as the sympathetic nervous system. Although these mechanisms maintain arterial blood pressure, they cause endothelial dysfunction, impaired skeletal muscle performance, and an increase in ventricular afterload in the longer term. In patients with CHF, increased sympathetic activity is related to muscular wasting (26), impaired exercise tolerance, and increased mortality (27).
When considering the various detrimental effects of sympathetic overactivity in patients with CHF, it is reasonable to postulate that sympathetic activation may be harmful in patients with chronic lung disease as well. We speculate that sympathetic overactivity may well be linked to skeletal muscle dysfunction or even to "respiratory pump" dysfunction in patients with chronic lung disease. As stimulation of sympathetic nerves to the lung induces an increase in pulmonary vascular resistance (28), we speculate that an increased sympathetic tone could be one of the pathogenetic factors in the development of pulmonary hypertension and cor pulmonale.
Evaluation of Methods and Limitations of the Study
Sympathetic activity is accurately quantified by the postganglionic sympathetic discharge to the vascular bed of the skeletal muscle (29). Previous investigations have demonstrated that MSNA is highly reproducible and shows a low day-to-day variability within individuals (30, 31). In general, microneurography is considered to be a reliable method for evaluating interindividual differences and intraindividual changes of sympathetic activity in a number of disorders. However, to our knowledge, microneurography has not yet been used in patients with lung disease before.
In our study, plasma catecholamines were not different in the patients with chronic hypoxemia and in the control subjects. Plasma and urinary norepinephrine concentrations do not reflect neurotransmitter release but rather the balance of spillover and clearance as only a fraction of neurally released norepinephrine appears in the plasma (32). Indeed, a number of studies failed to prove increased levels of plasma or urinary catecholamines in disorders that are undoubtedly accompanied by sympathetic overactivity (33, 34). Therefore, we do not believe that the lack of difference in plasma catecholamines between the two groups negates our finding that patients with chronic hypoxemia show a marked increase in MSNA. The lack of difference in plasma catecholamines may also be due to the small number of patients and control subjects included in our study.
We used respiratory inductive plethysmography (RIP) to monitor respiration in the patients and control subjects. Although RIP is the most widely accepted method for noninvasive respiratory measurements, there is as much as 10% deviation between RIP and spirometry in patients with lung disease even when using the least-squares calibration technique (17, 35). On the other hand, highly reliable methods to determine minute ventilation would implicate the use of a mouthpiece or a face mask, possibly giving rise to discomfort and alterations in the breathing pattern.
In our study, transcutaneous PO2 and PCO2 measurements were used to monitor blood gas changes during the experiment. In stable patients with respiratory disease, transcutaneous PCO2 and PO2 are linearly related to arterial PCO2 and PO2 but the standard error of estimate is higher for PO2 (12 mm Hg) compared with PCO2 (5 mm Hg) (18). The measurements of transcutaneous PO2 in our investigation are confirmed by the simultaneous pulse oximetry of arterial oxygen saturation. As arterial blood gases constitute the gold standard for evaluation of the adequacy of alveolar ventilation, in vivo calibration of the transcutaneous monitoring system was based upon arterial blood gases taken at the beginning of each experiment.
We would have expected correlations between MSNA and the factors known to influence survival in patients with COPD, which are hypoxemia and hypercapnia (36), body weight loss, pulmonary hypertension, and the clinical syndrome of cor pulmonale (37). However, there was no significant correlation between MSNA and the dyspnea level, PO2, PCO2, oxygen saturation, lung function data, or body mass index in our study. Again, this may be due to the small number of patients examined. As patients with both lung fibrosis and chronic obstructive lung disease (COLD) were included in our study, correlations may have been blurred by the different pathophysiological backgrounds of the two diseases.
In our study, only the effect of short-term oxygen on sympathetic activity in patients with chronic hypoxemia was examined. Further studies are needed to investigate the long-term effect of oxygen on MSNA in patients with chronic lung disease. This seems important as long-term oxygen treatment has been shown to improve mortality and morbidity in patients with chronic hypoxic COPD and respiratory failure by mechanisms that are not known so far (8, 9).
Conclusion
In conclusion, our study provides the first direct evidence of marked sympathetic activation in patients with chronic respiratory failure. This is partly explained by arterial chemoreflex activation and may have important consequences for respiratory muscle function, pulmonary circulation, right heart failure, and possibly for the prognosis of the disease.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Privatdozent Dr. Stefan Andreas, Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. E-mail: Sandreas{at}med.uni-goettingen.de
(Received in original form July 18, 2000 and in revised form January 17, 2001).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.orgAcknowledgments: The authors thank Mr. Kirchmeier for technical assistance and Mr. U. Munzel for statistical analyses.
This study was supported by the Deutsche Forschungsgemeinschaft (An 260/1-2).
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References |
|---|
|
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ABSTRACT
INTRODUCTION
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REFERENCES
|
|---|
1.
Hardy JC,
Gray K,
Whisler S,
Leuenberger U.
Sympathetic and blood
pressure responses to voluntary apnea are augmented by hypoxemia.
J Appl Physiol
1994;
77:
2360-2365
2.
Leuenberger U,
Gleeson K,
Wroblewski K,
Prophet S,
Zelis R,
Zwillich C,
Sinoway L.
Norepinephrine clearance is increased during acute hypoxemia in humans.
Am J Physiol
1991;
261:
H1659-H1664
3.
Morgan BJ,
Crabtree DC,
Palta M,
Skatrud JB.
Combined hypoxia and
hypercapnia evokes long-lasting sympathetic activation in humans.
J
Appl Physiol
1995;
79:
205-213
4.
Volterrani M,
Scalvini S,
Mazzuero G,
Lanfranchi P,
Colombo R,
Clark AL,
Levi G.
Decreased heart rate variability in patients with chronic
obstructive pulmonary disease.
Chest
1994;
106:
1432-1437
5. Scalvini S, Porta R, Zanelli E, Volterrani M, Vitacca M, Pagani M, Giordano A, Ambrosino N. Effects of oxygen on autonomic nervous system dysfunction in patients with chronic obstructive pulmonary disease. Eur Respir J 1999; 13: 119-124 [Abstract].
6.
Bartels MN,
Gonzalez JM,
Kim W,
De Meersman RE.
Oxygen supplementation and cardiac-autonomic modulation in COPD.
Chest
2000;
118:
691-696
7. Watson JP, Nolan J, Elliott MW. Autonomic dysfunction in patients with nocturnal hypoventilation in extrapulmonary restrictive disease. Eur Respir J 1999; 13: 1097-1102 [Abstract].
8. Group NOTT. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive airway disease: a clinical trial. Ann Intern Med 1980; 93: 391-398 .
9. Party MRCW. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981; i: 681-685 .
10.
Seals DR,
Johnson DG,
Fregosi RF.
Hyperoxia lowers sympathetic activity at rest but not during exercise in humans.
Am J Physiol
1991;
260:
R873-R878
11.
Engelstein ED,
Lerman BB,
Somers VK,
Rea RF.
Role of arterial
chemoreceptors in mediating the effects of endogenous adenosine on
sympathetic nerve activity.
Circulation
1994;
90:
2919-2926
12.
Narkiewicz K,
van de Borne PJ,
Montano N,
Dyken ME,
Phillips BG,
Somers VK.
Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea.
Circulation
1998;
97:
943-945
13. Stewart AG, Waterhouse JC, Howard P. Cardiovascular autonomic nerve function in patients with hypoxaemic chronic obstructive pulmonary disease. Eur Respir J 1991; 4: 1207-1214 [Abstract].
14. Calverley PMA, Georgopoulos D. Chronic obstructive pulmonary disease: symptoms and signs. In: Postma DS, Siafakas NM, editors. Management of chronic obstructive pulmonary disease. Copenhagen, Denmark: Munsgaard Ltd.; 1998. p. 6-24.
15.
Heindl S,
Dodt C,
Krahwinkel M,
Hasenfuss G,
Andreas S.
Short-term effect of continuous positive airway pressure on muscle sympathetic nerve
activity in patients with chronic heart failure.
Heart
2001;
85:
185-190
.
16. Van der Hoorn FAJ, Boosma F, Mann AJ, Schalekamp MADH. Determination of catecholamines in human plasma by high-performance liquid chromatography: comparison between a new method with fluorescence detection and an established method with electrochemical detection. J Chromatogr 1989; 487: 17-28 [Medline].
17. Chadha TS, Watson H, Birch S, Jenouri GA, Schneider AW, Cohn MA, Sackner MA. Validation of respiratory inductive plethysmography using different calibration procedures. Am Rev Respir Dis 1982; 125: 644-649 [Medline].
18.
Kesten S,
Chapman KR,
Rebuck AS.
Response characteristics of a dual
transcutaneous oxygen/carbon dioxide monitoring system.
Chest
1991;
99:
1211-1215
19. de Burgh Daly M. Interactions between respiration and circulation. In: Handbook of physiology. The respiratory system. New York: Oxford University Press; 1986. p. 529-594.
20.
Mark AL,
Victor RG,
Nerhed C,
Wallin BG.
Microneurographic studies
of the mechanisms of sympathetic nerve responses to static exercise in
humans.
Circ Res
1985;
57:
461-469
21. Mitchell JH, Schmidt RF. Cardiovascular reflex control by afferent fibers from skeletal muscle receptors. In: Shepherd JT, Abboud FM, editors. Handbook of physiology. The cardiovascular system. New York: Oxford University Press; 1983.
22.
Seals DR,
Suwarno O,
Dempsey JA.
Influence of lung volume on sympathetic nerve activity in normal humans.
Circ Res
1990;
67:
130-141
23. Persson B, Andersson OK, Hjemdahl P, Wysocki M, Agerwall S, Wallin G. Adrenaline infusion in man increases muscle sympathetic nerve activity and noradrenaline overflow to plasma. J Hypertens 1989; 7: 747-756 [Medline].
24.
Atuk NO,
Blaydes MC,
Westervelt FB,
Wood JE.
Effect of aminophylline on urinary excretion of epinephrine and norepinephrine in man.
Circulation
1967;
35:
745-753
25. DeChamplain J, Karas M, Toal C, Nadeau R, Larochelle P. Effects of antihypertensive therapies on the sympathetic nervous system. Can J Cardiol 1999;15(Suppl A):8-14.
26.
Anker SD,
Chua TP,
Ponikowski P,
Harrington D,
Swan JW,
Kox WJ,
Poole-Wilson PA,
Coats AJS.
Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia.
Circulation
1997;
96:
526-534
27.
Swedberg K,
Eneroth P,
Kjekshus J,
Wilhelmsen L.
Hormones regulating cardiovascular function in patients with severe congestive heart
failure and their relation to mortality.
Circulation
1990;
82:
1730-1736
28. Barnes PJ, Liu SF. Regulation of pulmonary vascular tone. Pharmacol Rev 1995; 47: 87-131 [Medline].
29. Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol 1993; 22: 72a-84a .
30.
Yamada Y,
Miyajima E,
Tochikubo O,
Matsukawa T,
Ishii M.
Age-related changes in muscle sympathetic nerve activity in essential hypertension.
Hypertension
1989;
13:
870-877
31.
Middlekauff HR,
Sontz EM.
Morning sympathetic nerve activity is not
increased in humans: implications for mechanisms underlying the circadian pattern of cardiac risk.
Circulation
1995;
91:
2549-2555
32.
Wallin BG,
Esler M,
Dorward P,
Eisenhofer G,
Ferrier C,
Westerman R,
Jennings G.
Simultaneous measurements of cardiac noradrenaline
spillover and sympathetic outflow to skeletal muscle in humans.
J
Physiol Lond
1992;
453:
45-58
33.
Grassi G,
Cattaneo BM,
Seravalle G,
Lanfranchi A,
Pozzi M,
Morganti A,
Carugo S,
Mancia G.
Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure.
Circulation
1997;
96:
1173-1179
34.
Grassi G,
Seravalle G,
Colombo M,
Bolla G,
Cattaneo BM,
Cavagnini F,
Mancia G.
Body weight reduction, sympathetic nerve traffic, and arterial baroreflex in obese normotensive humans.
Circulation
1998;
97:
2037-2042
35.
Tobin MJ,
Jenouri G,
Lind B,
Watson H,
Schneider A,
Sackner MA.
Validation of respiratory inductive plethysmography in patients with
pulmonary disease.
Chest
1983;
83:
615-620
36. Renzetti AD, McClement JH, Litt BD. The Veterans Administration Co-Operative Study of Pulmonary Function: III. Mortality in relation to respiratory function in chronic obstructive pulmonary disease. Am J Med 1966; 41: 115-119 [Medline].
37. Traver GA, Cline MG, Burrows B. Predictors of mortality in chronic obstructive pulmonary disease: a 15-year follow-up study. Am Rev Respir Dis 1979; 119: 895-902 [Medline].
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 G. R. Chiappa, A. Borghi-Silva, L. F. Ferreira, C. Carrascosa, C. C. Oliveira, J. Maia, A. C. Gimenes, F. Queiroga Jr, D. Berton, E. M. V. Ferreira, et al. Kinetics of muscle deoxygenation are accelerated at the onset of heavy-intensity exercise in patients with COPD: relationship to central cardiovascular dynamics J Appl Physiol, May 1, 2008; 104(5): 1341 - 1350. [Abstract] [Full Text] [PDF]
|
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|
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A. Boussuges and M. Gouitaa Arterial Stiffness and Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., April 15, 2008; 177(8): 929 - 929. [Full Text] [PDF]
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 |
|
 C. Lundby, R. Boushel, P. Robach, K. Moller, B. Saltin, and J. A. L. Calbet During hypoxic exercise some vasoconstriction is needed to match O2 delivery with O2 demand at the microcirculatory level J. Physiol., January 1, 2008; 586(1): 123 - 130. [Abstract] [Full Text] [PDF]
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D. D. Sin and S. F. P. Man Pharmacotherapy for Mortality Reduction in Chronic Obstructive Pulmonary Disease Proceedings of the ATS, September 1, 2006; 3(7): 624 - 629. [Abstract] [Full Text] [PDF]
|
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|
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B. J. Canning Reflex regulation of airway smooth muscle tone J Appl Physiol, September 1, 2006; 101(3): 971 - 985. [Abstract] [Full Text] [PDF]
|
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E. J. Oh, S. B. Mazzone, B. J. Canning, and D. Weinreich Reflex regulation of airway sympathetic nerves in guinea-pigs J. Physiol., June 1, 2006; 573(2): 549 - 564. [Abstract] [Full Text] [PDF]
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S. Andreas, C. Herrmann-Lingen, T. Raupach, L. Luthje, J. A. Fabricius, N. Hruska, W. Korber, B. Buchner, C-P. Criee, G. Hasenfuss, et al. Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial Eur. Respir. J., May 1, 2006; 27(5): 972 - 979. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Unterberg, L. Luthje, J. Szych, D. Vollmann, G. Hasenfuss, and S. Andreas Atrial overdrive pacing compared to CPAP in patients with obstructive sleep apnoea syndrome Eur. Heart J., December 1, 2005; 26(23): 2568 - 2575. [Abstract] [Full Text] [PDF]
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S. Andreas, S. D. Anker, P. D. Scanlon, and V. K. Somers Neurohumoral Activation as a Link to Systemic Manifestations of Chronic Lung Disease Chest, November 1, 2005; 128(5): 3618 - 3624. [Abstract] [Full Text] [PDF]
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L. Luthje, C. Unterberg-Buchwald, D. Dajani, D. Vollmann, G. Hasenfuss, and S. Andreas Atrial Overdrive Pacing in Patients with Sleep Apnea with Implanted Pacemaker Am. J. Respir. Crit. Care Med., July 1, 2005; 172(1): 118 - 122. [Abstract] [Full Text] [PDF]
|
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|
 |
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 A. Ciarka, B. Najem, N. Cuylits, M. Leeman, O. Xhaet, K. Narkiewicz, M. Antoine, J.-P. Degaute, and P. van de Borne Effects of Peripheral Chemoreceptors Deactivation on Sympathetic Activity in Heart Transplant Recipients Hypertension, May 1, 2005; 45(5): 894 - 900. [Abstract] [Full Text] [PDF]
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 S. Andreas, H. Reiter, L. Luthje, A. Delekat, R. W. Grunewald, G. Hasenfuss, and V. K. Somers Differential Effects of Theophylline on Sympathetic Excitation, Hemodynamics, and Breathing in Congestive Heart Failure Circulation, October 12, 2004; 110(15): 2157 - 2162. [Abstract] [Full Text] [PDF]
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S. Velez-Roa, A. Ciarka, B. Najem, J.-L. Vachiery, R. Naeije, and P. van de Borne Increased Sympathetic Nerve Activity in Pulmonary Artery Hypertension Circulation, September 7, 2004; 110(10): 1308 - 1312. [Abstract] [Full Text] [PDF]
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L. W. Raymond Vagal Pas de Deux: Heart-Lung Interplay in Postexercise Heart Rate Recovery Chest, April 1, 2004; 125(4): 1186 - 1190. [Full Text] [PDF]
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J. A L Calbet Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans J. Physiol., August 15, 2003; 551(1): 379 - 386. [Abstract] [Full Text] [PDF]
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D. D. Sin and S.F. P. Man Why Are Patients With Chronic Obstructive Pulmonary Disease at Increased Risk of Cardiovascular Diseases?: The Potential Role of Systemic Inflammation in Chronic Obstructive Pulmonary Disease Circulation, March 25, 2003; 107(11): 1514 - 1519. [Abstract] [Full Text] [PDF]
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J. Hansen and M. Sander Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia J. Physiol., February 1, 2003; 546(3): 921 - 929. [Abstract] [Full Text] [PDF]
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M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]
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