Hormonal, metabolic, and cardiovascular exercise in humans: influence of epidural M. KJflR, N. H. SECHER, F. W. BACH, D. R. REEVES, JR., AND J. H. MITCHELL
responses to static anesthesia
H. GALBO,
Departments of Anesthesia and Internal Medicine TTA, Rigshospitalet, Department of Clinical Chemistry, Gentofte Hospital and Department of Medical Physiology B, Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark
M., N. H. SECHER, F. W. BACH, H. GALBO, D. R. AND J. H. MITCHELL. Hormonal, metabolic, and cardiovascular responses to static exercise in humans: influence of epidural anesthesia. Am. J. Physiol. 261 (Endocrinol. Metab. 24): E214-E220, 1991.-To determine the role of reflex neural mechanisms for hormonal, metabolic, heart rate (HR), and blood pressure (MABP) changes during static exercise, seven healthy young males performed lo-min periods of two-legged static knee extension both during control and during epidural anesthesia. Comparisons were made at identical absolute (29 Nm) and relative [ 15% maximal voluntary contraction (MVC)] force. Afferent nerve blockade was verified by hypesthesia below Tlo-T12 and attenuated postexercise ischemic pressor response. Leg strength was reduced to 67 & 5% of control. At same relative force, increases in MABP and HR occurred more rapidly without than with epidural anesthesia (P < 0.05). This difference was diminished during identical absolute force. Changes in plasma concentrations of catecholamines followed the pattern of HR and MABP responses, with differences between epidural and control experiments being most pronounced early in the work period. Plasma ,&endorphin was elevated only after control exercise. No response at 15% MVC was found for growth hormone, adrenocorticotropic hormone, insulin, glucagon, cortisol, glycerol, free fatty acids, or glucose (P > 0.05). In conclusion, during static exercise with large muscle groups and moderate relative force, modest changes in plasma hormones and metabolites take place. Furthermore, afferent nervous feedback from contracting muscles is important in regulation of blood pressure, heart rate, and catecholamine responses during static exercise in humans. KJAZR, REEVES,
JR.,
14). On the other hand, experiments with epidural anesthesia have indicated that neural feedback from exercising muscles is involved in eliciting the ,&endorphin and ACTH responses to dynamic exercise (15). Compared with dynamic exercise, much less is known regarding the regulation of metabolism and circulation during static exercise. Regional anesthesia has been used to rule out a role of afferent nerves in regulation of cardiovascular responses to brief static contractions (9, 16), but afferent nerves appear to play an important role in cardiovascular regulation during sustained static contraction of a small muscle mass (20). Whether reflex neural mechanisms are involved in the regulation of hormonal and metabolic changes to static exercise is unknown. In the present study, we determined the role of reflex neural mechanisms for hormonal, metabolic, heart rate, and blood pressure changes during two-legged sustained static knee extension. Epidural anesthesia was used to reduce sensory feedback from contracting muscles. Epidural anesthesia, in addition to sensory blockade, also causes a reduction in maximal leg strength. Accordingly, responses during epidural anesthesia were compared with responses in control experiments both at identical absolute and relative forces. MATERIALS
AND
METHODS
command”) as well as reflex mechanisms are involved in the generation of hormonal and metabolic responses in humans, whereas reflex control dominates the cardiovascular responses (7, 13-E). With the use of partial neuromuscular blockade (with tubocurarine), which increases the subjective effort and probably the motor center activity necessary to fulfill a given work load, it is found that central command is involved in regulation of catecholamine, adrenocorticotropic hormone (ACTH), and growth hormone (GH) responses and of mobilization of glucose and free fatty acids (FFA) during exercise (13,
Subjects. Seven healthy males with a mean age of 26 yr (range 22-34 yr), weight of 71 kg (range 62-78 kg), and height of 177 cm (range 170-182 cm) gave informed consent to participate in the study, which was approved by the Municipal Ethical Committee of Copenhagen. None of the subjects were taking any medications, and none had a family history of endocrine disorders. All subjects had previously participated in exercise experiments conducted by the authors. Procedures. Each subject appeared in the laboratory on two occasions separated by 3-7 days. Each time, subjects were studied in a semisupine position, with the upper part of the body forming an angle of 45” with the couch. Static muscle contractions were performed with the knee extensors (quadriceps femoris), the knee angle being 90” (17). The force was determined with a circular strain gauge applied above the ankles. Results were calculated as a torque by multiplying the applied force by
E214
the American
arterial blood pressure; heart rate; catecholamines; epinephrine; norepinephrine; glucagon; insulin; growth hormone; @-endorphin; metabolic regulation
DURING
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EXERCISE
Central
019%1849/91
neural
$1.50
(“Central
Copyright
0 1991
Physiological
Society
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the distance from the ankles to the center for rotation in the knee. Subjects arrived in the laboratory at 8 A.M. after a loh overnight fast, having.abstained from training, alcohol, and tobacco on the day before. Before exercise, a l.O-mm inner diameter (ID) cannula was inserted into the left brachial artery and was connected to a pressure transducer posl’tioned at heart level. A 1.2mm ID venous catheter was placed in a vein on the back of the hand and was kept open by flushing with small amounts of saline (~200 ml). Subjects were allowed to drink water as wanted throughout the experimental period. The electrocardiogram was taken from bipolar chest electrodes. Heart rate, mean arterial blood pressure, and force were continuously monitored before, during, and after static contractions on a Siemens-Elema recorder. At the beginning of the experiment and before each exercise period, the combined strength of the two legs was established as the greatest of three maximal voluntary contractions (MVC). In control experiments, subjects performed two periods of 10 min static contractions aiming at a force corresponding to 15% of MVC determined immediately before exercise. The two exercise periods were separated by 30 min of rest. Perceived exertion was expressed by the subjects on a scale from 6 to 20 (4) where “7” represents hard, and “20” very very light, “13” means somewhat signifies very very hard exertion. On a second experimental day, a 20-gauge spinal needle was inserted in the epidural space through vertebral interspace L:,-L, in the midsagittal line employing the loss of resistance technique. Epidural anesthesia was induced by injection of 18-24 ml (according to body weight) of 1.5% lidocaine (Xylocain, Astra). The level and type of anesthesia was established both before and after exercise by clinical neurological examination of both legs. A cotton ball run along the leg determined sensation to light touch. Sharp pain and deep pain were evaluated by pin pricking and by squeezing the Achilles tendon, respectively. Temperature sensation was evaluated by alternately placing heated and cooled sides of a tuning fork against the leg. Position sense was evaluated by moving the big toe and with the subject telling its position (i.e., dorsiflexion). Finally, vibration sense was evaluated by placing a vibrating tuning fork upon the patella and the planta. During epidural anesthesia, subjects performed two IO-min periods of static contraction separated by 30 min of rest. In the first period, a force corresponding to 15% MVC was aimed at, whereas, in the second period, force was increased to match the force used in the control experiment. This order of the experimental periods during epidural anesthesia was chosen because unspecific stress, if present, during the experiment is expected to be highest in the beginning of an experiment, making it as difficult as possible for us to detect differences at same relative work force between experiments with epidural anesthesia and control experiments. Static contraction was begun when the level of cutaneous hypesthesia was constant over a 5-min period (40 t 5 min after administration of epidural anesthesia). Ten seconds before the end of the second exercise
EPIDURAL
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E215
period on both the day without and on the day with epidural anesthesia, circulatory occlusion of both legs was established with pneumatic pressure cuffs placed proximally on the thighs and inflated to 400 mmHg. Occlusion was verified by disappearance of arterial pulses on the feet. The cuffs remained inflated for the following 3 min of recovery. After deflation of the cuffs, recording was continued for further 2 min of rest. This procedure has earlier been shown to elicit a postexercise ischemic pressor response that is diminished when successful epidural blockade is present (7, 8). 1Methods. Blood for the various analyses was sampled from the arterial cannula before, during, and after static exercise at 5- or lo-min intervals (see Figs. l-5 and Tables 1 and 2). Blood for catecholamine analysis was collected into chilled glass tubes containing ethylene glycol-bis(P-aminoethyl ether)-N,N,N’,N’-tetraacetic acid and reduced glutathione and were placed on ice. Samples were promptly centrifuged at 4°C and plasma was stored at -8OOC. Catecholamine concentrations were determined by a single isotope radioenzymatic method (3). The concentrations of insulin (ll), pancreatic glucagon (l2), GH (12), ACTH (6), cortisol (12) and ,& endorphin (2) were determined with radioimmunoassays previously described by the authors. Plasma glucose was determined spectrophotometrically with the hexokinase method. FFA, glycerol, and lactate were determined by enzymatic fluorometric methods. Lidocaine and its active metabolite monoethylglycinxylidin were determined in serum by high-performance liquid chromatography ( 1). For statistical evaluation, Friedman’s test was used to test whether significant changes occurred with time (24). If so, the change was located by the Wilcoxon ranking test for paired data (Pratt’s modification). This test was also used to evaluate differences between epidural and control experiments. A P value of 0.05 (two-tailed testing) was considered significant. RESULTS
Evaluation of epidural anesthesia. At rest, all variables were similar on the two experimental days (Figs. l-5). Epidural anesthesia resulted in cutaneous hypesthesia below T9-Tll (mean Tlo) before onset of the first contraction period. After the end of the second contraction period, cutaneous hypesthesia was still present below Tlo-TiZ (mean T,,). In this area, sensations of light touch and sharp pain were diminished, and the sensations of deep pain and temperature were markedly impaired, whereas position and vibration senseswere unimpaired. Furthermore, epidural anesthesia attenuated the postexercise pressor response from 26 t 6 to 16 t 4 mmHg (mean t SE of individual mean differences between values obtained 1,2, and 3 min postexercise, respectively, and at baseline) (P < 0.05) (Fig. 1) and reduced the muscle strength to 67 t 5% of the control value (Table 1). Arterial plasma concentrations of lidocaine increased in all subjects after administration of epidural anesthesia (Table 2). In response to epidural anesthesia, plasma concentrations at rest of norepinephrine, epinephrine, ACTH, cortisol, and glucagon decreased by ll-45% (P
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0 -0
Control
.- -0
Epidural
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1. Static two-legged knee extension without and with epidural anesthesia
TABLE anesthesia
Period
MVC, Nm %MVC Force, Nm RPE (6-20)
1
Period
2
Control
Epidural
Control
Epidural
215k15 15kO.2 32t3 18.5kO.5
144*13* 15kO.3 22t2* 18.2kO.6
198t17 15kl.l 29t2 18.0t0.7
133*25* 21t3.0* 28-e3 l&7*0.4
Values are means k SE. Period I, identical relative work load; period 2, identical absolute work load in experiments with epidural anesthesia compared with control experiments. MVC, maximal voluntary contraction as an indication of maximal quadriceps strength, established by taking the greatest of 3 maximal 2legged knee extensions. RPE, rating of perceived exertion on a Borg-scale ranging from 6 to 20. * Significant difference from control value (P c 0.05).
60-
2. Plasma lidocaine concentration before and 40 min after epidural anesthesia TABLE
120-
Subject 1
80-
I**
OJ
( **
I
I**
Means
1
15% w
-40
WC
29 Nm I
0 10 Exercise
I
I
20 30 Rest
50 40 Exercise
60 65 min Recovery
FIG. 1. Heart rate and mean arterial blood pressure at rest and during IO-min periods of 2-legged static knee extension without (control) or with epidural anesthesia. Seven subjects were compared both at same relative [15% maximal voluntary contraction (MVC), this intensity being used in both exercise periods in control experiments] and at same absolute (29 Nm) force. -40, Blood samples taken immediately before administration of epidural anesthesia. When clinical evaluation indicated sufficient effect of epidural blockade, 2nd blood sample was taken 40 2 5 min later, immediately before exercise was started. Values are means & SE. SE are given only every 5th min and at points where statistically significant difference was obtained between experiments without and with blockade (** P < 0.05).
< 0.05) (Figs. 2, 3, and 4). Only for ACTH did the decrease result in a plasma concentration that immediately before onset of exercise was significantly lower than seen in control experiments (P < 0.05) (Fig. 3). Static exercise at sanze reZatiue force. In both experiments without and with epidural anesthesia, subjects maintained the intended relative force throughout the contraction period. Blood pressure and heart rate increased more rapidly in control than in epidural anesthesia experiments (Fig. 1). Furthermore, also plasma concentrations of epinephrine and norepinephrine rose more rapidly in experiments without than with epidural anesthesia (Fig. 2). Plasma concentrations of most remaining hormones did not change significantly (Figs. 3 and 4). However, in control experiments, but not in experiments with epidural anesthesia, plasma ,&endorphin concentrations reached a maximum 5 min postexercise (Fig. 3). Blood lactate increased similarly in experiments with-
2 3 4 5 6 7 t SE, mg/l
Basal
co.005 co.005 co.005 co.005 co.005 co.005 co.005 co.005
406 After
min Basal
0.129 0.386 0.309 1.179 0.655 0.497 0.145 0.471t0.137*
Basal value was obtained in arterial blood drawn immediately before administration of 18 ml (subjects I and 2) or 24 ml (subjects 3-7) 2% lidocaine in epidural space through vertebral interspace L,-L,. After administration of lidocaine (40+5 min), and immediately before onset of exercise, 2nd arterial sample was drawn. All samples contained CO.01 mg/l of lidocaine metabolite monoethylglycinxylidin. * Significant difference from basal value (P < 0.05).
out and with epidural anesthesia, whereas plasma glucose and FFA concentrations never changed significantly (Fig. 5). Glycerol concentration increased during twolegged knee extension, and this increase was not altered by administration of epidural anesthesia (Fig. 5). Within the recovery period after the first exercise period, all hormonal, metabolic, and cardiovascular parameters returned to basal levels (Figs. l-5). Static exercise at same absolute force. In control experiments, maximal force was slightly smaller in the second compared with the first exercise period, but the relative force (15% MVC) and rate of perceived exertion were kept unchanged (Table 1). Also, responses of heart rate, blood pressure, catecholamines, and lactate were similar in the first and second exercise periods in control experiments (Figs. 1, 2, and 5). In the second contraction period during epidural anesthesia, force was increased to become the same in absolute terms as in control experiments (Table 1). Accordingly, in epidural blockade experiments, relative force was higher in the second (21% MVC) compared with the first (15% MVC) exercise period, and blood pressure, heart rate, and epinephrine rose more rapidly in the former compared with the latter period (Figs. 1 and Z), whereas GH and ACTH concentrations only increased in the former (Fig. 3). In the second exercise period, blood pressure increased more rapidly in experiments without than with epidural
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STATIC
0 -0 o--o
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EPIDURAL
E217
ANESTHESIA
Control Epidural anesthesia
0l
w
0 Control
- -0
Epidural anesthesia
1611252
I
84-
I
* w
I
I I 1
I
I
I
I
I
I
1
.-C L p’;
07 2z w z &
4
32lOI
0.2 -
I
I
29 Nm
-40
0
10 Exercise
I
I
20
30 Rest
40 50 min Exercise
M;. 2. Catecholamine concentrations in plasma at rest, during, and after 2 static contraction periods. Seven subjects were studied without (control) or with epidural anesthesia. Values are means t SE. * Statistical difference between experiments (P < 0.05). For further explanation see Fig. 1.
blockade (Fig. 1). The same tendency was seen for norepinephrine concentrations (Fig. 2) (P < O.l), whereas heart rate and epinephrine responses were similar in control experiments and epidural blockade experiments (Figs. 1 and 2). In the second exercise period, GH and ACTH increased during epidural anesthesia (21% MVC) but not in control experiments (15% MVC) (Fig. 3). Remaining hormones and plasma glucose never changed from basal levels (Figs. 3-5). Blood lactate and plasma concentrations of glycerol and FFA rose similarly in response to exercise in control and epidural anesthesia experiments (P > 0.05) (Fig. 5). During recovery the cuffs maintained blood pressure and heart rate values more closely to exercise values in control experiments than in experiments with epidural blockade (Fig. 1). The postexercise ischemic pressor response [26 t 6 (control) vs. 16 t 4 mmHg (epidural)] and the postexercise heart rate response [ 23 t 4 (control) vs. 12 t 3 beats/min (epidural)] were significantly diminished (P < 0.05) by epidural blockade. DISCUSSION
In the first exercise period, responses of blood pressure, heart rate, and catecholamines to static two-legged contractions of the same relative force were less during epidural anesthesia than during control experiments, with the difference between experiments being most pronounced early in the exercise period (Figs. 1 and 2). These findings confirm previous observation for heart rate and blood pressure during static one-legged exercise (20). A significant increase in plasma ,0-endorphin concentrations was seen 5 min after control exercise,
-40
0
10
Exercise
20
30 Rest
40 50 min Exercise
FIG. 3. Effect of epidural anesthesia on concentrations of pituitary hormones [growth hormone (GH), ,8-endorphin, adrenocorticotropic hormone (ACTH)] and cortisol in plasma at rest and during 2 static contraction periods. Values are means & SE. * Statistical difference between experiments (P c 0.05). Values were different from previous value in experiments with (m) or without (A) epidural blockade (P < 0.05). For further explanation see Fig. 1.
whereas no increase was seen in response to exercise during epidural blockade (Fig. 3). As relative force as well as rate of perceived exertion (Table 1) were similar in the first exercise period in the two experiments, motor center activity was probably also identical. These findings indicate that afferent nervous feedback from exercising muscle significantly enhances the increase in blood pressure, heart rate, catecholamines, and ,&endorphin in response to static exercise. For blood pressure and heart rate, this is in accordance with findings obtained with epidural anesthesia both during static contraction with a smaller muscle mass than used here (one- vs. twolegged contraction) (20) and during dynamic bicycle exercise (7). Epidural blockade has previously been shown to abolish the P-endorphin response to dynamic exercise (15) In the second exercise period, absolute force was the same, but relative force was higher in epidural than in control experiments. Also in this period the responses of blood pressure and norepinephrine to static contractions tended to be less brisk during epidural blockade (Figs. 1 and 2), but differences were less marked than in the first
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STATIC
EXERCISE
0-0 Control l - -o Epidural
anesthesia
E218
DURING
EPIDURAL
0 -0
I 1
I
l
5%
I I
I
I
I
I I 1
I I
I
f?F
IO
Exercise
anesthesia
I
0.8 06 0.4 0.2 0 l
7 ‘;- 0.08
29 Nm I
40 0
Control
- -0 Epidural
I
r a>L g E -I E
I
ANESTHESIA
1
20 30 Rest
---
40
50 min
Exercise
FIG. 4. Effect of epidural blockade on plasma concentrations of pancreatic hormones at rest and during periods of static contraction. Values are means t SE. For further explanation see Fig. 1.
exercise period (Figs. 1 and 2). When cuffs were inflated at the end of two-legged, in contrast to one-legged static exercise, both blood pressure and heart rate responses were less well maintained during postexercise ischemia in epidural blockade compared with control experiments (Fig. 1). These findings enhance the conclusion that neural feedback is an important stimulus for sympathetic activity and cardiovascular responses during static exercise (20). However, epidural blockade did not abolish cardiovascular and hormonal response to static contractions. Furthermore, in experiments with epidural anesthesia, increases in relative force and perceived exertion from the first to the second exercise period were accompanied by increases in responses of blood pressure, heart rate, catecholamines, GH, and ACTH (Figs. l-3). These findings suggest that activity in motor centers may directly elicit autonomic neuroendocrine responses. The existence of such a central command mechanism has previously been proposed from dynamic exercise experiments in which motor center activity was varied by the use of partial neuromuscular blockade (14). This technique has also been used to demonstrate that central neural mechanisms are involved in blood pressure and heart rate responses to static exercise (17, 19, 26). Probably, both neural feedback from working muscle and central command mechanisms determine the activity in higher neuroendocrine centers during exercise. Redundancy of the two mechanisms as well as nonlinear relations between total stimulus (sum of central and peripheral input) and effects may explain that differences in responses of blood pressure, heart rate, and catecholamines between experiments with and without epidural blockade were most pronounced early during contractions and diminished as stimulus intensity increased with duration of exercise
I 0
j
r7YIrs%"VC
I
I
1
1
1
t
I
29 Nm
4
-40
0 10 20 30 40 50 min Exercise Rest Exercise FIG. 5. Effect of epidural blockade on plasma concentrations of glucose, glycerol, and free fatty acids (FFA) and on blood lactate concentrations in 7 subjects. Values are means & SE. For further explanation see Fig. 1.
(Figs. 1 and 2). Sensory nerve fibers were blocked in our subjects, as cutaneous hypesthesia was present below Tlo-T12. Throughout the study, a gradual regression of the level of the block took place. However, it is important to note that, as indicated by level of hypesthesia, the block remained at least as high as T10-T12 by the end of the study. This means that, at all times during the experimental period, cutaneous hypesthesia was present caudal to T10-T12. In addition to sensation of light touch, neurological examination revealed impairment of sharp and deep pain and temperature sensation in the same area, indicating that activity in small unmyelinated and myelinated sensory fibers from exercising extremities was markedly reduced. Furthermore, the ischemic pressor response, which normally is found after static exercise (17, 25), was diminished after exercise with epidural anesthesia (Fig. l), a finding that previously has been taken to indicate blockade of small unmyelinated sensory nerve fibers (7, 8). However, the postexercise ischemic pressor response was not abolished, indicating that blockade of unmyelinated fibers was not complete (Fig. 1). Thresholds for lidocaine blockade are identical in pain- and temperature-sensing and efferent sympathetic
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DURING
fibers. Accordingly, the finding that activity in the former fibers was impaired could suggest that also activity in the latter fibers should be impeded. However, pain- and temperature-sensing fibers are accessible to epidural blockade throughout the spinal cord, whereas sympathetic fibers do not project from the lower part of the spinal cord. The conclusion that efferent sympathetic nerves were probably not blocked is in agreement with a previous study in which we used an epidural anesthesia identical to the one in the present study. It was found that blood pressure responses both to 2 min of hand immersion in ice-cold water (cold pressor test) and to a Valsalva maneuver were not altered by epidural anesthesia (7). It could be argued that lidocaine administered epidurally, in addition to an effect on nerve fibers in the spinal cord, would have an effect on the measured parameters after uptake in the blood stream. However, the arterial plasma concentration of lidocaine measured immediately before exercise (Table 2) was lower than the concentrations known to be required for an effect on heart rate, blood pressure, and myocardial contractility (5). Furthermore, according to earlier studies of the time course of plasma lidocaine after epidural administration, plasma levels of lidocaine were even lower during the periods of static exercise (5). In the present study, a significant increase in plasma concentration of catecholamines was seen after 5 min of static knee extension at 15% of MVC (Fig. 2). In contrast, no significant increase in plasma catecholamines was found in a previous study of static knee extension at 25% of MVC for 5 min (18). Still, in that study the average increase in plasma catecholamine concentration was identical to the one obtained in the present study, but dispersion of data was too large, probably due to poor assay precision, to allow significance. The increase in plasma norepinephrine concentration during two-legged static contraction at 15% MVC in the present study (Fig. 2) was similar in magnitude to the norepinephrine response obtained previously during dynamic exercise at 39% maximal Oz uptake with the same active muscle mass (22). Interestingly, however, in the present experiment the epinephrine response was three- to four-fold higher compared with dynamic exercise with the same muscle groups (22). One explanation for the finding that the norepinephrine response is low relative to that of epinephrine in static compared with dynamic exercise could be that release of norepinephrine into the circulation from active sympathetic nerves in contracting skeletal muscle (23) is impeded due to a lower blood flow. In the present experiments, plasma concentrations of GH and ACTH did only increase when exercise intensity was >20% MVC (Fig. 3). In a previous study of 9 min of static handgrip exercise, no increase in GH and ACTH was found despite an exercise intensity of 30% MVC (2 1). Correspondingly, cathecholamine responses were higher in the present experiments than during exhaustive isometric handgrip at 24 and 30% MVC, respectively (18, 27). These findings demonstrate that the mass of active muscle is crucial for the hormonal response to static exercise. The concentrations of glucagon and insulin did not
EPIDURAL
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ANESTHESIA
change during static contractions (Fig. 4). A decrease in plasma glucose and an increase in sympathetic nervous activity, respectively, are the major determinants in secretion of these hormones during dynamic exercise (10). As plasma glucose levels did not change and norepinephrine responses were small during static contractions, the lack of pancreatic hormonal responses are compatible with the view that pancreatic hormonal secretion is controlled by the same mechanisms in static and dynamic exercise (Figs. 2, 4, and 5). From the present study, it is concluded that, during low-intensity static exercise with large muscle groups, only modest changes in plasma hormones and metabolites are seen. The mass of active muscle is crucial for the hormonal response to static exercise. The epinephrine response is high relative to that of norepinephrine during static compared with dynamic contractions. Furthermore, afferent nervous feedback from contracting muscles plays an important role in regulating blood pressure, heart rate, and catecholamine responses during static exercise in humans. Lisbeth Kall is thanked for performing excellent technical assistance. Helga Flachs and Finn Christensen from the Department of Clinical Chemistry, University Hospital of Copenhagen are thanked for performing the lidocaine analysis. This work was supported by the Danish Medical Research Council Grants 12-5936, 125903, 12-7797, and 12-9360, the Frank M. Ryburn, Jr., Chair in Heart Research, La Cours Fund, and Rogers Lacy Research Fund in Cardiovascular Disease. Present address of D. R. Reeves, Jr., and J. H. Mitchell: Harry S. Moss Heart Center, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 752359034. Address for reprint requests: M. Kjzer, Dept. of Medical Physiology B, Panum Institute, 3 Blegdamsvej, DK-2200, Copenhagen N, Denmark. Received
4 December
1990; accepted
in final
form
10 April
1991.
REFERENCES 1. ANGELO, H. R., J. BONDE, J. P. KAMPMANN, AND J. KASTRUP. A HPLC method for the simultaneous determination of disopyranide, lidocaine and their monodealkylated metabolites. Stand. J. Clin. Lab. Invest. 46: 623-627, 1986. 2. BACH, F. W., J. FAHRENKRUG, K. JENSEN, G. DAHLSTROM, AND R. EKMAN. Plasma B-endorphin during clinical and experimental ischaemic pain. Stand. J. Clin. Lab. Invest. 47: 751-758, 1987. 3. BEN-JONATHAN, N., AND J. C. PORTER. A sensitive radioenzymatic assay for dopamine, norepinephrine and epinephrine in plasma and tissue. Endocrinology 98: 1497-1507, 1976. 4. BORG, G. Perceived exertion as an indicator of somatic stress. Stand. J. Rehab. Med. 2: 92-98,197O. 5. COVINO, B. G., AND H. G. VASSALLO. Local Anesthetics-Mechanisms of Action and Clinical Use. New York: Grune & Stratton, 1976. 6. FARRELL, P. A., M. KJER, F. W. BACH, AND H. GALBO. Betaendorphin and adrencorticotropin response to supramaximal treadmill exercise in trained and untrained males. Actcz Physiol. Stand. 130: 619-625, 1987. 7. FERNANDES, A., H. GALBO, M. KJLIXR, J. H. MITCHELL, N. H. SECHER, AND S. N. THOMAS. Cardiovascular and ventilatory responses to dynamic exercise in man with epidural anaesthesia. J. Physiol. Lond. 420: 281-293, 1990. 8. FREUND, P. R., L. B. ROWELL, T. M. MURPHY, S. F. HOBBS, AND S. H. BUTLER. Blockade of the pressor response to muscle ischemia by sensory nerve block in man. Am. J. PhysioZ. 236 (Heart Circ. Physiol. 5): H433-H439, 1979. 9. FRIEDMAN, D. B., F. B. JENSEN, J. H. MITCHELL, AND N. H. SECHER. Heart rate and arterial blood pressure at the onset of static exercise in man with complete neural blockade. J. Physiol.
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Lond.423:543-550,199O. 10. GALBO, H. Hormonal and Metabolic Adaptation to Exercise. New York: Thieme, 1983. 11. GALBO, H., N. J. CHRISTENSEN, K. J. MIKINES, B. SONNE, J. HILSTED, C. HAGEN, A-ND J. FAHRENKRUG. The effect of fasting on the hormonal response to graded exercise. J. Clin. Endocrinol. Metab. 52: 1106-1112, 1981. 12. GALBO, H., J. J. HOLST, AND N. J. CHRISTENSEN. The effect of different diets and of insulin on the hormonal response to prolonged exercise. Acta Physiol. &and. 107: 19-32, 1979. 13. GALBO, H., M. KJAZR, AND N. H. SECHER. Cardiovascular, ventilatory and catecholamine responses to maximal dynamic exercise in partially curarized man. J. Physiol. Lond. 389: 557-568, 1989. 14. KJAXR, M., N. H. SECHER, F. W. BACH, AND H. GALBO. Role of motor center activity for hormonal changes and substrate mobilization in exercising man. Am. J. Physiol. 253 (Regulatory Integrative Comp. Physiol. 22): R687-R695, 1987. 15. KJAXR, M., N. H. SECHER, F. W. BACH, S. SHEIKH, AND H. GALBO. Hormonal and metabolic responses to dynamic exercise in humans: effect of sensory nervous blockade. Am. J. Physiol. 257 (Endocrinol. Metab. 20): E95-ElOl, 1989. 16. LASSEN, A., ,J. H. MITCHELL, D. R. REEVES, JR., H. B. ROGERS, AND N. H. SECHER. Cardiovascular responses to brief static contractions in man with topical nervous blockade. J. Physiol. Lond. 409: 333-341,1989. 17. LEONARD, B., J. H. MITCHELL, M. MIZUNO, N. RUBE, B. SALTIN, ANII N. H. SECHER. Partial neuromuscular blockade and cardiovascular responses to static exercise in man. J. Physiol. Lond. 359: 365-379, 1985. 18. LEWIS, S. F., P. G. SNELL, W. F. TAYLOR, M. HAMRA, R. M. GRAHAM, W. A. PETTINGER, AND C. G. BLOMQVIST. Role of muscle mass and mode of contraction in circulatory responses to exercise.
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J. Appl. Physiol. 58: 146-151, 1985. 19. MITCHELL, J. H., D. R. REEVES, JR., H. B. ROGERS, N. H. SECHER, AND R. G. VICTOR. Autonomic blockade and cardiovascular responses to static exercise in partially curarized man. J. Physiol. Lond. 413:433-445,1989. 20. MITCHELL, J. H., D. R. REEVES, JR., H. B. ROGERS, AND N. H. SECHER. Epidural anaesthesia and cardiovascular responses to static exercise in man. J. Physiol. Lond. 417: 13-24, 1989. 21. NAZAR, K., D. JEZOVA, AND E. KOWALIK-BOROWKA. Plasma vasopressin, growth hormone and ACTH responses to static handgrip in healthy subjects. Eur J. Appl. Physiol. Occup. Physiol. 58: 400404, 1989. 22. RICHTER, E. A., B. KIENS, B. SALTIN, N. J. CHRISTENSEN, AND G. SAVARD. Skeletal muscle glucose uptake during dynamic exercise in man: role of muscle mass. Am. J. Physiol. 254 (Endocrinol. Metab. 17): E555-E561, 1988. 23. SAVARD, G. K., S. STRANGE, B. KIENS, B. SALTIN, E. A. RICHTER, AND N. J. CHRISTENSEN. Norepinephrine spillover during exercise in active versus resting skeletal muscle in man. Acta Physiol. Stand. 131: 507-515,1987. 24. SIEGEL, S. Nonparametric Statistics for the Behavioral Sciences. Tokyo: McGraw-Hill Kogakusha, 1956. 25. STAUNTON, H. P., S. H. TAYLOR, AND K. W. DONALD. The effect of vascular occlusion on the pressor response to static muscular work. Clin. Sci. Lond. 27: 283-292, 1964. 26. VICTOR, R. G., S. L. PRYOR, N. H. SECHER, AND J. H. MITCHELL. Effects of partial neuromuscular blockade on sympathetic nerve responses to static exercise in humans. Circ. Res. 65: 468-476,1989. 27. WATSON, R. D. S., A. J. F. PAGE, W. A. LITTLER, D. H. JONES, AND J. L. REID. Plasma noradrenaline concentrations at different vascular sites during rest and isometric and dynamic exercise. Clin. Sci. Lond. 57: 545-547,1979.
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responses to static anesthesia
H. GALBO,
Departments of Anesthesia and Internal Medicine TTA, Rigshospitalet, Department of Clinical Chemistry, Gentofte Hospital and Department of Medical Physiology B, Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark
M., N. H. SECHER, F. W. BACH, H. GALBO, D. R. AND J. H. MITCHELL. Hormonal, metabolic, and cardiovascular responses to static exercise in humans: influence of epidural anesthesia. Am. J. Physiol. 261 (Endocrinol. Metab. 24): E214-E220, 1991.-To determine the role of reflex neural mechanisms for hormonal, metabolic, heart rate (HR), and blood pressure (MABP) changes during static exercise, seven healthy young males performed lo-min periods of two-legged static knee extension both during control and during epidural anesthesia. Comparisons were made at identical absolute (29 Nm) and relative [ 15% maximal voluntary contraction (MVC)] force. Afferent nerve blockade was verified by hypesthesia below Tlo-T12 and attenuated postexercise ischemic pressor response. Leg strength was reduced to 67 & 5% of control. At same relative force, increases in MABP and HR occurred more rapidly without than with epidural anesthesia (P < 0.05). This difference was diminished during identical absolute force. Changes in plasma concentrations of catecholamines followed the pattern of HR and MABP responses, with differences between epidural and control experiments being most pronounced early in the work period. Plasma ,&endorphin was elevated only after control exercise. No response at 15% MVC was found for growth hormone, adrenocorticotropic hormone, insulin, glucagon, cortisol, glycerol, free fatty acids, or glucose (P > 0.05). In conclusion, during static exercise with large muscle groups and moderate relative force, modest changes in plasma hormones and metabolites take place. Furthermore, afferent nervous feedback from contracting muscles is important in regulation of blood pressure, heart rate, and catecholamine responses during static exercise in humans. KJAZR, REEVES,
JR.,
14). On the other hand, experiments with epidural anesthesia have indicated that neural feedback from exercising muscles is involved in eliciting the ,&endorphin and ACTH responses to dynamic exercise (15). Compared with dynamic exercise, much less is known regarding the regulation of metabolism and circulation during static exercise. Regional anesthesia has been used to rule out a role of afferent nerves in regulation of cardiovascular responses to brief static contractions (9, 16), but afferent nerves appear to play an important role in cardiovascular regulation during sustained static contraction of a small muscle mass (20). Whether reflex neural mechanisms are involved in the regulation of hormonal and metabolic changes to static exercise is unknown. In the present study, we determined the role of reflex neural mechanisms for hormonal, metabolic, heart rate, and blood pressure changes during two-legged sustained static knee extension. Epidural anesthesia was used to reduce sensory feedback from contracting muscles. Epidural anesthesia, in addition to sensory blockade, also causes a reduction in maximal leg strength. Accordingly, responses during epidural anesthesia were compared with responses in control experiments both at identical absolute and relative forces. MATERIALS
AND
METHODS
command”) as well as reflex mechanisms are involved in the generation of hormonal and metabolic responses in humans, whereas reflex control dominates the cardiovascular responses (7, 13-E). With the use of partial neuromuscular blockade (with tubocurarine), which increases the subjective effort and probably the motor center activity necessary to fulfill a given work load, it is found that central command is involved in regulation of catecholamine, adrenocorticotropic hormone (ACTH), and growth hormone (GH) responses and of mobilization of glucose and free fatty acids (FFA) during exercise (13,
Subjects. Seven healthy males with a mean age of 26 yr (range 22-34 yr), weight of 71 kg (range 62-78 kg), and height of 177 cm (range 170-182 cm) gave informed consent to participate in the study, which was approved by the Municipal Ethical Committee of Copenhagen. None of the subjects were taking any medications, and none had a family history of endocrine disorders. All subjects had previously participated in exercise experiments conducted by the authors. Procedures. Each subject appeared in the laboratory on two occasions separated by 3-7 days. Each time, subjects were studied in a semisupine position, with the upper part of the body forming an angle of 45” with the couch. Static muscle contractions were performed with the knee extensors (quadriceps femoris), the knee angle being 90” (17). The force was determined with a circular strain gauge applied above the ankles. Results were calculated as a torque by multiplying the applied force by
E214
the American
arterial blood pressure; heart rate; catecholamines; epinephrine; norepinephrine; glucagon; insulin; growth hormone; @-endorphin; metabolic regulation
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Central
019%1849/91
neural
$1.50
(“Central
Copyright
0 1991
Physiological
Society
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the distance from the ankles to the center for rotation in the knee. Subjects arrived in the laboratory at 8 A.M. after a loh overnight fast, having.abstained from training, alcohol, and tobacco on the day before. Before exercise, a l.O-mm inner diameter (ID) cannula was inserted into the left brachial artery and was connected to a pressure transducer posl’tioned at heart level. A 1.2mm ID venous catheter was placed in a vein on the back of the hand and was kept open by flushing with small amounts of saline (~200 ml). Subjects were allowed to drink water as wanted throughout the experimental period. The electrocardiogram was taken from bipolar chest electrodes. Heart rate, mean arterial blood pressure, and force were continuously monitored before, during, and after static contractions on a Siemens-Elema recorder. At the beginning of the experiment and before each exercise period, the combined strength of the two legs was established as the greatest of three maximal voluntary contractions (MVC). In control experiments, subjects performed two periods of 10 min static contractions aiming at a force corresponding to 15% of MVC determined immediately before exercise. The two exercise periods were separated by 30 min of rest. Perceived exertion was expressed by the subjects on a scale from 6 to 20 (4) where “7” represents hard, and “20” very very light, “13” means somewhat signifies very very hard exertion. On a second experimental day, a 20-gauge spinal needle was inserted in the epidural space through vertebral interspace L:,-L, in the midsagittal line employing the loss of resistance technique. Epidural anesthesia was induced by injection of 18-24 ml (according to body weight) of 1.5% lidocaine (Xylocain, Astra). The level and type of anesthesia was established both before and after exercise by clinical neurological examination of both legs. A cotton ball run along the leg determined sensation to light touch. Sharp pain and deep pain were evaluated by pin pricking and by squeezing the Achilles tendon, respectively. Temperature sensation was evaluated by alternately placing heated and cooled sides of a tuning fork against the leg. Position sense was evaluated by moving the big toe and with the subject telling its position (i.e., dorsiflexion). Finally, vibration sense was evaluated by placing a vibrating tuning fork upon the patella and the planta. During epidural anesthesia, subjects performed two IO-min periods of static contraction separated by 30 min of rest. In the first period, a force corresponding to 15% MVC was aimed at, whereas, in the second period, force was increased to match the force used in the control experiment. This order of the experimental periods during epidural anesthesia was chosen because unspecific stress, if present, during the experiment is expected to be highest in the beginning of an experiment, making it as difficult as possible for us to detect differences at same relative work force between experiments with epidural anesthesia and control experiments. Static contraction was begun when the level of cutaneous hypesthesia was constant over a 5-min period (40 t 5 min after administration of epidural anesthesia). Ten seconds before the end of the second exercise
EPIDURAL
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period on both the day without and on the day with epidural anesthesia, circulatory occlusion of both legs was established with pneumatic pressure cuffs placed proximally on the thighs and inflated to 400 mmHg. Occlusion was verified by disappearance of arterial pulses on the feet. The cuffs remained inflated for the following 3 min of recovery. After deflation of the cuffs, recording was continued for further 2 min of rest. This procedure has earlier been shown to elicit a postexercise ischemic pressor response that is diminished when successful epidural blockade is present (7, 8). 1Methods. Blood for the various analyses was sampled from the arterial cannula before, during, and after static exercise at 5- or lo-min intervals (see Figs. l-5 and Tables 1 and 2). Blood for catecholamine analysis was collected into chilled glass tubes containing ethylene glycol-bis(P-aminoethyl ether)-N,N,N’,N’-tetraacetic acid and reduced glutathione and were placed on ice. Samples were promptly centrifuged at 4°C and plasma was stored at -8OOC. Catecholamine concentrations were determined by a single isotope radioenzymatic method (3). The concentrations of insulin (ll), pancreatic glucagon (l2), GH (12), ACTH (6), cortisol (12) and ,& endorphin (2) were determined with radioimmunoassays previously described by the authors. Plasma glucose was determined spectrophotometrically with the hexokinase method. FFA, glycerol, and lactate were determined by enzymatic fluorometric methods. Lidocaine and its active metabolite monoethylglycinxylidin were determined in serum by high-performance liquid chromatography ( 1). For statistical evaluation, Friedman’s test was used to test whether significant changes occurred with time (24). If so, the change was located by the Wilcoxon ranking test for paired data (Pratt’s modification). This test was also used to evaluate differences between epidural and control experiments. A P value of 0.05 (two-tailed testing) was considered significant. RESULTS
Evaluation of epidural anesthesia. At rest, all variables were similar on the two experimental days (Figs. l-5). Epidural anesthesia resulted in cutaneous hypesthesia below T9-Tll (mean Tlo) before onset of the first contraction period. After the end of the second contraction period, cutaneous hypesthesia was still present below Tlo-TiZ (mean T,,). In this area, sensations of light touch and sharp pain were diminished, and the sensations of deep pain and temperature were markedly impaired, whereas position and vibration senseswere unimpaired. Furthermore, epidural anesthesia attenuated the postexercise pressor response from 26 t 6 to 16 t 4 mmHg (mean t SE of individual mean differences between values obtained 1,2, and 3 min postexercise, respectively, and at baseline) (P < 0.05) (Fig. 1) and reduced the muscle strength to 67 t 5% of the control value (Table 1). Arterial plasma concentrations of lidocaine increased in all subjects after administration of epidural anesthesia (Table 2). In response to epidural anesthesia, plasma concentrations at rest of norepinephrine, epinephrine, ACTH, cortisol, and glucagon decreased by ll-45% (P
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E216
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0 -0
Control
.- -0
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1. Static two-legged knee extension without and with epidural anesthesia
TABLE anesthesia
Period
MVC, Nm %MVC Force, Nm RPE (6-20)
1
Period
2
Control
Epidural
Control
Epidural
215k15 15kO.2 32t3 18.5kO.5
144*13* 15kO.3 22t2* 18.2kO.6
198t17 15kl.l 29t2 18.0t0.7
133*25* 21t3.0* 28-e3 l&7*0.4
Values are means k SE. Period I, identical relative work load; period 2, identical absolute work load in experiments with epidural anesthesia compared with control experiments. MVC, maximal voluntary contraction as an indication of maximal quadriceps strength, established by taking the greatest of 3 maximal 2legged knee extensions. RPE, rating of perceived exertion on a Borg-scale ranging from 6 to 20. * Significant difference from control value (P c 0.05).
60-
2. Plasma lidocaine concentration before and 40 min after epidural anesthesia TABLE
120-
Subject 1
80-
I**
OJ
( **
I
I**
Means
1
15% w
-40
WC
29 Nm I
0 10 Exercise
I
I
20 30 Rest
50 40 Exercise
60 65 min Recovery
FIG. 1. Heart rate and mean arterial blood pressure at rest and during IO-min periods of 2-legged static knee extension without (control) or with epidural anesthesia. Seven subjects were compared both at same relative [15% maximal voluntary contraction (MVC), this intensity being used in both exercise periods in control experiments] and at same absolute (29 Nm) force. -40, Blood samples taken immediately before administration of epidural anesthesia. When clinical evaluation indicated sufficient effect of epidural blockade, 2nd blood sample was taken 40 2 5 min later, immediately before exercise was started. Values are means & SE. SE are given only every 5th min and at points where statistically significant difference was obtained between experiments without and with blockade (** P < 0.05).
< 0.05) (Figs. 2, 3, and 4). Only for ACTH did the decrease result in a plasma concentration that immediately before onset of exercise was significantly lower than seen in control experiments (P < 0.05) (Fig. 3). Static exercise at sanze reZatiue force. In both experiments without and with epidural anesthesia, subjects maintained the intended relative force throughout the contraction period. Blood pressure and heart rate increased more rapidly in control than in epidural anesthesia experiments (Fig. 1). Furthermore, also plasma concentrations of epinephrine and norepinephrine rose more rapidly in experiments without than with epidural anesthesia (Fig. 2). Plasma concentrations of most remaining hormones did not change significantly (Figs. 3 and 4). However, in control experiments, but not in experiments with epidural anesthesia, plasma ,&endorphin concentrations reached a maximum 5 min postexercise (Fig. 3). Blood lactate increased similarly in experiments with-
2 3 4 5 6 7 t SE, mg/l
Basal
co.005 co.005 co.005 co.005 co.005 co.005 co.005 co.005
406 After
min Basal
0.129 0.386 0.309 1.179 0.655 0.497 0.145 0.471t0.137*
Basal value was obtained in arterial blood drawn immediately before administration of 18 ml (subjects I and 2) or 24 ml (subjects 3-7) 2% lidocaine in epidural space through vertebral interspace L,-L,. After administration of lidocaine (40+5 min), and immediately before onset of exercise, 2nd arterial sample was drawn. All samples contained CO.01 mg/l of lidocaine metabolite monoethylglycinxylidin. * Significant difference from basal value (P < 0.05).
out and with epidural anesthesia, whereas plasma glucose and FFA concentrations never changed significantly (Fig. 5). Glycerol concentration increased during twolegged knee extension, and this increase was not altered by administration of epidural anesthesia (Fig. 5). Within the recovery period after the first exercise period, all hormonal, metabolic, and cardiovascular parameters returned to basal levels (Figs. l-5). Static exercise at same absolute force. In control experiments, maximal force was slightly smaller in the second compared with the first exercise period, but the relative force (15% MVC) and rate of perceived exertion were kept unchanged (Table 1). Also, responses of heart rate, blood pressure, catecholamines, and lactate were similar in the first and second exercise periods in control experiments (Figs. 1, 2, and 5). In the second contraction period during epidural anesthesia, force was increased to become the same in absolute terms as in control experiments (Table 1). Accordingly, in epidural blockade experiments, relative force was higher in the second (21% MVC) compared with the first (15% MVC) exercise period, and blood pressure, heart rate, and epinephrine rose more rapidly in the former compared with the latter period (Figs. 1 and Z), whereas GH and ACTH concentrations only increased in the former (Fig. 3). In the second exercise period, blood pressure increased more rapidly in experiments without than with epidural
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STATIC
0 -0 o--o
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EPIDURAL
E217
ANESTHESIA
Control Epidural anesthesia
0l
w
0 Control
- -0
Epidural anesthesia
1611252
I
84-
I
* w
I
I I 1
I
I
I
I
I
I
1
.-C L p’;
07 2z w z &
4
32lOI
0.2 -
I
I
29 Nm
-40
0
10 Exercise
I
I
20
30 Rest
40 50 min Exercise
M;. 2. Catecholamine concentrations in plasma at rest, during, and after 2 static contraction periods. Seven subjects were studied without (control) or with epidural anesthesia. Values are means t SE. * Statistical difference between experiments (P < 0.05). For further explanation see Fig. 1.
blockade (Fig. 1). The same tendency was seen for norepinephrine concentrations (Fig. 2) (P < O.l), whereas heart rate and epinephrine responses were similar in control experiments and epidural blockade experiments (Figs. 1 and 2). In the second exercise period, GH and ACTH increased during epidural anesthesia (21% MVC) but not in control experiments (15% MVC) (Fig. 3). Remaining hormones and plasma glucose never changed from basal levels (Figs. 3-5). Blood lactate and plasma concentrations of glycerol and FFA rose similarly in response to exercise in control and epidural anesthesia experiments (P > 0.05) (Fig. 5). During recovery the cuffs maintained blood pressure and heart rate values more closely to exercise values in control experiments than in experiments with epidural blockade (Fig. 1). The postexercise ischemic pressor response [26 t 6 (control) vs. 16 t 4 mmHg (epidural)] and the postexercise heart rate response [ 23 t 4 (control) vs. 12 t 3 beats/min (epidural)] were significantly diminished (P < 0.05) by epidural blockade. DISCUSSION
In the first exercise period, responses of blood pressure, heart rate, and catecholamines to static two-legged contractions of the same relative force were less during epidural anesthesia than during control experiments, with the difference between experiments being most pronounced early in the exercise period (Figs. 1 and 2). These findings confirm previous observation for heart rate and blood pressure during static one-legged exercise (20). A significant increase in plasma ,0-endorphin concentrations was seen 5 min after control exercise,
-40
0
10
Exercise
20
30 Rest
40 50 min Exercise
FIG. 3. Effect of epidural anesthesia on concentrations of pituitary hormones [growth hormone (GH), ,8-endorphin, adrenocorticotropic hormone (ACTH)] and cortisol in plasma at rest and during 2 static contraction periods. Values are means & SE. * Statistical difference between experiments (P c 0.05). Values were different from previous value in experiments with (m) or without (A) epidural blockade (P < 0.05). For further explanation see Fig. 1.
whereas no increase was seen in response to exercise during epidural blockade (Fig. 3). As relative force as well as rate of perceived exertion (Table 1) were similar in the first exercise period in the two experiments, motor center activity was probably also identical. These findings indicate that afferent nervous feedback from exercising muscle significantly enhances the increase in blood pressure, heart rate, catecholamines, and ,&endorphin in response to static exercise. For blood pressure and heart rate, this is in accordance with findings obtained with epidural anesthesia both during static contraction with a smaller muscle mass than used here (one- vs. twolegged contraction) (20) and during dynamic bicycle exercise (7). Epidural blockade has previously been shown to abolish the P-endorphin response to dynamic exercise (15) In the second exercise period, absolute force was the same, but relative force was higher in epidural than in control experiments. Also in this period the responses of blood pressure and norepinephrine to static contractions tended to be less brisk during epidural blockade (Figs. 1 and 2), but differences were less marked than in the first
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STATIC
EXERCISE
0-0 Control l - -o Epidural
anesthesia
E218
DURING
EPIDURAL
0 -0
I 1
I
l
5%
I I
I
I
I
I I 1
I I
I
f?F
IO
Exercise
anesthesia
I
0.8 06 0.4 0.2 0 l
7 ‘;- 0.08
29 Nm I
40 0
Control
- -0 Epidural
I
r a>L g E -I E
I
ANESTHESIA
1
20 30 Rest
---
40
50 min
Exercise
FIG. 4. Effect of epidural blockade on plasma concentrations of pancreatic hormones at rest and during periods of static contraction. Values are means t SE. For further explanation see Fig. 1.
exercise period (Figs. 1 and 2). When cuffs were inflated at the end of two-legged, in contrast to one-legged static exercise, both blood pressure and heart rate responses were less well maintained during postexercise ischemia in epidural blockade compared with control experiments (Fig. 1). These findings enhance the conclusion that neural feedback is an important stimulus for sympathetic activity and cardiovascular responses during static exercise (20). However, epidural blockade did not abolish cardiovascular and hormonal response to static contractions. Furthermore, in experiments with epidural anesthesia, increases in relative force and perceived exertion from the first to the second exercise period were accompanied by increases in responses of blood pressure, heart rate, catecholamines, GH, and ACTH (Figs. l-3). These findings suggest that activity in motor centers may directly elicit autonomic neuroendocrine responses. The existence of such a central command mechanism has previously been proposed from dynamic exercise experiments in which motor center activity was varied by the use of partial neuromuscular blockade (14). This technique has also been used to demonstrate that central neural mechanisms are involved in blood pressure and heart rate responses to static exercise (17, 19, 26). Probably, both neural feedback from working muscle and central command mechanisms determine the activity in higher neuroendocrine centers during exercise. Redundancy of the two mechanisms as well as nonlinear relations between total stimulus (sum of central and peripheral input) and effects may explain that differences in responses of blood pressure, heart rate, and catecholamines between experiments with and without epidural blockade were most pronounced early during contractions and diminished as stimulus intensity increased with duration of exercise
I 0
j
r7YIrs%"VC
I
I
1
1
1
t
I
29 Nm
4
-40
0 10 20 30 40 50 min Exercise Rest Exercise FIG. 5. Effect of epidural blockade on plasma concentrations of glucose, glycerol, and free fatty acids (FFA) and on blood lactate concentrations in 7 subjects. Values are means & SE. For further explanation see Fig. 1.
(Figs. 1 and 2). Sensory nerve fibers were blocked in our subjects, as cutaneous hypesthesia was present below Tlo-T12. Throughout the study, a gradual regression of the level of the block took place. However, it is important to note that, as indicated by level of hypesthesia, the block remained at least as high as T10-T12 by the end of the study. This means that, at all times during the experimental period, cutaneous hypesthesia was present caudal to T10-T12. In addition to sensation of light touch, neurological examination revealed impairment of sharp and deep pain and temperature sensation in the same area, indicating that activity in small unmyelinated and myelinated sensory fibers from exercising extremities was markedly reduced. Furthermore, the ischemic pressor response, which normally is found after static exercise (17, 25), was diminished after exercise with epidural anesthesia (Fig. l), a finding that previously has been taken to indicate blockade of small unmyelinated sensory nerve fibers (7, 8). However, the postexercise ischemic pressor response was not abolished, indicating that blockade of unmyelinated fibers was not complete (Fig. 1). Thresholds for lidocaine blockade are identical in pain- and temperature-sensing and efferent sympathetic
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STATIC
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DURING
fibers. Accordingly, the finding that activity in the former fibers was impaired could suggest that also activity in the latter fibers should be impeded. However, pain- and temperature-sensing fibers are accessible to epidural blockade throughout the spinal cord, whereas sympathetic fibers do not project from the lower part of the spinal cord. The conclusion that efferent sympathetic nerves were probably not blocked is in agreement with a previous study in which we used an epidural anesthesia identical to the one in the present study. It was found that blood pressure responses both to 2 min of hand immersion in ice-cold water (cold pressor test) and to a Valsalva maneuver were not altered by epidural anesthesia (7). It could be argued that lidocaine administered epidurally, in addition to an effect on nerve fibers in the spinal cord, would have an effect on the measured parameters after uptake in the blood stream. However, the arterial plasma concentration of lidocaine measured immediately before exercise (Table 2) was lower than the concentrations known to be required for an effect on heart rate, blood pressure, and myocardial contractility (5). Furthermore, according to earlier studies of the time course of plasma lidocaine after epidural administration, plasma levels of lidocaine were even lower during the periods of static exercise (5). In the present study, a significant increase in plasma concentration of catecholamines was seen after 5 min of static knee extension at 15% of MVC (Fig. 2). In contrast, no significant increase in plasma catecholamines was found in a previous study of static knee extension at 25% of MVC for 5 min (18). Still, in that study the average increase in plasma catecholamine concentration was identical to the one obtained in the present study, but dispersion of data was too large, probably due to poor assay precision, to allow significance. The increase in plasma norepinephrine concentration during two-legged static contraction at 15% MVC in the present study (Fig. 2) was similar in magnitude to the norepinephrine response obtained previously during dynamic exercise at 39% maximal Oz uptake with the same active muscle mass (22). Interestingly, however, in the present experiment the epinephrine response was three- to four-fold higher compared with dynamic exercise with the same muscle groups (22). One explanation for the finding that the norepinephrine response is low relative to that of epinephrine in static compared with dynamic exercise could be that release of norepinephrine into the circulation from active sympathetic nerves in contracting skeletal muscle (23) is impeded due to a lower blood flow. In the present experiments, plasma concentrations of GH and ACTH did only increase when exercise intensity was >20% MVC (Fig. 3). In a previous study of 9 min of static handgrip exercise, no increase in GH and ACTH was found despite an exercise intensity of 30% MVC (2 1). Correspondingly, cathecholamine responses were higher in the present experiments than during exhaustive isometric handgrip at 24 and 30% MVC, respectively (18, 27). These findings demonstrate that the mass of active muscle is crucial for the hormonal response to static exercise. The concentrations of glucagon and insulin did not
EPIDURAL
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ANESTHESIA
change during static contractions (Fig. 4). A decrease in plasma glucose and an increase in sympathetic nervous activity, respectively, are the major determinants in secretion of these hormones during dynamic exercise (10). As plasma glucose levels did not change and norepinephrine responses were small during static contractions, the lack of pancreatic hormonal responses are compatible with the view that pancreatic hormonal secretion is controlled by the same mechanisms in static and dynamic exercise (Figs. 2, 4, and 5). From the present study, it is concluded that, during low-intensity static exercise with large muscle groups, only modest changes in plasma hormones and metabolites are seen. The mass of active muscle is crucial for the hormonal response to static exercise. The epinephrine response is high relative to that of norepinephrine during static compared with dynamic contractions. Furthermore, afferent nervous feedback from contracting muscles plays an important role in regulating blood pressure, heart rate, and catecholamine responses during static exercise in humans. Lisbeth Kall is thanked for performing excellent technical assistance. Helga Flachs and Finn Christensen from the Department of Clinical Chemistry, University Hospital of Copenhagen are thanked for performing the lidocaine analysis. This work was supported by the Danish Medical Research Council Grants 12-5936, 125903, 12-7797, and 12-9360, the Frank M. Ryburn, Jr., Chair in Heart Research, La Cours Fund, and Rogers Lacy Research Fund in Cardiovascular Disease. Present address of D. R. Reeves, Jr., and J. H. Mitchell: Harry S. Moss Heart Center, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 752359034. Address for reprint requests: M. Kjzer, Dept. of Medical Physiology B, Panum Institute, 3 Blegdamsvej, DK-2200, Copenhagen N, Denmark. Received
4 December
1990; accepted
in final
form
10 April
1991.
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