Acetazolamide alters temperature during submaximal exercise W. F. BRECHUE Human
AND
Performance
J. M. STAGER
Laboratory,
Indiana
University,
BRECHUE, W. F., AND J. M. STAGER. AcetaxoZamide alters temperature regulation during submaximal exercise. J. Appl. Physiol. 69(4): 1402-1407, 1990.-Acetazolamide (ACZ), a potent carbonic anhydrase inhibitor, is known to decreasesubmaximal exercisetolerance under normoxic and hypoxic conditions. These decrements in performance occur despite the maintenance of O2 consumption and CO, removal. Because AC2 is a diuretic, it induces a moderate hypohydration that may have a role in reducing the ability to sustain exercise through cardiovascular and thermoregulatory impairment. To investigate this potential impairment, seven healthy males between 21 and 35 yr of age were studied in a double-blind crossoverdesign (placebo vs. ACZ). ACZ was administered in three 250-mgoral doses14,8, and 2 h before exercise. Subjects exercisedat 70%peak O2uptake for 30 min on a cycle ergometer in a normoxic thermoneutral environment (ZSOC,40% relative humidity). Results indicate that exercise minute ventilation was greater but O2 uptake, CO2 output, and respiratory exchange ratio did not differ with ACZ. ACZ led to lower mean skin (0.7”C), higher rectal (0.6”C), and higher mean body temperatures (0.4”C) after 30 min of exercise. Whole-body sweat loss was reduced 23%, and heat storage during the exercisebout wasincreased55%. Stroke volume decreased25%, and arteriovenous O2 difference increased 15%. A significant inverse relationship (r = -0.63) between heart rate and stroke volume was observed.It is concluded that previously reported decreasesin the ability to sustain submaximal exercise with ACZ may be related to hypohydration-induced impairment of the cardiovascular and thermoregulatory systems. body temperature; carbonic anhydrase; acute mountain sickness;altitude ANHYDRASE is the enzyme that catalyzes the reversible hydration of CO2 and the dehydration of HCO; (21). As such, carbonic anhydrase is the principal enzyme in the pathway for transport and elimination of metabolic and nonmetabolic COZ. Because early investigators considered the enzyme so essential to the maintenance of CO2 flux, they predicted that complete carbonic anhydrase inhibition during heavy exercise would be life threatening (33). However, when tested during heavy exercise at near-maximal rates of CO2 production (VCO~), COn output was maintained regardless of the 98.8% inhibition of erythrocyte carbonic anhydrase (33). Despite the lack of a significant disruption of gas exchange with carbonic anhydrase inhibition during exercise, recent observations suggest that clinically prescribed doses of acetazolamide (ACZ) reduce submaximal exercise endurance time in humans by -30% under acute hypoxic as well as normoxic conditions (32). Currently CARBONIC
1402
regulation
0161-7567/90 $1.50 Copyright
0
Bloomington,
Indiana
47405
the mechanism(s) responsible for the decreased ability to sustain submaximal exercise with ACZ is unknown. Because ACZ is a diuretic, the inability to sustain submaximal exercise with carbonic anhydrase inhibition may reflect losses in body water (4). Disturbances in body water volumes are well known to influence cardiovascular and thermoregulatory function and the ability to sustain prolonged submaximal exercise (1, 17, 26, 29). Hypovolemia reportedly leads to cardiovascular adjustments during exercise that ultimately act to preserve central blood volume and blood pressure at the expense of the ability to thermoregulate (12, 24). Heat loss is limited and prevents continuation of exercise as a result of excessive hyperthermia. ACZ continues to be effectively employed as a prophylaxis for acute mountain sickness (3) and as a treatment for glaucoma (34). Many individuals using ACZ expect to engage in physical activity, particularly those visiting moderate altitudes; therefore an understanding of the consequences of its use is warranted (22). The objective of the present investigation was to quantify the effects of carbonic anhydrase inhibition by ACZ on appropriate measures of cardiovascular and thermoregulatory function during submaximal exercise. It was hypothesized that therapeutic doses of ACZ would impair exercise thermoregulation by means of dehydration. METHODS
Seven untrained healthy active males participated in this investigation. Descriptive data are found in Table 1. Each subject received a written and oral explanation of all procedures and potential risks and provided written consent in accordance with the Indiana University Committee for the Protection of Human Subjects. Experimental protocol. Each subject participated in an incremental maximal exercise test and two 30-min submaximal exercise tests on a cycle ergometer. One week separated each of the three exercise bouts. The submaximal exercise bouts were administered in a repeatedmeasures crossover design for treatment (placebo vs. ACZ). The order of treatments was randomized, and the drug was dispensed in double-blind fashion. The submaximal exercise bouts were performed at 70% peak 02 consumption (~oJ in a normoxic thermoneutral environment (barometric pressure 741.5 t 3.7 Torr, ambient temperature 25 t 0.3OC, relative humidity 48 t 2.0%). ACZ was administered in three oral doses of 250 mg 14, 8, and 2 h before the submaximal exercise bout (30).
1990 the American
Physiological
Society
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
ACETAZOLAMIDE
DURING
1. Subject characteristics
TABLE Age, Yr
30.3t5.2 Values
Peak 00,
Height, cm
Weight, kg
l/min
183.1k6.3
81.53t11.00
3.58t0.60
are means
& SD of
ml. kg-’
l
min-l
44.2t7.4
7 subjs.
To conceal identity, both treatments were administered in identical fashion and packaged in unmarked gelatin capsules. All subjects were 10 h postprandial for each experiment, and water was provided ad libitium. Measurement of peak VOW. Peak Vo2 was determined using a modified, continuous, progressive work load protocol on a cycle ergometer (Monark 686) (2). Pedal frequency was maintained at 60 rpm throughout the test. Criteria for termination of the test were 1) no further increase in Vo2 with increased work load, 2) volitional exhaustion, and 3) respiratory exchange ratio (R) >l.lO. Respiratory gas collec tions with an open-flow indirect calorimetry system were made while the subject breathed ambient air through a two-way nonbreathing valve (model 2700, Hans Rudolph, Kansas City, MO). Expired gases were passed through a &liter mixing chamber from which a sample was continuously drawn by O2 (model S3Al) and COa (model CD-3A) medical gas analyzers (Applied Electrochemistry, Ametek Instruments, P ittsburgh, PA). The analyzers were calibrated before and after each test with gases previously verified by ’ the micro -Scholander technique. Minute ventilation m was determined by an electronic turbine-based flowmeter (model VMM-2, Sensormedics, Anaheim, CA) mounted on the inspired side. Analog outputs from all three devices were continuously monitored by an on-line microcomputer (PC-XT, IBM, Armonk, NY) via an analogto-digital board (DT-2801, Data Translations, Marlborough, MA). Heart rate was monitored continuously with an Exersentry cardiotachometer (Computer Instrument, Hempstead, NY). SubmaximaL bout protocol. On reporting to the laboratory, subjects voided their bladder and nude body weight (kO.01 kg) was recorded. After collection of a preexercise blood sample and preexercise metabolic data, subjects began pedaling at 60 rpm with no resistance. In three l-mm intervals the ergometer resistance was increased in equal stages to a work load that corresponded to 70% peak vo2. VE, v02, CO:! production (%02), and R were determined using the previously described indirect calorimetry system before exercise and after 15 @Id and 30 min of exercise (t&. Thermoregulatory variables. Body core temperature (rectal, T,) was estimated by insertion of a vinyl-clad thermistor 10 cm beyond the anal sphincter (no. 511, Yellow Springs Instruments). Mean skin temperature was determined from a weighted average of skin temperatures (Tsk) at four sites: chest, arm, medial thigh, and lateral calf (27). Mean body temperature (Tb) was calculated by weighted T,k and T, according to Burton (6). All thermistors were calibrated against a National Bureau of Standards certified thermometer. Whole-body sweat loss was estimated from the difference between pre- and postexercise body weight corrected for respira-
SUBMAXIMAL
EXERCISE
1403
tory water loss (23). Whole-body conductance was calculated from metabolic rate and changes in T, and T,k (25) CLdiovascuZar variables. Cardiac output was calculated from the product of heart rate and stroke volume before exercise and at t15and taO.Heart rate was measured for 30 s during exercise by palpation of the radial artery. Stroke volume was estim .ated by elec trical impedance cardiography using a Minnesota impedance cardiograph (Surcom, Minneapolis, MN). Subjects were asked to stop exercise momentarily to alleviate motion artifact, which disrupts the impedance signal. Techn .iques and equations of Kubicek et al. (19) were used with a resi .stivity correction for hematocrit. The i.mpedance cardiograp lh was calib rated at each use with an internal standard and a simple resistance-capacitance circuit of known impedance. Cardiograph source signal and amplitude and frequency were verified before the study by use of an oscilloscope. Blood variables. Blood samples were obtained from an antecubital vein without stasis before exercise and at t15 and tao. The before-exercise sample was collected after 30 min in the upright seated position. All blood was collected in heparinized syringes. After centrifugation and separation, aliquots of plasma were analyzed for osmolality by vapor point depression, Na+ and K+ by flame photometry, and total proteins by refractometry. Whole-blood was analyzed for total hemoglobin spectrophotometrically (OSM-3, Radiometer, Copenhagen), and blood gases and pH were analyzed by el .ectrode (ABL-3, was determined Radiometer, Copenhagen .). Hematocrit by microcapillary technique in quadruplicate and corrected for changes in venous-to-whole-body ratio and trapped plasma (8). Blood volume was estimated by use of CO rebreathing (27). Changes in plasma volume were estimated by changes in hemoglobin concentration and hematocrit according to Dill and Costill (9). Statisticat analysis. Dependent variables measured during the submaximal exercise bouts were applied to a time series analysis. F ratios were computed using analysis of variance on the SPSS-X statistical package. Family-wise type I error rate was set at 0.5 and controlled during multiple F tests by correcting the per comparison error rate with the modified Bonferroni technique (18). Bonferroni adjustments resulted in an alpha level of 0.04 for omnibus F tests and 0.03 on follow-up tests. Post hoc analysis consisted of tests of simple main effects and the Tukey test where appropriate (18). All data are presented as means t SE. RESULTS
ACZ resulted in a moderate hypohydration before exercise, evidenced by a 9.1% decrease in plasma volume compared with placebo. Plasma volume decreased during the first 15 min of exercise with placebo and ACZ (Table 2), with the greatest loss occurring during the placebo trials (542 ml at t15vs. 410 ml, placebo and ACZ, respectively). No further significant losses in plasma volume were observed in either treatment. Plasma osmolality, [Na’], and [K+] were not different between treatments, nor did they change with exercise. Metabolic acidosis as
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
1404
ACETAZOLAMIDE
DURING
SUBMAXIMAL
in ACZ or placebo trials were observed. Cardiac output and heart rate with ACZ were not different from placebo before exercise or at t15 and t30 (Table 5). It is important to note that technical problems inherent in the impedance procedure allowed analysis of cardiac impedance data on four of the seven subjects. Nevertheless a significant negative correlation between stroke volume and heart rate (r = -0.62, P < 0.02) was observed. Arteriovenous O2 difference was greater with ACZ (Table 5), whereas the changes in arteriovenous O2 difference were negatively correlated with cardiac output between trials
2. Plasma volume and protein concentrations
TABLE
Exercise
%Change in plasma volume Plasma volume, liters Difference, ml Total protein, g/d1 Total circulating protein, g Values 0.03.
are means
t15
Exercise
tSO
Placebo
ACZ
Placebo
ACZ
15.02
12.25
15.23
12.50
3.09t0.17
2.90t0.18*
3.07t0.17
2.90*0.14*
542249 8.19rtO.09 252tlO
410t61* 8.64*0.10* 250tll
554t57 8.19t0.10 251tll
410t76* 8.72t0.14* 251211
t SE of 7 subjs.
* Different
between
trials,
EXERCISE
(r = -0.71, P = 0.03).
P c
a consequence of ACZ was confirmed by a decrease in venous pH and HCO; (Table 3). The decreases in venous blood pH and HCO; observed before exercise were maintained throughout the 30 min of exercise. Total protein concentration increased from rest to exercise (5% at t15 and 6% at t3*) with ACZ, but no difference was observed with ACZ compared with placebo (Table 2). MetaboZic data. VOW, VCO~, and R were unaffected by ACZ before exercise and at each exercise interval compared with placebo (Table 4). Thus the relative intensity of the exercise, which was *designed to correspond to a work load of -70% peak Voz was unaffected by ACZ (69.9% peak %70z for placebo and 71.1% peak VO, for ACZ). VE was not different with ACZ at rest. However, VE during exercise with ACZ was greater (9.8% at t15 and 14.1% at t3*) than with placebo. Ventilatory equivalents (vE/v02 and vE/h02) with ACZ were higher at rest and at both exercise intervals with ACZ (Table 4). Furthermore, vE/v02 and vE/h02 were higher at t30 than at t15 within the ACZ trial. Thermoregulatory data. At rest, ACZ did not significantly alter mean Tb, mean Tsk, or T,,. After exercise, Tb in the ACZ trial was 0.4OC higher than in the placebo trial (36.2 vs. 36.6”C). ACZ reduced T,k 0.5OC at t15 and 0.7”C at t30 compared with placebo trials. T,k was not different between t15 and t3* in either treatment (Fig. 1B). There was no difference in T, between t15 and t30 in the placebo trial. T, at t30 in the ACZ trial was 0.7OC higher than at t15 (37.5 vs. 38.2”C) in the ACZ trial and 0.6OC higher than T, at t30 (37.6 vs. 38.2”C) in the placebo trial (Fig. 1A). Whole-body sweat loss was reduced 23%, from 30.0 to 23.1 g/min, with ACZ across the 30-min exercise period. Whole-body conductance did not differ at t15 between treatments but was lower at t30 with ACZ (Fig. ID). Cardiovascular data. Stroke volume was 26% less with ACZ (126 vs. 94 ml/beat) at t15 and 24% less at t30 (122 vs. 105 ml/beat, 24%; Table 5). No progressive changes
DISCUSSION
Thermoregulatory effects. The evidence indicating that ACZ alters thermoregulation during exercise stems from the greater increases in Tb with ACZ than with placebo. The greater increase in T,, and Tb with ACZ (Fig. 1A) is suggestive of an imbalance between heat gain and heat loss similar to that caused by hypovolemia and/or dehydration (12-14, 24). The exercise bouts employed were constant and identical in both treatments, and because no difference in Vo2 was observed across treatments, the possibility of any difference in the rate of heat production and mechanical or metabolic efficiency with ACZ is precluded. Furthermore, increases in Tb and heat content were not evident at rest with ACZ, suggesting that adequate heat loss was maintained during basal rates of internal heat production. Tb was affected only when challenged by high rates of heat generation (8-9 times greater than rest) requiring appropriate active heat loss responses. The increased heat production during exercise was not matched by adequate heat loss, as evident from a greater Tb rise with ACZ, which did not appear to approach steady state during the 30 min of exercise (Fig. lA ). Without artificial convection, radiation and evaporation are the principal routes of heat transfer available during stationary cycle ergometry. The present data suggest that ACZ leads to reductions in both of these avenues of heat loss. A reduction in the rate of heat transfer between the core and periphery was observed as reflected by the reduction in whole-body conductance (Fig. 1B). During exercise, an expansion of the warmer core isotherms is expected as heat transfer to the periphery is increased as a result of greater skin blood flow. This classic response to exercise was seen in both trials as indexed by increased whole-body conductance and T,k in transition from rest to exercise. However, the magnitude of the increase was blunted during ACZ trials. The lower whole-body conductance and T,k observed with ACZ is
3. Blood gas and acid-base status
TABLE
Rest
Exercise
Placebo
PH HCO;, Pvco,, Values
mM Torr
are means
ACZ
7.278kO.013 23.7t0.5 43.6t1.8 t SE of 7 subjs.
7.194t0.007 18.7t0.6* 40.8t1.8 Pvco,,
venous
Pco~. * Different
Placebo
Exercise ACZ
7.296kO.015 19.5t0.8 46.2t0.8 between
t15
7.216t0.007 14.lt0.6* 51.7t1.5* trials,
Placebo
7.326t0.010 19.9t0.8 45.1t0.9
tSO ACZ
7.249kO.016 14.3t0.7* 50.3t0.7*
P < 0.03.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
ACETAZOLAMIDE
DURING
SUBMAXIMAL
1405
EXERCISE
4, Metabolic data
TABLE
Rest Placebo
TjE, l/min BTPS I&, l/min VCO2, l/min R
Values
are means
AC2
8.4t0.5 0.31t0.01 0.25t0.02 0.81IltO.02 25.3kO.3 31.4t0.5
TjE/Vo2(ST~~) VE/Vco2(ST~~)
f: SE of 7 subjs.
Exercise Placebo
9.8t0.4 0.33kO.02 0.27rtO.02 0.82+0.02 27,9+0.2* 34.0*0.4*
* Different
between
t15 AC2
61.8t1.4 2.61kO.10 2.50t0.08 0.96t0.02 22.120.7 23.1kO.7 trials,
Exercise
across
trials,
ACZ
Placebo
68.4t2.5" 2.67t0.15 2.52t0.14 0.95t0.02 24.Oltl.3* 25.4kO.6"
P c 0.03; t different
tSO
64.3tl.l 2.58t0.15 2.4320.10 0.94t0.02 23.3t0.7 24.7kO.7
74.9+3.3? 2.67kO.14 2.48t0.12 0.92t0.02 26.2&1.7* 28.2t0.9*
P < 0.03.
33.0
38.8
32.5
s? z3
37.8
2 3 Ii $E
32.0
37.3
gG r"
31.5
5 iitp )- -
3 8 CL
z s5
36.8
31.0
30.5 I
I
15
Rest
6 3
I 30
I
1
I
Rest
15
30
I 15
I 30
FIG. 1. Thermoregulatory data. q , Placebo; A, ACZ. * Significantly different from placebo trial, P c 0.003; ** significant difference within trial as well as difference from placebo trial.
8 50.0 $iU-y 40.o ON Eg rE 30.0 gs 2s e3 20.0
IO.0 -
35.0 I
I
Rest
15
Time
TABLE
I 30
0.0 l
’ Rest
Time
(min.)
5. Cardiovascular
(min.)
data Rest
Heart rate, beats/min Stoke volume, ml Cardiac output, l/min Arteriovenous 02 difference, Values
are means
ml 02/100
t SE of 7 subjs.
* Difference
Exercise
Placebo
AC2
Placebo
68k9
67+10
140*14 126t2* 17.720.7 153t5
ml between
trials,
Exercise
t15 AC2
158&10 94t5 15.Ok1.3 178t4*
Placebo
1491r9 122*10* 18.3t0.3 141t5
.
tSO AC2
161217 105t8 17.Okl.l 157*5*
P < 0.03.
interpreted as being due to greater vasomotor tone and thus reduced cutaneous blood flow. This has previously been proposed during exercise after preexercise reductions in plasma volume (12, 24), and these studies have similarly concluded that the rise in T,, is due to impaired heat loss rather than an overt increase in heat production or a shift in the temperature at which the body is maintained.
Of greater consequence than the apparent reduction in radiative loss is the decreased evaporative heat loss observed during exercise with ACZ. Sweat loss was reduced 23% with ACZ compared with the placebo trial. This finding is also consistent with previous reports of decrements in sweat loss during hypohydration (10, 13, 17). The reduced sweating is reported to be related to both central and peripheral effects of preexercise hypo-
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
1406
ACETAZOLAMIDE
DURING
volemia. It has been suggested that afferent input to the hypothalmic thermoregulatory centers is reduced, with hypohydration altering the sweating response in situations similar to that observed here (13). Local control of reduced sweating is related to reduced peripheral blood flow, decreases in sweat gland activity (ll), and perhaps alteration of peripheral responsiveness to central sweating drive (24). Cardio vascular function. The disturbances in heat loss .re most likely secondary to alterations in cardiovasc ular control caused by ACZ. During a prolonged exercise bout, the increase in peripheral circulation necessary for metabolic and thermal purposes results in competition between the core and periphery for a proportion of cardiac output (24, 29). In effect, the metabolic requirement of the active tissues competes with blood flow needed for heat exchange mechanisms. During relatively mild exercise in the heat (40% maximal iToz) cardiac output has been shown to increase above that of cool environments, thus meeting the increased overall demand for blood flow (29). In contrast, vigorous exercise in the heat has been shown to be associated with reduced cardiac output, presumably due to a loss of plasma volume and, therefore, a reduced stroke volume. Because there is only limited ability to increase heart rate to compensate for the loss of blood volume, reductions in stroke volume below -100 ml/beat result in increased baroreceptor output and peripheral vasoconstriction to conserve central blood volume (24). This exacerbates competition for blood flow and acts to impede heat loss through evaporative and nonevaporative means, as discussed above. The limitations of the cardiovascular system are increased by preexercise hypohydration. Cardiovascular responses to exercise in the hypohydrated state are similar to those of euhydration; however, reductions in stroke volume are observed earlier and at higher body temperatures. Increases in heart rate are less effective in compensating for reduced stroke volume during dehydration. The overall effect is a reduction in stroke volume and thus a reduction in cardiac output (5, 12, 14, 24). The circulatory effects of ACZ we observed appear to be similar to those reported for other diuretics. The 13% decrease in plasma volume, 25% decrement in stroke volume, and 15% increase in arteriovenous O2 difference during exercise with ACZ observed in the present study are both qualitatively and quantitatively similar to studies using triamterene and hydrochlorothiazide to induce hypohydration (24). The observed reduction in stroke volume with ACZ is of sufficient magnitude to impair heat loss through alterations in cardiovascular control
(10, 14, 24, 29).
Thermal and diuretic dehydration resulting in l-4% decreases in body water before exercise leads to greater elevation in T,, ‘than in the euhydrated state (10, 17). Such body water reductions have further been shown to decrease the ability to sustain exercise by lo-20% (1, 26), again without observed decrements in aerobic capacity. The effect on prolonged sustained activity without an effect on aerobic capacity is similar to that observed after ACZ (32). The data from the present study are limited to a relatively brief dose period. It is currently unclear how long the. ACZ effects persist with extended
SUBMAXIMAL
EXERCISE
prescription or whether compensatory mechanisms lessen the magnitude of the hypovolemic response beyond 24 h. Additional consequences of ACZ that may explain the reduction in the ability to sustain exercise after an acute dose are only briefly considered here. Studies on metabolic consequences of ACZ report lower blood lactate levels during exercise (22), presumably as a function of altered acid-base status. However, hypercapnia has also been associated with reduced glycolytic flux and thus lower blood lactate (13,16). ACZ use before exercise may therefore be associated with significant disturbances in intermediary metabolism. ACZ is also associated with significant increases in iTE at rest and during exercise (8, 30,32,33). The explanation for the increased VE is most likely peripheral chemoreceptor response to decreases in arterial pH, although direct temperature effects on VE during exercise have also been proposed (20, 35). In the present study, ACZ resulted in increases in temperature greater than the 1°C “threshold temperature” reported as necessary to mediate a thermal-induced ventilatory increase (35). Finally, increases in Tb and VE of the magnitude reported here for ACZ have been shown to alter one’s perception of effort (31). Because perception of effort has been reported to be a factor potentially limiting the ability to sustain submaximal efforts, the greater VE during exercise may have a role here. In summary, evidence has been presented describing the effects of ACZ, a potent carbonic anhydrase inhibitor, on thermoregulatory and cardiovascular function during exercise. Tb is elevated, peripheral blood flow may be reduced, and cardiac accommodation to exercise is limited with ACZ. However, other mechanisms, physiological and psychological, that coincidentally impede the ability to sustain submaximal exercise, are also likely. There exists an apparent trade-off between the efficacy of ACZ to minimize the symptoms of acute mountain sickness and the constraints imposed by the use of ACZ on the ability to tolerate prolonged submaximal exercise. The authors appreciate the expert criticisms of Drs. Thomas H. Maren and Wendell N. Stainsby. This study was supported in part by a grant from the Indiana University Graduate School. Address for reprint requests: W. F. Brechue, Dept. of Pharmacology and Therapeutics, University of Florida College of Medicine, Box J267, JHMHC, Gainesville, FL 32610. Received 2 November 1989; accepted in final form 6 June 1990. REFERENCES 1. ARMSTRONG,
diuretic-induced
L. E., D. L. COSTILL, AND W. J. FINK. Influence of dehydration on competitive running performance.
Med. Sci. Sports Exercise 2. ASTRAND, P. O., AND
17: 456-461,19&L
B. SALTIN. Maximal oxygen uptake and heart rate in various types of muscular activity. J. Appl. Physiol.
16: 977-981,196l. MEDICAL RESEARCH EXPEDITIONARY 3. BIRMINGHAM MOUNTAIN SICKNESS STUDY GROUP. Acetazolamide acute mountain sickness. Lancet 1: 180-183, 1981. 4. BRECHUE, W. F., J. M. STAGER, AND H. C. LUKASKI.
and electrolyte
responses to acetazolamide
SOCIETY.
in control of
Body water in humans. J. Appl.
Physiol. 69: 1397-1401, 1990. G. L., P. R. FREUND, 5. BRENGELMANN, OLEURD, AND K. K. KRANNING. Altered
L. B. ROWELL, J. E. control of skin blood flow during exercise at high internal temperatures. J. Appl. Physiol. 43:
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
ACETAZOLAMIDE
DURING
790-794,1977. 6. BURTON, A. C. Human calorimetry. II. The average temperature of the tissues of the body. J. Nutr. 9: 261-269, 1935. 7. CAIN, S. M. A ventilatory effect of carbonic anhydrase inhibition in man. Proc. Sot. Exp. Biol. Med. 106: 7-10, 1960. 8. COSTILL, D. L., AND B. SALTIN. Changes in ratio of venous to body hematocrit following dehydration. J. AppZ. Physiol. 36: 608-610, 1974. 9. DILL, D. B., AND D. L. COSTILL. Calculation of percentage changes in volumes of blood, plasma and red cells in dehydration. J. Appl. Physiol. 37: 247-248, 1974. 10. EKBLOM, B., C. J. GREENLEAF, J. E. GREENLEAF, AND L. HERMANSEN. Temperature regulation during exercise dehydration in man. Acta Physiol. Stand. 79: 475-483, 1970. 11. ELIZONDO, R. S. Local control of eccrine sweat gland function. Federation Proc. 32: 1583-1587,1973. 12. FORTNEY, S. M., E. R. NADEL, C. B. WENGER, AND J. R. BOVE. Effect of acute alterations of blood volume on circulatory performance in humans. J. Appl. Physiol. 50: 292-298, 1981. 13. FORTNEY, S. M., E. R. NADEL, C. B. WENGER, AND J. R. BOVE. Effect of blood volume on sweating rate and body fluids in exercising humans. J. Appl. Physiol. 51: 1594-1600, 1981. 14. FORTNEY, S. M., AND N. B. VROMAN. Exercise, performance and temperature control: temperature regulation during exercise and implications for sports performance and training. Sports Med. 2: g-20,1985. M., AND M. FLORENTZ. Effects of hypercapnia on the 15. GIMENEZ, glycolytic metabolism enzyme activity and myoglobin of stimulated skeletal muscle in the rat. Bull. Eur. Physiopathol. Respir. 15: 269294,1979. 16. GRAHAM, T. E., B. A. WILSON, M. SAMPLE, J. VAN DIJK, AND B. GOSLIN. The effects of hypercapnia on metabolic response to steady state exercise. Med. Sci. Sports Exercise 14: 286-291, 1982. J. E., AND B. L. CASTLE. Exercise temperature regu17. GREENLEAF, lation in man during hypohydration and hyperhydration. J. Appl. Physiol. 30: 847-853, 1971. 18. KEPPEL, G. Design and Analysis (2nd ed.). Englewood Cliffs, NJ: Prentice-Hall, 1982. 19. KUBICEK, W. G., R. P. PATTERSON, AND D. A. WITSOE. Impedance cardiography as a noninvasive method of monitoring cardiac function and other parameters of the cardiovascular system. Ann. NY Acad. Sci. 170: 724-732, 1970. (Int. Conf. Bioelectrical Impedance) 20. LAHIRI, S., AND R. GELFAND. Mechanisms of acute ventilatory responses. In: Regulation of Breathing, edited by T. F. Hornbein. New York: Dekker, 1981, vol. 17, part II, p. 773-844. (Lung Biol.
SUBMAXIMAL
EXERCISE
1407
Health Dis. Ser.) 21. MAREN, T. H. Carbonic anhydrase: chemistry, physiology, and inhibition. Physiol. Rev. 47: 595-781, 1967. 22. MCLELLAN, T., I. JACOBS, AND W. LEWIS. Acute altitude exposure and altered acid-base state. II. Effects on exercise performance and muscle lactate. Eur. J. Appl. Physiol. Occup. Physiol. 57: 445-451, 1988. 23. MITCHELL, J. W., E. R. NADEL, AND J. A. J. STOLWIJK. Respiratory weight losses during exercise. J. Appl. PhysioZ. 32: 474-476, 1972. 24. NADEL, E. R., S. M. FORTNEY, AND C. B. WENGER. Effect of hydration state on circulatory and thermal regulations. J. Appl. Physiol. 49: 715-721, 1980. 25. NEWBURGH, W. B. Physiology of Heat Regulation. Philadelphia, PA: Saunders, 1949. 26. NIELSON, G., R. KUBICA, A. BONNENSEN, I. B. RASMUSSEN, J. STOKLOSA, AND B. WILK. Physical work capacity after dehydration and hyperthermia. Stand. J. Sports Sci. 3: 2-10, 1981. 27. PIVARNIK, J. M., M. P. GOETTING, AND L. C. SENAY. The effects of body position and exercise on plasma volume dynamics. Eur. J. Appl. Physiol. Occup. Physiol. 55: 450-456, 1986. 28. RAMANATHAN, N. L. A new weighting system for mean surface temperature of the human body. J. Appl. Physiol. 19: 531-533, 1964. 29. SALTIN, B. Circulatory response to submaximal and maximal exercise after thermal dehydration. J. Appl. Physiol. 19: 1125-1132, 1964. 30. SCHOENE, R. B., P. W. BATES, E. B. LARSON, AND D. J. PIERSON. Effects of acetazolamide on normoxic and hypoxic exercise in humans at sea level. J. Appl. Physiol. 55: 1772-1776, 1983. 31. SHEPHARD, R. J. Physiology and Biochemistry of Exercise (1st ed.). New York: Praeger, 1982, p. 98. 32. STAGER, J. M., A. TUCKER, L. CORDAIN, B. J. ENGERBRETSEN, W. F. BRECHUE, AND C. C. MATULICH. Normoxic and hypoxic exercise tolerance in man following carbonic anhydrase inhibition with acetazolamide. Med. Sci. Sports Exercise 22: 178-184, 1990. 33. SWENSON, E. R., AND T. H. MAREN. A quantitative analysis of CO, transport at rest and during maximal exercise. Respir. Physiol. 35: 129-159,1978. 34. WETTREL, K., AND M. PANDOLFI. Propranolol vs. acetazolamide: a long-term double masked study of the effect on intraocular pressure and blood pressure. Arch. Ophthalmol. 97: 280-283, 1979. 35. WHIPP, B. J., AND J. A. DAVIS. Peripheral chemoreceptor and exercise hyperpnea. Med. Sci. Sports Exercise 11: 204-212, 1979.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
AND
Performance
J. M. STAGER
Laboratory,
Indiana
University,
BRECHUE, W. F., AND J. M. STAGER. AcetaxoZamide alters temperature regulation during submaximal exercise. J. Appl. Physiol. 69(4): 1402-1407, 1990.-Acetazolamide (ACZ), a potent carbonic anhydrase inhibitor, is known to decreasesubmaximal exercisetolerance under normoxic and hypoxic conditions. These decrements in performance occur despite the maintenance of O2 consumption and CO, removal. Because AC2 is a diuretic, it induces a moderate hypohydration that may have a role in reducing the ability to sustain exercise through cardiovascular and thermoregulatory impairment. To investigate this potential impairment, seven healthy males between 21 and 35 yr of age were studied in a double-blind crossoverdesign (placebo vs. ACZ). ACZ was administered in three 250-mgoral doses14,8, and 2 h before exercise. Subjects exercisedat 70%peak O2uptake for 30 min on a cycle ergometer in a normoxic thermoneutral environment (ZSOC,40% relative humidity). Results indicate that exercise minute ventilation was greater but O2 uptake, CO2 output, and respiratory exchange ratio did not differ with ACZ. ACZ led to lower mean skin (0.7”C), higher rectal (0.6”C), and higher mean body temperatures (0.4”C) after 30 min of exercise. Whole-body sweat loss was reduced 23%, and heat storage during the exercisebout wasincreased55%. Stroke volume decreased25%, and arteriovenous O2 difference increased 15%. A significant inverse relationship (r = -0.63) between heart rate and stroke volume was observed.It is concluded that previously reported decreasesin the ability to sustain submaximal exercise with ACZ may be related to hypohydration-induced impairment of the cardiovascular and thermoregulatory systems. body temperature; carbonic anhydrase; acute mountain sickness;altitude ANHYDRASE is the enzyme that catalyzes the reversible hydration of CO2 and the dehydration of HCO; (21). As such, carbonic anhydrase is the principal enzyme in the pathway for transport and elimination of metabolic and nonmetabolic COZ. Because early investigators considered the enzyme so essential to the maintenance of CO2 flux, they predicted that complete carbonic anhydrase inhibition during heavy exercise would be life threatening (33). However, when tested during heavy exercise at near-maximal rates of CO2 production (VCO~), COn output was maintained regardless of the 98.8% inhibition of erythrocyte carbonic anhydrase (33). Despite the lack of a significant disruption of gas exchange with carbonic anhydrase inhibition during exercise, recent observations suggest that clinically prescribed doses of acetazolamide (ACZ) reduce submaximal exercise endurance time in humans by -30% under acute hypoxic as well as normoxic conditions (32). Currently CARBONIC
1402
regulation
0161-7567/90 $1.50 Copyright
0
Bloomington,
Indiana
47405
the mechanism(s) responsible for the decreased ability to sustain submaximal exercise with ACZ is unknown. Because ACZ is a diuretic, the inability to sustain submaximal exercise with carbonic anhydrase inhibition may reflect losses in body water (4). Disturbances in body water volumes are well known to influence cardiovascular and thermoregulatory function and the ability to sustain prolonged submaximal exercise (1, 17, 26, 29). Hypovolemia reportedly leads to cardiovascular adjustments during exercise that ultimately act to preserve central blood volume and blood pressure at the expense of the ability to thermoregulate (12, 24). Heat loss is limited and prevents continuation of exercise as a result of excessive hyperthermia. ACZ continues to be effectively employed as a prophylaxis for acute mountain sickness (3) and as a treatment for glaucoma (34). Many individuals using ACZ expect to engage in physical activity, particularly those visiting moderate altitudes; therefore an understanding of the consequences of its use is warranted (22). The objective of the present investigation was to quantify the effects of carbonic anhydrase inhibition by ACZ on appropriate measures of cardiovascular and thermoregulatory function during submaximal exercise. It was hypothesized that therapeutic doses of ACZ would impair exercise thermoregulation by means of dehydration. METHODS
Seven untrained healthy active males participated in this investigation. Descriptive data are found in Table 1. Each subject received a written and oral explanation of all procedures and potential risks and provided written consent in accordance with the Indiana University Committee for the Protection of Human Subjects. Experimental protocol. Each subject participated in an incremental maximal exercise test and two 30-min submaximal exercise tests on a cycle ergometer. One week separated each of the three exercise bouts. The submaximal exercise bouts were administered in a repeatedmeasures crossover design for treatment (placebo vs. ACZ). The order of treatments was randomized, and the drug was dispensed in double-blind fashion. The submaximal exercise bouts were performed at 70% peak 02 consumption (~oJ in a normoxic thermoneutral environment (barometric pressure 741.5 t 3.7 Torr, ambient temperature 25 t 0.3OC, relative humidity 48 t 2.0%). ACZ was administered in three oral doses of 250 mg 14, 8, and 2 h before the submaximal exercise bout (30).
1990 the American
Physiological
Society
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
ACETAZOLAMIDE
DURING
1. Subject characteristics
TABLE Age, Yr
30.3t5.2 Values
Peak 00,
Height, cm
Weight, kg
l/min
183.1k6.3
81.53t11.00
3.58t0.60
are means
& SD of
ml. kg-’
l
min-l
44.2t7.4
7 subjs.
To conceal identity, both treatments were administered in identical fashion and packaged in unmarked gelatin capsules. All subjects were 10 h postprandial for each experiment, and water was provided ad libitium. Measurement of peak VOW. Peak Vo2 was determined using a modified, continuous, progressive work load protocol on a cycle ergometer (Monark 686) (2). Pedal frequency was maintained at 60 rpm throughout the test. Criteria for termination of the test were 1) no further increase in Vo2 with increased work load, 2) volitional exhaustion, and 3) respiratory exchange ratio (R) >l.lO. Respiratory gas collec tions with an open-flow indirect calorimetry system were made while the subject breathed ambient air through a two-way nonbreathing valve (model 2700, Hans Rudolph, Kansas City, MO). Expired gases were passed through a &liter mixing chamber from which a sample was continuously drawn by O2 (model S3Al) and COa (model CD-3A) medical gas analyzers (Applied Electrochemistry, Ametek Instruments, P ittsburgh, PA). The analyzers were calibrated before and after each test with gases previously verified by ’ the micro -Scholander technique. Minute ventilation m was determined by an electronic turbine-based flowmeter (model VMM-2, Sensormedics, Anaheim, CA) mounted on the inspired side. Analog outputs from all three devices were continuously monitored by an on-line microcomputer (PC-XT, IBM, Armonk, NY) via an analogto-digital board (DT-2801, Data Translations, Marlborough, MA). Heart rate was monitored continuously with an Exersentry cardiotachometer (Computer Instrument, Hempstead, NY). SubmaximaL bout protocol. On reporting to the laboratory, subjects voided their bladder and nude body weight (kO.01 kg) was recorded. After collection of a preexercise blood sample and preexercise metabolic data, subjects began pedaling at 60 rpm with no resistance. In three l-mm intervals the ergometer resistance was increased in equal stages to a work load that corresponded to 70% peak vo2. VE, v02, CO:! production (%02), and R were determined using the previously described indirect calorimetry system before exercise and after 15 @Id and 30 min of exercise (t&. Thermoregulatory variables. Body core temperature (rectal, T,) was estimated by insertion of a vinyl-clad thermistor 10 cm beyond the anal sphincter (no. 511, Yellow Springs Instruments). Mean skin temperature was determined from a weighted average of skin temperatures (Tsk) at four sites: chest, arm, medial thigh, and lateral calf (27). Mean body temperature (Tb) was calculated by weighted T,k and T, according to Burton (6). All thermistors were calibrated against a National Bureau of Standards certified thermometer. Whole-body sweat loss was estimated from the difference between pre- and postexercise body weight corrected for respira-
SUBMAXIMAL
EXERCISE
1403
tory water loss (23). Whole-body conductance was calculated from metabolic rate and changes in T, and T,k (25) CLdiovascuZar variables. Cardiac output was calculated from the product of heart rate and stroke volume before exercise and at t15and taO.Heart rate was measured for 30 s during exercise by palpation of the radial artery. Stroke volume was estim .ated by elec trical impedance cardiography using a Minnesota impedance cardiograph (Surcom, Minneapolis, MN). Subjects were asked to stop exercise momentarily to alleviate motion artifact, which disrupts the impedance signal. Techn .iques and equations of Kubicek et al. (19) were used with a resi .stivity correction for hematocrit. The i.mpedance cardiograp lh was calib rated at each use with an internal standard and a simple resistance-capacitance circuit of known impedance. Cardiograph source signal and amplitude and frequency were verified before the study by use of an oscilloscope. Blood variables. Blood samples were obtained from an antecubital vein without stasis before exercise and at t15 and tao. The before-exercise sample was collected after 30 min in the upright seated position. All blood was collected in heparinized syringes. After centrifugation and separation, aliquots of plasma were analyzed for osmolality by vapor point depression, Na+ and K+ by flame photometry, and total proteins by refractometry. Whole-blood was analyzed for total hemoglobin spectrophotometrically (OSM-3, Radiometer, Copenhagen), and blood gases and pH were analyzed by el .ectrode (ABL-3, was determined Radiometer, Copenhagen .). Hematocrit by microcapillary technique in quadruplicate and corrected for changes in venous-to-whole-body ratio and trapped plasma (8). Blood volume was estimated by use of CO rebreathing (27). Changes in plasma volume were estimated by changes in hemoglobin concentration and hematocrit according to Dill and Costill (9). Statisticat analysis. Dependent variables measured during the submaximal exercise bouts were applied to a time series analysis. F ratios were computed using analysis of variance on the SPSS-X statistical package. Family-wise type I error rate was set at 0.5 and controlled during multiple F tests by correcting the per comparison error rate with the modified Bonferroni technique (18). Bonferroni adjustments resulted in an alpha level of 0.04 for omnibus F tests and 0.03 on follow-up tests. Post hoc analysis consisted of tests of simple main effects and the Tukey test where appropriate (18). All data are presented as means t SE. RESULTS
ACZ resulted in a moderate hypohydration before exercise, evidenced by a 9.1% decrease in plasma volume compared with placebo. Plasma volume decreased during the first 15 min of exercise with placebo and ACZ (Table 2), with the greatest loss occurring during the placebo trials (542 ml at t15vs. 410 ml, placebo and ACZ, respectively). No further significant losses in plasma volume were observed in either treatment. Plasma osmolality, [Na’], and [K+] were not different between treatments, nor did they change with exercise. Metabolic acidosis as
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
1404
ACETAZOLAMIDE
DURING
SUBMAXIMAL
in ACZ or placebo trials were observed. Cardiac output and heart rate with ACZ were not different from placebo before exercise or at t15 and t30 (Table 5). It is important to note that technical problems inherent in the impedance procedure allowed analysis of cardiac impedance data on four of the seven subjects. Nevertheless a significant negative correlation between stroke volume and heart rate (r = -0.62, P < 0.02) was observed. Arteriovenous O2 difference was greater with ACZ (Table 5), whereas the changes in arteriovenous O2 difference were negatively correlated with cardiac output between trials
2. Plasma volume and protein concentrations
TABLE
Exercise
%Change in plasma volume Plasma volume, liters Difference, ml Total protein, g/d1 Total circulating protein, g Values 0.03.
are means
t15
Exercise
tSO
Placebo
ACZ
Placebo
ACZ
15.02
12.25
15.23
12.50
3.09t0.17
2.90t0.18*
3.07t0.17
2.90*0.14*
542249 8.19rtO.09 252tlO
410t61* 8.64*0.10* 250tll
554t57 8.19t0.10 251tll
410t76* 8.72t0.14* 251211
t SE of 7 subjs.
* Different
between
trials,
EXERCISE
(r = -0.71, P = 0.03).
P c
a consequence of ACZ was confirmed by a decrease in venous pH and HCO; (Table 3). The decreases in venous blood pH and HCO; observed before exercise were maintained throughout the 30 min of exercise. Total protein concentration increased from rest to exercise (5% at t15 and 6% at t3*) with ACZ, but no difference was observed with ACZ compared with placebo (Table 2). MetaboZic data. VOW, VCO~, and R were unaffected by ACZ before exercise and at each exercise interval compared with placebo (Table 4). Thus the relative intensity of the exercise, which was *designed to correspond to a work load of -70% peak Voz was unaffected by ACZ (69.9% peak %70z for placebo and 71.1% peak VO, for ACZ). VE was not different with ACZ at rest. However, VE during exercise with ACZ was greater (9.8% at t15 and 14.1% at t3*) than with placebo. Ventilatory equivalents (vE/v02 and vE/h02) with ACZ were higher at rest and at both exercise intervals with ACZ (Table 4). Furthermore, vE/v02 and vE/h02 were higher at t30 than at t15 within the ACZ trial. Thermoregulatory data. At rest, ACZ did not significantly alter mean Tb, mean Tsk, or T,,. After exercise, Tb in the ACZ trial was 0.4OC higher than in the placebo trial (36.2 vs. 36.6”C). ACZ reduced T,k 0.5OC at t15 and 0.7”C at t30 compared with placebo trials. T,k was not different between t15 and t3* in either treatment (Fig. 1B). There was no difference in T, between t15 and t30 in the placebo trial. T, at t30 in the ACZ trial was 0.7OC higher than at t15 (37.5 vs. 38.2”C) in the ACZ trial and 0.6OC higher than T, at t30 (37.6 vs. 38.2”C) in the placebo trial (Fig. 1A). Whole-body sweat loss was reduced 23%, from 30.0 to 23.1 g/min, with ACZ across the 30-min exercise period. Whole-body conductance did not differ at t15 between treatments but was lower at t30 with ACZ (Fig. ID). Cardiovascular data. Stroke volume was 26% less with ACZ (126 vs. 94 ml/beat) at t15 and 24% less at t30 (122 vs. 105 ml/beat, 24%; Table 5). No progressive changes
DISCUSSION
Thermoregulatory effects. The evidence indicating that ACZ alters thermoregulation during exercise stems from the greater increases in Tb with ACZ than with placebo. The greater increase in T,, and Tb with ACZ (Fig. 1A) is suggestive of an imbalance between heat gain and heat loss similar to that caused by hypovolemia and/or dehydration (12-14, 24). The exercise bouts employed were constant and identical in both treatments, and because no difference in Vo2 was observed across treatments, the possibility of any difference in the rate of heat production and mechanical or metabolic efficiency with ACZ is precluded. Furthermore, increases in Tb and heat content were not evident at rest with ACZ, suggesting that adequate heat loss was maintained during basal rates of internal heat production. Tb was affected only when challenged by high rates of heat generation (8-9 times greater than rest) requiring appropriate active heat loss responses. The increased heat production during exercise was not matched by adequate heat loss, as evident from a greater Tb rise with ACZ, which did not appear to approach steady state during the 30 min of exercise (Fig. lA ). Without artificial convection, radiation and evaporation are the principal routes of heat transfer available during stationary cycle ergometry. The present data suggest that ACZ leads to reductions in both of these avenues of heat loss. A reduction in the rate of heat transfer between the core and periphery was observed as reflected by the reduction in whole-body conductance (Fig. 1B). During exercise, an expansion of the warmer core isotherms is expected as heat transfer to the periphery is increased as a result of greater skin blood flow. This classic response to exercise was seen in both trials as indexed by increased whole-body conductance and T,k in transition from rest to exercise. However, the magnitude of the increase was blunted during ACZ trials. The lower whole-body conductance and T,k observed with ACZ is
3. Blood gas and acid-base status
TABLE
Rest
Exercise
Placebo
PH HCO;, Pvco,, Values
mM Torr
are means
ACZ
7.278kO.013 23.7t0.5 43.6t1.8 t SE of 7 subjs.
7.194t0.007 18.7t0.6* 40.8t1.8 Pvco,,
venous
Pco~. * Different
Placebo
Exercise ACZ
7.296kO.015 19.5t0.8 46.2t0.8 between
t15
7.216t0.007 14.lt0.6* 51.7t1.5* trials,
Placebo
7.326t0.010 19.9t0.8 45.1t0.9
tSO ACZ
7.249kO.016 14.3t0.7* 50.3t0.7*
P < 0.03.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
ACETAZOLAMIDE
DURING
SUBMAXIMAL
1405
EXERCISE
4, Metabolic data
TABLE
Rest Placebo
TjE, l/min BTPS I&, l/min VCO2, l/min R
Values
are means
AC2
8.4t0.5 0.31t0.01 0.25t0.02 0.81IltO.02 25.3kO.3 31.4t0.5
TjE/Vo2(ST~~) VE/Vco2(ST~~)
f: SE of 7 subjs.
Exercise Placebo
9.8t0.4 0.33kO.02 0.27rtO.02 0.82+0.02 27,9+0.2* 34.0*0.4*
* Different
between
t15 AC2
61.8t1.4 2.61kO.10 2.50t0.08 0.96t0.02 22.120.7 23.1kO.7 trials,
Exercise
across
trials,
ACZ
Placebo
68.4t2.5" 2.67t0.15 2.52t0.14 0.95t0.02 24.Oltl.3* 25.4kO.6"
P c 0.03; t different
tSO
64.3tl.l 2.58t0.15 2.4320.10 0.94t0.02 23.3t0.7 24.7kO.7
74.9+3.3? 2.67kO.14 2.48t0.12 0.92t0.02 26.2&1.7* 28.2t0.9*
P < 0.03.
33.0
38.8
32.5
s? z3
37.8
2 3 Ii $E
32.0
37.3
gG r"
31.5
5 iitp )- -
3 8 CL
z s5
36.8
31.0
30.5 I
I
15
Rest
6 3
I 30
I
1
I
Rest
15
30
I 15
I 30
FIG. 1. Thermoregulatory data. q , Placebo; A, ACZ. * Significantly different from placebo trial, P c 0.003; ** significant difference within trial as well as difference from placebo trial.
8 50.0 $iU-y 40.o ON Eg rE 30.0 gs 2s e3 20.0
IO.0 -
35.0 I
I
Rest
15
Time
TABLE
I 30
0.0 l
’ Rest
Time
(min.)
5. Cardiovascular
(min.)
data Rest
Heart rate, beats/min Stoke volume, ml Cardiac output, l/min Arteriovenous 02 difference, Values
are means
ml 02/100
t SE of 7 subjs.
* Difference
Exercise
Placebo
AC2
Placebo
68k9
67+10
140*14 126t2* 17.720.7 153t5
ml between
trials,
Exercise
t15 AC2
158&10 94t5 15.Ok1.3 178t4*
Placebo
1491r9 122*10* 18.3t0.3 141t5
.
tSO AC2
161217 105t8 17.Okl.l 157*5*
P < 0.03.
interpreted as being due to greater vasomotor tone and thus reduced cutaneous blood flow. This has previously been proposed during exercise after preexercise reductions in plasma volume (12, 24), and these studies have similarly concluded that the rise in T,, is due to impaired heat loss rather than an overt increase in heat production or a shift in the temperature at which the body is maintained.
Of greater consequence than the apparent reduction in radiative loss is the decreased evaporative heat loss observed during exercise with ACZ. Sweat loss was reduced 23% with ACZ compared with the placebo trial. This finding is also consistent with previous reports of decrements in sweat loss during hypohydration (10, 13, 17). The reduced sweating is reported to be related to both central and peripheral effects of preexercise hypo-
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
1406
ACETAZOLAMIDE
DURING
volemia. It has been suggested that afferent input to the hypothalmic thermoregulatory centers is reduced, with hypohydration altering the sweating response in situations similar to that observed here (13). Local control of reduced sweating is related to reduced peripheral blood flow, decreases in sweat gland activity (ll), and perhaps alteration of peripheral responsiveness to central sweating drive (24). Cardio vascular function. The disturbances in heat loss .re most likely secondary to alterations in cardiovasc ular control caused by ACZ. During a prolonged exercise bout, the increase in peripheral circulation necessary for metabolic and thermal purposes results in competition between the core and periphery for a proportion of cardiac output (24, 29). In effect, the metabolic requirement of the active tissues competes with blood flow needed for heat exchange mechanisms. During relatively mild exercise in the heat (40% maximal iToz) cardiac output has been shown to increase above that of cool environments, thus meeting the increased overall demand for blood flow (29). In contrast, vigorous exercise in the heat has been shown to be associated with reduced cardiac output, presumably due to a loss of plasma volume and, therefore, a reduced stroke volume. Because there is only limited ability to increase heart rate to compensate for the loss of blood volume, reductions in stroke volume below -100 ml/beat result in increased baroreceptor output and peripheral vasoconstriction to conserve central blood volume (24). This exacerbates competition for blood flow and acts to impede heat loss through evaporative and nonevaporative means, as discussed above. The limitations of the cardiovascular system are increased by preexercise hypohydration. Cardiovascular responses to exercise in the hypohydrated state are similar to those of euhydration; however, reductions in stroke volume are observed earlier and at higher body temperatures. Increases in heart rate are less effective in compensating for reduced stroke volume during dehydration. The overall effect is a reduction in stroke volume and thus a reduction in cardiac output (5, 12, 14, 24). The circulatory effects of ACZ we observed appear to be similar to those reported for other diuretics. The 13% decrease in plasma volume, 25% decrement in stroke volume, and 15% increase in arteriovenous O2 difference during exercise with ACZ observed in the present study are both qualitatively and quantitatively similar to studies using triamterene and hydrochlorothiazide to induce hypohydration (24). The observed reduction in stroke volume with ACZ is of sufficient magnitude to impair heat loss through alterations in cardiovascular control
(10, 14, 24, 29).
Thermal and diuretic dehydration resulting in l-4% decreases in body water before exercise leads to greater elevation in T,, ‘than in the euhydrated state (10, 17). Such body water reductions have further been shown to decrease the ability to sustain exercise by lo-20% (1, 26), again without observed decrements in aerobic capacity. The effect on prolonged sustained activity without an effect on aerobic capacity is similar to that observed after ACZ (32). The data from the present study are limited to a relatively brief dose period. It is currently unclear how long the. ACZ effects persist with extended
SUBMAXIMAL
EXERCISE
prescription or whether compensatory mechanisms lessen the magnitude of the hypovolemic response beyond 24 h. Additional consequences of ACZ that may explain the reduction in the ability to sustain exercise after an acute dose are only briefly considered here. Studies on metabolic consequences of ACZ report lower blood lactate levels during exercise (22), presumably as a function of altered acid-base status. However, hypercapnia has also been associated with reduced glycolytic flux and thus lower blood lactate (13,16). ACZ use before exercise may therefore be associated with significant disturbances in intermediary metabolism. ACZ is also associated with significant increases in iTE at rest and during exercise (8, 30,32,33). The explanation for the increased VE is most likely peripheral chemoreceptor response to decreases in arterial pH, although direct temperature effects on VE during exercise have also been proposed (20, 35). In the present study, ACZ resulted in increases in temperature greater than the 1°C “threshold temperature” reported as necessary to mediate a thermal-induced ventilatory increase (35). Finally, increases in Tb and VE of the magnitude reported here for ACZ have been shown to alter one’s perception of effort (31). Because perception of effort has been reported to be a factor potentially limiting the ability to sustain submaximal efforts, the greater VE during exercise may have a role here. In summary, evidence has been presented describing the effects of ACZ, a potent carbonic anhydrase inhibitor, on thermoregulatory and cardiovascular function during exercise. Tb is elevated, peripheral blood flow may be reduced, and cardiac accommodation to exercise is limited with ACZ. However, other mechanisms, physiological and psychological, that coincidentally impede the ability to sustain submaximal exercise, are also likely. There exists an apparent trade-off between the efficacy of ACZ to minimize the symptoms of acute mountain sickness and the constraints imposed by the use of ACZ on the ability to tolerate prolonged submaximal exercise. The authors appreciate the expert criticisms of Drs. Thomas H. Maren and Wendell N. Stainsby. This study was supported in part by a grant from the Indiana University Graduate School. Address for reprint requests: W. F. Brechue, Dept. of Pharmacology and Therapeutics, University of Florida College of Medicine, Box J267, JHMHC, Gainesville, FL 32610. Received 2 November 1989; accepted in final form 6 June 1990. REFERENCES 1. ARMSTRONG,
diuretic-induced
L. E., D. L. COSTILL, AND W. J. FINK. Influence of dehydration on competitive running performance.
Med. Sci. Sports Exercise 2. ASTRAND, P. O., AND
17: 456-461,19&L
B. SALTIN. Maximal oxygen uptake and heart rate in various types of muscular activity. J. Appl. Physiol.
16: 977-981,196l. MEDICAL RESEARCH EXPEDITIONARY 3. BIRMINGHAM MOUNTAIN SICKNESS STUDY GROUP. Acetazolamide acute mountain sickness. Lancet 1: 180-183, 1981. 4. BRECHUE, W. F., J. M. STAGER, AND H. C. LUKASKI.
and electrolyte
responses to acetazolamide
SOCIETY.
in control of
Body water in humans. J. Appl.
Physiol. 69: 1397-1401, 1990. G. L., P. R. FREUND, 5. BRENGELMANN, OLEURD, AND K. K. KRANNING. Altered
L. B. ROWELL, J. E. control of skin blood flow during exercise at high internal temperatures. J. Appl. Physiol. 43:
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
ACETAZOLAMIDE
DURING
790-794,1977. 6. BURTON, A. C. Human calorimetry. II. The average temperature of the tissues of the body. J. Nutr. 9: 261-269, 1935. 7. CAIN, S. M. A ventilatory effect of carbonic anhydrase inhibition in man. Proc. Sot. Exp. Biol. Med. 106: 7-10, 1960. 8. COSTILL, D. L., AND B. SALTIN. Changes in ratio of venous to body hematocrit following dehydration. J. AppZ. Physiol. 36: 608-610, 1974. 9. DILL, D. B., AND D. L. COSTILL. Calculation of percentage changes in volumes of blood, plasma and red cells in dehydration. J. Appl. Physiol. 37: 247-248, 1974. 10. EKBLOM, B., C. J. GREENLEAF, J. E. GREENLEAF, AND L. HERMANSEN. Temperature regulation during exercise dehydration in man. Acta Physiol. Stand. 79: 475-483, 1970. 11. ELIZONDO, R. S. Local control of eccrine sweat gland function. Federation Proc. 32: 1583-1587,1973. 12. FORTNEY, S. M., E. R. NADEL, C. B. WENGER, AND J. R. BOVE. Effect of acute alterations of blood volume on circulatory performance in humans. J. Appl. Physiol. 50: 292-298, 1981. 13. FORTNEY, S. M., E. R. NADEL, C. B. WENGER, AND J. R. BOVE. Effect of blood volume on sweating rate and body fluids in exercising humans. J. Appl. Physiol. 51: 1594-1600, 1981. 14. FORTNEY, S. M., AND N. B. VROMAN. Exercise, performance and temperature control: temperature regulation during exercise and implications for sports performance and training. Sports Med. 2: g-20,1985. M., AND M. FLORENTZ. Effects of hypercapnia on the 15. GIMENEZ, glycolytic metabolism enzyme activity and myoglobin of stimulated skeletal muscle in the rat. Bull. Eur. Physiopathol. Respir. 15: 269294,1979. 16. GRAHAM, T. E., B. A. WILSON, M. SAMPLE, J. VAN DIJK, AND B. GOSLIN. The effects of hypercapnia on metabolic response to steady state exercise. Med. Sci. Sports Exercise 14: 286-291, 1982. J. E., AND B. L. CASTLE. Exercise temperature regu17. GREENLEAF, lation in man during hypohydration and hyperhydration. J. Appl. Physiol. 30: 847-853, 1971. 18. KEPPEL, G. Design and Analysis (2nd ed.). Englewood Cliffs, NJ: Prentice-Hall, 1982. 19. KUBICEK, W. G., R. P. PATTERSON, AND D. A. WITSOE. Impedance cardiography as a noninvasive method of monitoring cardiac function and other parameters of the cardiovascular system. Ann. NY Acad. Sci. 170: 724-732, 1970. (Int. Conf. Bioelectrical Impedance) 20. LAHIRI, S., AND R. GELFAND. Mechanisms of acute ventilatory responses. In: Regulation of Breathing, edited by T. F. Hornbein. New York: Dekker, 1981, vol. 17, part II, p. 773-844. (Lung Biol.
SUBMAXIMAL
EXERCISE
1407
Health Dis. Ser.) 21. MAREN, T. H. Carbonic anhydrase: chemistry, physiology, and inhibition. Physiol. Rev. 47: 595-781, 1967. 22. MCLELLAN, T., I. JACOBS, AND W. LEWIS. Acute altitude exposure and altered acid-base state. II. Effects on exercise performance and muscle lactate. Eur. J. Appl. Physiol. Occup. Physiol. 57: 445-451, 1988. 23. MITCHELL, J. W., E. R. NADEL, AND J. A. J. STOLWIJK. Respiratory weight losses during exercise. J. Appl. PhysioZ. 32: 474-476, 1972. 24. NADEL, E. R., S. M. FORTNEY, AND C. B. WENGER. Effect of hydration state on circulatory and thermal regulations. J. Appl. Physiol. 49: 715-721, 1980. 25. NEWBURGH, W. B. Physiology of Heat Regulation. Philadelphia, PA: Saunders, 1949. 26. NIELSON, G., R. KUBICA, A. BONNENSEN, I. B. RASMUSSEN, J. STOKLOSA, AND B. WILK. Physical work capacity after dehydration and hyperthermia. Stand. J. Sports Sci. 3: 2-10, 1981. 27. PIVARNIK, J. M., M. P. GOETTING, AND L. C. SENAY. The effects of body position and exercise on plasma volume dynamics. Eur. J. Appl. Physiol. Occup. Physiol. 55: 450-456, 1986. 28. RAMANATHAN, N. L. A new weighting system for mean surface temperature of the human body. J. Appl. Physiol. 19: 531-533, 1964. 29. SALTIN, B. Circulatory response to submaximal and maximal exercise after thermal dehydration. J. Appl. Physiol. 19: 1125-1132, 1964. 30. SCHOENE, R. B., P. W. BATES, E. B. LARSON, AND D. J. PIERSON. Effects of acetazolamide on normoxic and hypoxic exercise in humans at sea level. J. Appl. Physiol. 55: 1772-1776, 1983. 31. SHEPHARD, R. J. Physiology and Biochemistry of Exercise (1st ed.). New York: Praeger, 1982, p. 98. 32. STAGER, J. M., A. TUCKER, L. CORDAIN, B. J. ENGERBRETSEN, W. F. BRECHUE, AND C. C. MATULICH. Normoxic and hypoxic exercise tolerance in man following carbonic anhydrase inhibition with acetazolamide. Med. Sci. Sports Exercise 22: 178-184, 1990. 33. SWENSON, E. R., AND T. H. MAREN. A quantitative analysis of CO, transport at rest and during maximal exercise. Respir. Physiol. 35: 129-159,1978. 34. WETTREL, K., AND M. PANDOLFI. Propranolol vs. acetazolamide: a long-term double masked study of the effect on intraocular pressure and blood pressure. Arch. Ophthalmol. 97: 280-283, 1979. 35. WHIPP, B. J., AND J. A. DAVIS. Peripheral chemoreceptor and exercise hyperpnea. Med. Sci. Sports Exercise 11: 204-212, 1979.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (129.008.242.067) on November 30, 2018. Copyright © 1990 the American Physiological Society. All rights reserved.
