- Email: [email protected]
Blood magnesium and potassium alterations with maximal treadmill exercise testing: Effects of β-adrenergic blockade
Blood magnesium and potassium alterations with maximal treadmill exercise testing: Effects of ,&adrenergic blockade To test alterations in plasma potassium and magnesium levels with maximal exercise, 15 sedentary, healthy men (mean age 29 years) participated in a double-blind crossover study for 11 weeks with propranolol, atenolol, and placebo. Maximal exercise tests were done at baseline and after placebo and &blockade phases. Blood for analysis was collected via indwelling brachial vein angiocatheters at baseline and during and after testing. Plasma potassium and magnesium levels increased at peak exercise with atenolol, propranolol, and placebo. There was no difference among groups in baseline recovery for magnesium (mean 28 minutes, range 24 to 30 minutes). Potassium levels returned to baseline more rapidly (compared with magnesium) in the placebo and atenolol groups (mean 10 minutes); however, recovery time was prolonged with propranolol (28 minutes) compared with placebo and atenolol (p < 0.01). In conclusion, plasma magnesium and potassium levels increase significantly with maximal exercise and are unaffected by atenolol or propranolol p-blockade. Propranolol, however (compared with atenolol and placebo), prolongs the time of return to baseline of plasma potassium after exercise. (AM HEART J 1990;121:105.)
Gerald F. Fletcher, MD, Mary Ellen Sweeney, MD, and Barbara J. Fletcher, RN, MN. Atlanta, Ga.
With the current interest in exercise in both healthy subjects and patients with cardiovascular disease, the state of hydration and blood electrolyte concentration has become of increasing concern. Knochel et al.,’ for example, have reported significant potassium depletion in men undergoing intense physical training in hot climates, and sweating is believed to be the major cause of potassium loss. More recently, Lauler et a1.2 addressed in some detail the problem of magnesium deficiency, but little attention was directed to the role of exercise and serum magnesium. In clinical practice, many patients with cardiovascular disease are taking various types of P-adrenergic-blocking agents. Nonselective preparations have been reported to affect blood potassium levels3; for instance, propranolol may augment the increase in plasma potassium during infusion of epinephrine and potasFrom the Department of Rehabilitation Medicine (Division of Cardiac Rehabilitation), Emory University School of Medicine: and the Emory Health Enhancement Program, Atlanta, Georgia. Supported Received
in part by a research for publication
Reprint requests: Program, Woodruff GA 30322. 4l1125124
Mar.
grant
from
ICI Pharmaceuticals
16, 1990; accepted
Gerald F. Fletcher, Physical Education
July
Group.
20, 1990.
MD, Emory Health Enhancement Center, 600 Asbury Circle, Atlanta,
sium chloride.4 Lundborg, in his review of the literature, revealed that the increase in serum potassium with p-blockade cannot be explained simply by potassium retention alone but is probably caused by a redistribution of potassium from intracellular to extracellular compartments. ,&Adrenergic mechanisms seem to be involved in the extrarenal handling of potassium, presumably by inducing an increased uptake of potassium in muscle cells and liver cells. These P-adrenergic mechanisms are probably of the S2 type.
Current data6-lo also suggest a relationship between the concentrations of various blood electrolytes (particularly potassium) and the presence of ventricular ectopic activity and ventricular tachycardia, especially in the setting of myocardial infarction. Kafka et alli have reported data on 590 patients who were admitted to the coronary care unit in whom hypomagnesemia occurred (4 % 1, but it occurred more commonly in those with acute infarction (6% with versus 3% without). Notably, ventricular arrhythmias occurred in 10 of the 13 patients with both acute infarction and hypomagnesemia; however, eight of these also had hypokalemia. To the contrary, however, in one small study12 of exercise testing in hypertensive patients with hydrochlorothiaxide ver105
January
106
Fletcher, Sweeney, and Fletcher
American
A Baseline + Propronolol
Recovery
(min)
Fig. 1. Trends in plasma potassium levels during exercise testing. (a), Represents atenolol treatment versus placebo; (b), represents propranolol treatment versus placebo. (Note: abcissa is not drawn to linear time scale.)
sus placebo therapy, there was no mention of exercise-induced arrhythmias. Although often suspected clinically, exercise-related hypokalemia (or potassium flux in general) has never been proven to be associated with or causative of arrhythmia. The role of blood magnesium and its changes with exercise and @-blockade has not been studied extensively. One report13 of 18 subjects who had electrolyte measurements after a standard marathon revealed a significant decrease in serum magnesium concentration with increases in both potassium and sodium levels. This finding may be of particular importance in the “cardiac patient” who is beginning or increasing the intensity of exercise and who is also on a /?adrenergic blocking agent. Because of these concerns, particularly those that relate to varying intensities of exercise in training programs and possible associated blood electrolyte changes in patients who are receiving ,&blockade medication, the current study was initiated. METHODS To test both the degree and duration of potassium and magnesium elevation with acute exercise, 17 sedentary, healthy men were randomized to and 15 completed a double-blind, two-treatment, two-period crossover study (mean age 29 years, range 19 to 44 years). The study was
1991
Heart Journal
approved by the institutional committee on human research. Informed consent was obtained from each subject after the nature of the procedures of the study had been fully explained. After they had received placebo for 3 weeks, the subjects received atenolol 100 mg daily or propranolol80 mg twice daily for 3 weeks. On the day of exercise testing, the drug was ingested between 1 and 2 hours before the test. This was followed by a 2-week period of placebo washout, after which the same subjects received the alternate P-blockade medication. Maximal exercise tests were done at baseline and after each placebo and /?blockade phase, that is, at weeks 3,6,8, and 11. Tests were performed on a motorized treadmill according to the Bruce protocol, and each subject was exercised until exhaustion. Blood samples for plasma potassium and magnesium were collected by indwelling brachial vein angiocatheters immediately (less than 2 minutes) before exercise testing, during the last 30 to 45 seconds of each stage of exercise testing, at peak of exercise testing, and for 120 minutes after testing (immediately and at 1,3,5,10,20,30,45,60 and 120 minutes). Plasma potassium levels were analyzed by flame emission on the SMA-IIc (Technicon Instruments Corp., Tarrytown, N.Y.). Plasma magnesium was assayed on the Cobas Bio (Roche Diagnostic Systems Inc., Montclair, N.J.). All data from indices from all tests were expressed as changes from baseline with the placebo lead-in period defined as the baseline period for the first double-blind period and the placebo washout period defined as the baseline period for the second double-blind period. These changes from baseline were then subjected to analysis of covariance with the respective baseline measurements as the covariate. The statistical model was based on a two-period, twotreatment crossover design and accounted for variation that was due to patients, treatment, period, and baseline. Time to recovery of plasma potassium and magnesium was estimated as follows: with the measurement at the end of exercise at time 0, a quadratic log-log response was estimated for each treadmill exercise test for each subject. A quadratic time response was then estimated to determine the time at which the subject returned to the preexercise level. Time determinations that exceeded the limit of the sampling times (0 and 120 minutes) were set to the limits for the analyses. RESULTS
All subjects completed the study without complications. Baseline maximal oxygen uptake for all (mean + SE) was 36.6 + 1.7 ml/kg/min, which was consistent with a maximal level of physical effort in nontrained individuals and an average to good maximal oxygen uptake for their age. Results are displayed in Figs. 1 and 2 for each treatment with the baseline period defined as the placebo period before each double-blind treatment. There was no significant difference in preexercise plasma potassium or magnesium between the groups
Volume 121 Number 1, Part 1
in either placebo, atenolol, or propranolol phases. Plasma potassium increased with exercise from 4.03 + 0.09 to 5.23 + 0.12 mmol/L with the atenolol treatment and from 3.94 + 0.08 to 5.34 + 0.14 mmol/ L with the propranolol treatment (p < 0.05). Plasma magnesium increased with atenolol from 0.84 f 0.02 mmol/L to 0.89 ? 0.02 mmol/L with exercise and from 0.82 f 0.01 mmol/L to 0.89 + 0.03 mmol/L with propranolol (p < 0.05). There was no difference between treatment groups with respect to preexercise or peak exercise potassium or magnesium levels. Within each group, both potassium and magnesium levels increased significantly with exercise (p < 0.05). Plasma potassium and magnesium levels were measured immediately and at 1,3,5,10,20,30,45,60, and 120 minutes during recovery after exercise. Plasma magnesium continued to increase during the first minute of recovery and then returned to baseline levels at 29.6 * 9.9 minutes and 23.9 k 7.0 minutes in the placebo groups and at 31.6 +- 9.4 minutes and 26.1 f. 8.3 minutes in the atenolol and propranolol groups, respectively (Fig. 2). There was no difference in this return to baseline between atenolol-treated and propranolol-treated groups. All groups showed a decline in plasma magnesium below baseline levels at approximately 45 minutes into recovery but returned to baseline by 120 minutes. There was no difference in this effect. Potassium returned to preexercise levels by 10.3 + 2.1 minutes and 10.4 -I- 2.4 minutes in the placebo groups and by 10.9 + 2.0 minutes in the atenolol treatment group. Potassium time to recovery, however, was significantly prolonged in the propranolol-treated group to 26.0 * 4.1 minutes when compared with the atenolol-treated group (p < 0.01). DISCUSSION
Because serum magnesium and potassium fluctuations may affect several clinical states, it is appropriate to elaborate on these as various subsets. Exercise. As noted in the aforementioned results, exercise testing to exhaustion in normal healthy volunteers significantly increased both plasma potassium and magnesium levels. Such has been noted in other studies on potassium changes with exercise,14-lg but fewer data are available with regard to magnesium. Lukaski et a1.20 have studied maximum oxygen consumption as related to magnesium concentrations in 44 healthy male university athletes and 20 untrained men. They found that maximum oxygen consumption was significantly correlated with increased plasma magnesium levels in the athletes but only weakly correlated in the untrained men. They hypothesized that ionic magnesium may facil-
Potassium
changes with exercise testing
107
0.90,
Rscovsry
(min)
Fig. 2. Trends in plasma magnesium with exercise testing. (a), Represents atenolol treatment versus placebo; (b), represents propranolol treatment versus placebo. (Note: abcissa is not drawn to linear time scale.)
itate oxygen delivery to working muscle tissue in trained subjects. Chadda et aL2r reported observations on serum and red blood cell magnesium in treadmill exercise-induced cardiac ischemia. There was no significant difference in the serum and red blood cell magnesium on the basis of exercise test results or ischemia; however, whole blood magnesium, hematocrit, and total proteins increased in both groups. Deuster et al. 22 showed that high-intensity anaerobic exercise induced a transient but significant decrease in plasma magnesium content, and over 85% of this loss or decrease was accounted for by a shift to the erythrocytes. Significant increases in urinary excretion were also observed. These data indicate that high-intensity anaerobic exercise increases intercompartmental magnesium shifts in blood, which return to preexercise values within 2 hours and urinary losses that occur during the day of exercise, which return to baseline the day after exercise. These changes may depend on the intensity of the exercise and the relative contribution of anaerobic metabolism to the total energy expended during exercise. Papademetriou et al.12 studied 10 patients with uncomplicated hypertension who had exercise testing twice while receiving placebo and twice while receiving hydrochlorothiazide 100 mg daily, at 2 to 4 weeks and 12 weeks of therapy. The authors found
108
Fletcher, Sweeney, and Fletcher
that exercise testing resulted in a small but significant increase in plasma potassium and magnesium levels but that the exercise-induced increase in magnesium returned to baseline in 10 minutes compared with the study results of greater than 20 minutes herein described. In addition, however, these 10 subjects had persistent elevation of their serum potassium levels at the lo-minute period. B-Adrenergic blockade. With the frequent use of various /?-blockade medications (both selective and nonselective) in patients with cardiovascular disease, there is concern regarding the effects of these drugs on the normal fluctuations of both serum potassium and magnesium levels. With regard to ,!?-adrenergic receptors and their stimulation and blockade, several studies are available. Williams et a1.23 studied six healthy subjects with maximal exercise tests under three conditions: with no medications (control), during P-blockade with propranolol, and during LYblockade with phentolamine. They found that, compared with controls, propranolol caused a greater rise and a more sustained elevation in potassium during recovery. Phentolamine, on the other hand, diminished the rise of potassium and lowered the potassium level throughout the recovery compared with controls. Kullmer and Kindermannz4 studied physical performance and serum potassium during long-term ,&blockade. They evaluated 63 healthy physical education students who received either 100 mg metoprolol, 80 mg of propranolol, or placebo for 3 months. They showed that, after 3 months of B-blockade treatment, serum potassium levels during acute exercise were significantly higher than in control subjects who were receiving placebo. It also took longer for the serum potassium to return to resting levels as compared with the control subjects. These findings confirm existence of a &receptor-regulated potassium transport system in human skeletal muscle and indicate that the transmembrane potassium transport in human skeletal muscle is predominantly regulated via &-receptors, although &-receptors also seem to be involved. Castellino et a1.25 studied the adrenergic modulation of potassium metabolism during exercise in normal and diabetic humans. They found that nonselective /3-adrenergic blockade caused a greater increase in serum potassium when compared with exercise alone. Selective &-adrenergic blockade exacerbated exercise-induced hyperkalemia in controls but not in diabetic subjects. This may reflect pathophysiologic alterations in the autonomic nervous system in the diabetics. Cardiovascular disease. Rasmussen et al? have recently described the hemodynamic effects of intra-
January American
1991
Heart Journal
venously administered magnesium in patients with ischemic heart disease. Fifteen patients with both chronic ischemic heart disease and heart failure were studied. They were given 12 mmol magnesium chloride intravenously. Results revealed arterial and pulmonary artery pressure reductions of 10% and 7 % , respectively. Heart rate, cardiac index, stroke volume, and stroke index increased slightly. These observed hemodynamic effects of magnesium infusion may be beneficial in the setting of acute infarction by reducing left ventricular afterload. Therefore along with the antiarrhythmic effect, magnesium may exert a positive influence on hemodynamic function, thereby reducing patient mortality during acute infarction. More recently, Miyagi et a1.27 have reported (in a small group of 20 patients) the suppression of angina1 attacks induced by hyperventilation by giving magnesium sulfate intravenously before induction of hyperventilation. In our study, the postexercise potassium in the propranolol group remained elevated significantly (for approximately 25 minutes) compared with atenolol and placebo (mean of 10 minutes), whereas there was no difference in the time for return to baseline for the magnesium. There were no resting or exercise-induced differences among the propranolol, atenolol, or placebo groups for potassium or magnesium. Because of the concern about blood electrolyte fluctuations in cardiovascular patients and the use of various P-adrenergic (selective and nonselective) agents, the implications of this study are helpful in that they reveal no difference in the exercise levels of potassium and magnesium in the presence of either @-adrenergic selective or nonselective blockade as compared with placebo. This may be clinically helpful in the exercise training setting and in patients who are taking p-blockade medications with reference to arrhythmias, particularly ventricular arrhythmias. The fact that postexercise potassium levels remain elevated for a longer period while patients are taking propranolol would not be expected to produce any significant clinical consequences. The absence of significant elevation in resting potassium with administration of propranolol may be related to the short duration of treatment (13 weeks). There are several general clinical implications relative to the role of blood potassium and magnesium levels during both exercise and P-blockade. In the study herein described, the parallel increase of serum potassium and magnesium with exercise may reflect a “protective role” with regard to arrhythmias that may be provoked with depressed states of these serum cations, particularly in patients who are taking digitalis. One might also hypothesize that during cardiopulmonary resuscitation at the time of cate-
Volume 121 Number 1, Part 1
cholamine stimulation (or infusion), blood potassium and magnesium levels may be depressed. The use of small doses of &blockers, particularly nonselective agents in this setting, may be helpful in maintaining the appropriate normal levels of both magnesium and potassium and perhaps averting further arrhythmias. As discussed previously,ll the clinical implication of the value of maintaining potassium and magnesium levels after infarction implies a “cardioprotective effect” that is relative to the importance of the normal levels of these two cations. With regard to the increases or decreases in magnesium in the exercise setting, it is unclear as to what this may reflect at the biochemical level. Perhaps in subjects who are not well-trained and who are exposed to high-intensity exercise, the depressions of magnesium may reflect overutilization of this cation in the exercise process. This is reflected in the study by Deuster et al. 22but was not found to be true in our subjects who were also untrained but who consistently elevated their magnesium levels with acute exercise. However, our subjects did demonstrate average to good maximal oxygen uptake for their age, and the degree of elevation in plasma magnesium with exercise may have been affected by this. Again, the study by Lukaski et a1.20 in university athletes reflected that trained athletes had increased plasma magnesium that correlated with an increased oxygen consumption. Therefore contrasting data exist regarding the role of magnesium as measured by peripheral samples. The data herein described differ from that reported previously in several respects. Because few data are available with regard to the effects of exercise on blood magnesium, the current study expands this data pool. Compared with other studies,22 the exercise-induced magnesium elevations in the data herein reported persisted longer in recovery (more than 20 minutes), whereas the potassium recovery with atenolol and placebo occurred earlier (mean of 10 minutes) compared with propranolol (approximately 25 minutes). In addition, there was no difference in the exercise-induced increase in blood potassium or magnesium levels with selective or nonselective P-blockade and placebo, compared with previous data,25 which resulted in a greater increase in serum potassium with nonselective ,&blockade compared with exercise alone. Lastly, the elevation of blood magnesium in the sedentary, nontrained subjects reported herein and by otherslg in university athletes differs from that reported in nontrained subjects21 who had depression of blood magnesium with exercise of higher intensity. With the overall frequent use of P-blockers in patients (and in some normal subjects) who are also of-
Potassium
changes with exercise testing
109
ten involved in exercise programs, the results of this study that show exercise and p-blockade as enhancing or permitting a higher level of magnesium or potassium has clinical impact. It is even more significant considering the enthusiasm for and frequent use of higher levels of exercise, particularly in patients with cardiovascular disease, who are taking B-blockers in that the data herein described may involve a safety factor because the elevations of magnesium and potassium are preserved. In conclusion, plasma magnesium and potassium levels increase significantly with acute exercise, and the magnitude of this increase is not affected by the addition of selective or nonselective P-adrenergic blockade. Nonselective p-blockade, however, appears to prolong the time to recovery of plasma potassium levels after exercise. These effects may be beneficial in terms of decreased cardiac arrhythmias, particularly in the postmyocardial infarction period, and possibly in terms of improved hemodynamic function. The of ICI display
authors thank Pharmaceuticals of the data.
Ms. Cassandra Dooley and Mr. Robert Bonk for their writing assistance and graphic
REFERENCES
1. Knochel JP, Dotin LN, Hamburger RJ. Pathophysiology of intense physical conditioning in a hot climate. J Clin Invest 1972;51:242-55. 2. Lauler DP. A symposium: magnesium deficiency-pathogenic, prevalence, and strategies of repletion. Am J Cardiol 1989;63:1a-46a. 3. Vincent HH, Mean In? Veld AJ, Boomsma F, Schalekamp MADH. Prevention of epinephrine-induced hypokalemia by nonselective beta blockers. Am J Cardiol 1985;56:1OD-14D. 4. Rosa RM, Silva P, Young JB, Landsberg L, Brown RS, Rowe JW, Epstein FH. Adrenergic modulation of extrarenal potassium disposal. N Engl J Med 1980;302:431-4. 5. Lundborg P. The effect of adrenergic blockade on potassium concentrations in different conditions. Acta Med Stand 1983; 672(suppl):121-6. 6. Dyckner T, Helmers C, Lundman T, Wester PO. Initial serum potassium level in relation to early complications and prognosis in patients with acute myocardial infarction. Acta Med Stand 1975;197:207-10. 7. Beck OA, Hochrein H. Initial serum potassium level in relation to cardiac arrhythmias in acute myocardial infarction. Z Kardiol 1977;66:187-90. 8. Duke M. Thiazide-induced hypokalemia. Association with acute myocardial infarction and ventricular fibrillation. JAMA 1978;239:43-5. 9. Hulting J. In-hospital ventricular fibrillation and its relation to serum potassium. Acta Med Stand 1981;647(suppl):109-16. 10. Solomon RJ, Cole AG. Importance of potassium in patients with acute myocardial infarction. Acta Med Stand 1981; 647(suppl):87-93. 11. Kafka H, Langevin L, Armstrong PW. Serum magnesium and potassium in acute myocardial infarction. Arch Intern Med 1987;147:465-9. 12. Papademetriou V, Costello R, Notargiacomo A, Sethi E, Singh S, Fletcher R. Exercise testing in diuretic treated hypertensive patients [Abstract]. J Am Co11 Cardiol 1988;11:198A. 13. Cohen I, Zimmerman AL. Changes in serum electrolyte levels during marathon running. S Afr Med J 1978;53:449-53.
Fletcher,
Sweeney, and Fletcher
American
14. Coplan NL, Gleim GW, Nicholas JA. Relation of potassium flux during incremental exercise to exercise intensity. Am J Cardiol 1988;62:334-5. 15. Affrime MB, Lowenthal DT, Falkner B, Gould A, Shirk J, Hauser A, Borruso J. The influence of clonidine on potassium disposition during aerobic exercise [Abstract]. Clin Pharmaco1 Ther 1981;29:231. 16. Bonelli J, Waldhousl W, Magometschnigg D, Schwarzmeier J, Korn A, Hitzenberger G. Effect of exercise and of prolonged oral administration of propranolol on hemodynamic variables, plasma renin concentration, plasma aldosterone and c-AMP. Eur J Clin Invest 1977;7:337-43. 17. Carlsson E, Fellenius E, Lundborg P, Svenson L. beta Adrenoceptor blockers, plasma-potassium, and exercise. Lancet 1978;2:424-5. 18. Francesconi R, Maher J, Bynum G, Mason J. Recurrent heat exposure: effects on levels of plasma and urinary sodium and potassium in resting and exercising men. Aviat Space Environ Med 1977;48:399-404. 19. Kilburn KH. Muscular origin of elevated plasma potassium during exercise. J Appl Physiol 1966;21:675-8. 20. Lukaski HC. Bolonchuk WW. Klevav LM. Milne DB. Sandstead HH. Maximal oxygen consumption as related to magnesium, copper, and zinc nutriture. Am J Clin Nutr 1983;37:40715.
January 1991 Heart Journal
21. Chadda KD, Cohen J, Werner BM, Gorfien P. Observations on serum and red blood cell magnesium changes in treadmill exercise-induced cardiac ischemia. J Am Co11 Nutr 1985;4:15763.
Deuster PA, Dolev E, Kyle SB, Anderson RA, Schoomaker EB. Magnesium homeostasis during high-intensity anaerobic exercise in men. J Appl Physiol 1987;62:545-50. 23. Williams ME, Gervino EV, Rosa RM, Landsberg L, Young JB, Silva P, Epstein FH. Catecholamine modulation of rapid potassium shifts during exercise. N Engl J Med 1985;312(13): 22.
823-7.
Kullmer T, Kindermann W. Physical performance and serum potassium under chronic beta-blockade. Eur J Appl Physiol 1985;54:350-4. 25. Castellino P, Simonson DC, DeFronzo RA. Adrenergic modulation of potassium metabolism during exercise in normal and diabetic humans. Am J Physiol 1987;252:E68-E76. 26. Rasmussen HS, Larsen OG, Meier K, Larsen J. Hemodynamic effects of intravenously administered magnesium on patients with ischemic heart disease. Clin Cardiol 1988;11:824-8. 27. Miyagi H, Yasue H, Okumura K, Ogawa H, Goto K, Oshima S. Effect of magnesium on angina1 attack induced by hyperventilation in patients with variant angina. Circulation 1989;79:597-602. 24.
Angiographic contrast media interference with laser-induced fluorescence excitation and detection in atherosclerotic human coronary arteries Laser-induced fluorescence has been used in conjunction with angiography for laser angioplasty gutdance. the effect of radiopaque contrast media on the excitation and detection of arterial fluorescence has not been previously reported. Accordingly, fluorescence emission spectra from human coronary artery necropsy specimens (n = 7) during excitation with pulsed excimer laser excitation (308 nm) was examined before and after the addition of three different contrast media, sodium and meglumine diatriroate, sodium and meglumine ioxaglate, and iopamidol. A decrease in overall fluorescence intensity was observed at all wavelengths for each contrast agent examined. The decrease in intensity of fluorescence emission was more marked at wavelengths less than 410 nm than at wavelengths above 425 nm. Similar effects were observed for contrast media diluted with whole blood. Absorption spectra for all three contrast media demonstrated absorption in the ultraviolet centered around 240 nm. We conclude that preferential absorption in the ultraviolet range by contrast media interferes with the excitation and detection of laser-induced fluorescence; use of visible light excitation may obviate interference with laser-induced fluorescence analysis of plaque. (AM HEART J 1991;121:110.)
Alexandra R. Lucas, MD,” Thomas Gauthier Jeffrey M. Isner, MD.” Boston, Muss.
From *Tufts New England Medical Center, Division of Cardiology; University School of Medicine; and bDepartment of Chemistry, University.
PhD,b Richard H. Clarke, PhD,b and
CTufts Boston
This work was performed while Dr. Lucas was an Alberta Heritage Foundation for Medical Research (AHFMR) Clinical Research Fellow in the Division of Cardiology at Tufts New England Medical Center.
110
Received
for publication
March
1, 1990; accepted
Reprint requests: Dr. Alexandra R. Lucas, Division X2, Walter Mackenzie Center, University of Alberta Alberta, Canada T6G-2R7. 4/1/24851
July
9, 1990.
of Cardiology, Room Hospitals, Edmonton,
Gerald F. Fletcher, MD, Mary Ellen Sweeney, MD, and Barbara J. Fletcher, RN, MN. Atlanta, Ga.
With the current interest in exercise in both healthy subjects and patients with cardiovascular disease, the state of hydration and blood electrolyte concentration has become of increasing concern. Knochel et al.,’ for example, have reported significant potassium depletion in men undergoing intense physical training in hot climates, and sweating is believed to be the major cause of potassium loss. More recently, Lauler et a1.2 addressed in some detail the problem of magnesium deficiency, but little attention was directed to the role of exercise and serum magnesium. In clinical practice, many patients with cardiovascular disease are taking various types of P-adrenergic-blocking agents. Nonselective preparations have been reported to affect blood potassium levels3; for instance, propranolol may augment the increase in plasma potassium during infusion of epinephrine and potasFrom the Department of Rehabilitation Medicine (Division of Cardiac Rehabilitation), Emory University School of Medicine: and the Emory Health Enhancement Program, Atlanta, Georgia. Supported Received
in part by a research for publication
Reprint requests: Program, Woodruff GA 30322. 4l1125124
Mar.
grant
from
ICI Pharmaceuticals
16, 1990; accepted
Gerald F. Fletcher, Physical Education
July
Group.
20, 1990.
MD, Emory Health Enhancement Center, 600 Asbury Circle, Atlanta,
sium chloride.4 Lundborg, in his review of the literature, revealed that the increase in serum potassium with p-blockade cannot be explained simply by potassium retention alone but is probably caused by a redistribution of potassium from intracellular to extracellular compartments. ,&Adrenergic mechanisms seem to be involved in the extrarenal handling of potassium, presumably by inducing an increased uptake of potassium in muscle cells and liver cells. These P-adrenergic mechanisms are probably of the S2 type.
Current data6-lo also suggest a relationship between the concentrations of various blood electrolytes (particularly potassium) and the presence of ventricular ectopic activity and ventricular tachycardia, especially in the setting of myocardial infarction. Kafka et alli have reported data on 590 patients who were admitted to the coronary care unit in whom hypomagnesemia occurred (4 % 1, but it occurred more commonly in those with acute infarction (6% with versus 3% without). Notably, ventricular arrhythmias occurred in 10 of the 13 patients with both acute infarction and hypomagnesemia; however, eight of these also had hypokalemia. To the contrary, however, in one small study12 of exercise testing in hypertensive patients with hydrochlorothiaxide ver105
January
106
Fletcher, Sweeney, and Fletcher
American
A Baseline + Propronolol
Recovery
(min)
Fig. 1. Trends in plasma potassium levels during exercise testing. (a), Represents atenolol treatment versus placebo; (b), represents propranolol treatment versus placebo. (Note: abcissa is not drawn to linear time scale.)
sus placebo therapy, there was no mention of exercise-induced arrhythmias. Although often suspected clinically, exercise-related hypokalemia (or potassium flux in general) has never been proven to be associated with or causative of arrhythmia. The role of blood magnesium and its changes with exercise and @-blockade has not been studied extensively. One report13 of 18 subjects who had electrolyte measurements after a standard marathon revealed a significant decrease in serum magnesium concentration with increases in both potassium and sodium levels. This finding may be of particular importance in the “cardiac patient” who is beginning or increasing the intensity of exercise and who is also on a /?adrenergic blocking agent. Because of these concerns, particularly those that relate to varying intensities of exercise in training programs and possible associated blood electrolyte changes in patients who are receiving ,&blockade medication, the current study was initiated. METHODS To test both the degree and duration of potassium and magnesium elevation with acute exercise, 17 sedentary, healthy men were randomized to and 15 completed a double-blind, two-treatment, two-period crossover study (mean age 29 years, range 19 to 44 years). The study was
1991
Heart Journal
approved by the institutional committee on human research. Informed consent was obtained from each subject after the nature of the procedures of the study had been fully explained. After they had received placebo for 3 weeks, the subjects received atenolol 100 mg daily or propranolol80 mg twice daily for 3 weeks. On the day of exercise testing, the drug was ingested between 1 and 2 hours before the test. This was followed by a 2-week period of placebo washout, after which the same subjects received the alternate P-blockade medication. Maximal exercise tests were done at baseline and after each placebo and /?blockade phase, that is, at weeks 3,6,8, and 11. Tests were performed on a motorized treadmill according to the Bruce protocol, and each subject was exercised until exhaustion. Blood samples for plasma potassium and magnesium were collected by indwelling brachial vein angiocatheters immediately (less than 2 minutes) before exercise testing, during the last 30 to 45 seconds of each stage of exercise testing, at peak of exercise testing, and for 120 minutes after testing (immediately and at 1,3,5,10,20,30,45,60 and 120 minutes). Plasma potassium levels were analyzed by flame emission on the SMA-IIc (Technicon Instruments Corp., Tarrytown, N.Y.). Plasma magnesium was assayed on the Cobas Bio (Roche Diagnostic Systems Inc., Montclair, N.J.). All data from indices from all tests were expressed as changes from baseline with the placebo lead-in period defined as the baseline period for the first double-blind period and the placebo washout period defined as the baseline period for the second double-blind period. These changes from baseline were then subjected to analysis of covariance with the respective baseline measurements as the covariate. The statistical model was based on a two-period, twotreatment crossover design and accounted for variation that was due to patients, treatment, period, and baseline. Time to recovery of plasma potassium and magnesium was estimated as follows: with the measurement at the end of exercise at time 0, a quadratic log-log response was estimated for each treadmill exercise test for each subject. A quadratic time response was then estimated to determine the time at which the subject returned to the preexercise level. Time determinations that exceeded the limit of the sampling times (0 and 120 minutes) were set to the limits for the analyses. RESULTS
All subjects completed the study without complications. Baseline maximal oxygen uptake for all (mean + SE) was 36.6 + 1.7 ml/kg/min, which was consistent with a maximal level of physical effort in nontrained individuals and an average to good maximal oxygen uptake for their age. Results are displayed in Figs. 1 and 2 for each treatment with the baseline period defined as the placebo period before each double-blind treatment. There was no significant difference in preexercise plasma potassium or magnesium between the groups
Volume 121 Number 1, Part 1
in either placebo, atenolol, or propranolol phases. Plasma potassium increased with exercise from 4.03 + 0.09 to 5.23 + 0.12 mmol/L with the atenolol treatment and from 3.94 + 0.08 to 5.34 + 0.14 mmol/ L with the propranolol treatment (p < 0.05). Plasma magnesium increased with atenolol from 0.84 f 0.02 mmol/L to 0.89 ? 0.02 mmol/L with exercise and from 0.82 f 0.01 mmol/L to 0.89 + 0.03 mmol/L with propranolol (p < 0.05). There was no difference between treatment groups with respect to preexercise or peak exercise potassium or magnesium levels. Within each group, both potassium and magnesium levels increased significantly with exercise (p < 0.05). Plasma potassium and magnesium levels were measured immediately and at 1,3,5,10,20,30,45,60, and 120 minutes during recovery after exercise. Plasma magnesium continued to increase during the first minute of recovery and then returned to baseline levels at 29.6 * 9.9 minutes and 23.9 k 7.0 minutes in the placebo groups and at 31.6 +- 9.4 minutes and 26.1 f. 8.3 minutes in the atenolol and propranolol groups, respectively (Fig. 2). There was no difference in this return to baseline between atenolol-treated and propranolol-treated groups. All groups showed a decline in plasma magnesium below baseline levels at approximately 45 minutes into recovery but returned to baseline by 120 minutes. There was no difference in this effect. Potassium returned to preexercise levels by 10.3 + 2.1 minutes and 10.4 -I- 2.4 minutes in the placebo groups and by 10.9 + 2.0 minutes in the atenolol treatment group. Potassium time to recovery, however, was significantly prolonged in the propranolol-treated group to 26.0 * 4.1 minutes when compared with the atenolol-treated group (p < 0.01). DISCUSSION
Because serum magnesium and potassium fluctuations may affect several clinical states, it is appropriate to elaborate on these as various subsets. Exercise. As noted in the aforementioned results, exercise testing to exhaustion in normal healthy volunteers significantly increased both plasma potassium and magnesium levels. Such has been noted in other studies on potassium changes with exercise,14-lg but fewer data are available with regard to magnesium. Lukaski et a1.20 have studied maximum oxygen consumption as related to magnesium concentrations in 44 healthy male university athletes and 20 untrained men. They found that maximum oxygen consumption was significantly correlated with increased plasma magnesium levels in the athletes but only weakly correlated in the untrained men. They hypothesized that ionic magnesium may facil-
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0.90,
Rscovsry
(min)
Fig. 2. Trends in plasma magnesium with exercise testing. (a), Represents atenolol treatment versus placebo; (b), represents propranolol treatment versus placebo. (Note: abcissa is not drawn to linear time scale.)
itate oxygen delivery to working muscle tissue in trained subjects. Chadda et aL2r reported observations on serum and red blood cell magnesium in treadmill exercise-induced cardiac ischemia. There was no significant difference in the serum and red blood cell magnesium on the basis of exercise test results or ischemia; however, whole blood magnesium, hematocrit, and total proteins increased in both groups. Deuster et al. 22 showed that high-intensity anaerobic exercise induced a transient but significant decrease in plasma magnesium content, and over 85% of this loss or decrease was accounted for by a shift to the erythrocytes. Significant increases in urinary excretion were also observed. These data indicate that high-intensity anaerobic exercise increases intercompartmental magnesium shifts in blood, which return to preexercise values within 2 hours and urinary losses that occur during the day of exercise, which return to baseline the day after exercise. These changes may depend on the intensity of the exercise and the relative contribution of anaerobic metabolism to the total energy expended during exercise. Papademetriou et al.12 studied 10 patients with uncomplicated hypertension who had exercise testing twice while receiving placebo and twice while receiving hydrochlorothiazide 100 mg daily, at 2 to 4 weeks and 12 weeks of therapy. The authors found
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that exercise testing resulted in a small but significant increase in plasma potassium and magnesium levels but that the exercise-induced increase in magnesium returned to baseline in 10 minutes compared with the study results of greater than 20 minutes herein described. In addition, however, these 10 subjects had persistent elevation of their serum potassium levels at the lo-minute period. B-Adrenergic blockade. With the frequent use of various /?-blockade medications (both selective and nonselective) in patients with cardiovascular disease, there is concern regarding the effects of these drugs on the normal fluctuations of both serum potassium and magnesium levels. With regard to ,!?-adrenergic receptors and their stimulation and blockade, several studies are available. Williams et a1.23 studied six healthy subjects with maximal exercise tests under three conditions: with no medications (control), during P-blockade with propranolol, and during LYblockade with phentolamine. They found that, compared with controls, propranolol caused a greater rise and a more sustained elevation in potassium during recovery. Phentolamine, on the other hand, diminished the rise of potassium and lowered the potassium level throughout the recovery compared with controls. Kullmer and Kindermannz4 studied physical performance and serum potassium during long-term ,&blockade. They evaluated 63 healthy physical education students who received either 100 mg metoprolol, 80 mg of propranolol, or placebo for 3 months. They showed that, after 3 months of B-blockade treatment, serum potassium levels during acute exercise were significantly higher than in control subjects who were receiving placebo. It also took longer for the serum potassium to return to resting levels as compared with the control subjects. These findings confirm existence of a &receptor-regulated potassium transport system in human skeletal muscle and indicate that the transmembrane potassium transport in human skeletal muscle is predominantly regulated via &-receptors, although &-receptors also seem to be involved. Castellino et a1.25 studied the adrenergic modulation of potassium metabolism during exercise in normal and diabetic humans. They found that nonselective /3-adrenergic blockade caused a greater increase in serum potassium when compared with exercise alone. Selective &-adrenergic blockade exacerbated exercise-induced hyperkalemia in controls but not in diabetic subjects. This may reflect pathophysiologic alterations in the autonomic nervous system in the diabetics. Cardiovascular disease. Rasmussen et al? have recently described the hemodynamic effects of intra-
January American
1991
Heart Journal
venously administered magnesium in patients with ischemic heart disease. Fifteen patients with both chronic ischemic heart disease and heart failure were studied. They were given 12 mmol magnesium chloride intravenously. Results revealed arterial and pulmonary artery pressure reductions of 10% and 7 % , respectively. Heart rate, cardiac index, stroke volume, and stroke index increased slightly. These observed hemodynamic effects of magnesium infusion may be beneficial in the setting of acute infarction by reducing left ventricular afterload. Therefore along with the antiarrhythmic effect, magnesium may exert a positive influence on hemodynamic function, thereby reducing patient mortality during acute infarction. More recently, Miyagi et a1.27 have reported (in a small group of 20 patients) the suppression of angina1 attacks induced by hyperventilation by giving magnesium sulfate intravenously before induction of hyperventilation. In our study, the postexercise potassium in the propranolol group remained elevated significantly (for approximately 25 minutes) compared with atenolol and placebo (mean of 10 minutes), whereas there was no difference in the time for return to baseline for the magnesium. There were no resting or exercise-induced differences among the propranolol, atenolol, or placebo groups for potassium or magnesium. Because of the concern about blood electrolyte fluctuations in cardiovascular patients and the use of various P-adrenergic (selective and nonselective) agents, the implications of this study are helpful in that they reveal no difference in the exercise levels of potassium and magnesium in the presence of either @-adrenergic selective or nonselective blockade as compared with placebo. This may be clinically helpful in the exercise training setting and in patients who are taking p-blockade medications with reference to arrhythmias, particularly ventricular arrhythmias. The fact that postexercise potassium levels remain elevated for a longer period while patients are taking propranolol would not be expected to produce any significant clinical consequences. The absence of significant elevation in resting potassium with administration of propranolol may be related to the short duration of treatment (13 weeks). There are several general clinical implications relative to the role of blood potassium and magnesium levels during both exercise and P-blockade. In the study herein described, the parallel increase of serum potassium and magnesium with exercise may reflect a “protective role” with regard to arrhythmias that may be provoked with depressed states of these serum cations, particularly in patients who are taking digitalis. One might also hypothesize that during cardiopulmonary resuscitation at the time of cate-
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cholamine stimulation (or infusion), blood potassium and magnesium levels may be depressed. The use of small doses of &blockers, particularly nonselective agents in this setting, may be helpful in maintaining the appropriate normal levels of both magnesium and potassium and perhaps averting further arrhythmias. As discussed previously,ll the clinical implication of the value of maintaining potassium and magnesium levels after infarction implies a “cardioprotective effect” that is relative to the importance of the normal levels of these two cations. With regard to the increases or decreases in magnesium in the exercise setting, it is unclear as to what this may reflect at the biochemical level. Perhaps in subjects who are not well-trained and who are exposed to high-intensity exercise, the depressions of magnesium may reflect overutilization of this cation in the exercise process. This is reflected in the study by Deuster et al. 22but was not found to be true in our subjects who were also untrained but who consistently elevated their magnesium levels with acute exercise. However, our subjects did demonstrate average to good maximal oxygen uptake for their age, and the degree of elevation in plasma magnesium with exercise may have been affected by this. Again, the study by Lukaski et a1.20 in university athletes reflected that trained athletes had increased plasma magnesium that correlated with an increased oxygen consumption. Therefore contrasting data exist regarding the role of magnesium as measured by peripheral samples. The data herein described differ from that reported previously in several respects. Because few data are available with regard to the effects of exercise on blood magnesium, the current study expands this data pool. Compared with other studies,22 the exercise-induced magnesium elevations in the data herein reported persisted longer in recovery (more than 20 minutes), whereas the potassium recovery with atenolol and placebo occurred earlier (mean of 10 minutes) compared with propranolol (approximately 25 minutes). In addition, there was no difference in the exercise-induced increase in blood potassium or magnesium levels with selective or nonselective P-blockade and placebo, compared with previous data,25 which resulted in a greater increase in serum potassium with nonselective ,&blockade compared with exercise alone. Lastly, the elevation of blood magnesium in the sedentary, nontrained subjects reported herein and by otherslg in university athletes differs from that reported in nontrained subjects21 who had depression of blood magnesium with exercise of higher intensity. With the overall frequent use of P-blockers in patients (and in some normal subjects) who are also of-
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ten involved in exercise programs, the results of this study that show exercise and p-blockade as enhancing or permitting a higher level of magnesium or potassium has clinical impact. It is even more significant considering the enthusiasm for and frequent use of higher levels of exercise, particularly in patients with cardiovascular disease, who are taking B-blockers in that the data herein described may involve a safety factor because the elevations of magnesium and potassium are preserved. In conclusion, plasma magnesium and potassium levels increase significantly with acute exercise, and the magnitude of this increase is not affected by the addition of selective or nonselective P-adrenergic blockade. Nonselective p-blockade, however, appears to prolong the time to recovery of plasma potassium levels after exercise. These effects may be beneficial in terms of decreased cardiac arrhythmias, particularly in the postmyocardial infarction period, and possibly in terms of improved hemodynamic function. The of ICI display
authors thank Pharmaceuticals of the data.
Ms. Cassandra Dooley and Mr. Robert Bonk for their writing assistance and graphic
REFERENCES
1. Knochel JP, Dotin LN, Hamburger RJ. Pathophysiology of intense physical conditioning in a hot climate. J Clin Invest 1972;51:242-55. 2. Lauler DP. A symposium: magnesium deficiency-pathogenic, prevalence, and strategies of repletion. Am J Cardiol 1989;63:1a-46a. 3. Vincent HH, Mean In? Veld AJ, Boomsma F, Schalekamp MADH. Prevention of epinephrine-induced hypokalemia by nonselective beta blockers. Am J Cardiol 1985;56:1OD-14D. 4. Rosa RM, Silva P, Young JB, Landsberg L, Brown RS, Rowe JW, Epstein FH. Adrenergic modulation of extrarenal potassium disposal. N Engl J Med 1980;302:431-4. 5. Lundborg P. The effect of adrenergic blockade on potassium concentrations in different conditions. Acta Med Stand 1983; 672(suppl):121-6. 6. Dyckner T, Helmers C, Lundman T, Wester PO. Initial serum potassium level in relation to early complications and prognosis in patients with acute myocardial infarction. Acta Med Stand 1975;197:207-10. 7. Beck OA, Hochrein H. Initial serum potassium level in relation to cardiac arrhythmias in acute myocardial infarction. Z Kardiol 1977;66:187-90. 8. Duke M. Thiazide-induced hypokalemia. Association with acute myocardial infarction and ventricular fibrillation. JAMA 1978;239:43-5. 9. Hulting J. In-hospital ventricular fibrillation and its relation to serum potassium. Acta Med Stand 1981;647(suppl):109-16. 10. Solomon RJ, Cole AG. Importance of potassium in patients with acute myocardial infarction. Acta Med Stand 1981; 647(suppl):87-93. 11. Kafka H, Langevin L, Armstrong PW. Serum magnesium and potassium in acute myocardial infarction. Arch Intern Med 1987;147:465-9. 12. Papademetriou V, Costello R, Notargiacomo A, Sethi E, Singh S, Fletcher R. Exercise testing in diuretic treated hypertensive patients [Abstract]. J Am Co11 Cardiol 1988;11:198A. 13. Cohen I, Zimmerman AL. Changes in serum electrolyte levels during marathon running. S Afr Med J 1978;53:449-53.
Fletcher,
Sweeney, and Fletcher
American
14. Coplan NL, Gleim GW, Nicholas JA. Relation of potassium flux during incremental exercise to exercise intensity. Am J Cardiol 1988;62:334-5. 15. Affrime MB, Lowenthal DT, Falkner B, Gould A, Shirk J, Hauser A, Borruso J. The influence of clonidine on potassium disposition during aerobic exercise [Abstract]. Clin Pharmaco1 Ther 1981;29:231. 16. Bonelli J, Waldhousl W, Magometschnigg D, Schwarzmeier J, Korn A, Hitzenberger G. Effect of exercise and of prolonged oral administration of propranolol on hemodynamic variables, plasma renin concentration, plasma aldosterone and c-AMP. Eur J Clin Invest 1977;7:337-43. 17. Carlsson E, Fellenius E, Lundborg P, Svenson L. beta Adrenoceptor blockers, plasma-potassium, and exercise. Lancet 1978;2:424-5. 18. Francesconi R, Maher J, Bynum G, Mason J. Recurrent heat exposure: effects on levels of plasma and urinary sodium and potassium in resting and exercising men. Aviat Space Environ Med 1977;48:399-404. 19. Kilburn KH. Muscular origin of elevated plasma potassium during exercise. J Appl Physiol 1966;21:675-8. 20. Lukaski HC. Bolonchuk WW. Klevav LM. Milne DB. Sandstead HH. Maximal oxygen consumption as related to magnesium, copper, and zinc nutriture. Am J Clin Nutr 1983;37:40715.
January 1991 Heart Journal
21. Chadda KD, Cohen J, Werner BM, Gorfien P. Observations on serum and red blood cell magnesium changes in treadmill exercise-induced cardiac ischemia. J Am Co11 Nutr 1985;4:15763.
Deuster PA, Dolev E, Kyle SB, Anderson RA, Schoomaker EB. Magnesium homeostasis during high-intensity anaerobic exercise in men. J Appl Physiol 1987;62:545-50. 23. Williams ME, Gervino EV, Rosa RM, Landsberg L, Young JB, Silva P, Epstein FH. Catecholamine modulation of rapid potassium shifts during exercise. N Engl J Med 1985;312(13): 22.
823-7.
Kullmer T, Kindermann W. Physical performance and serum potassium under chronic beta-blockade. Eur J Appl Physiol 1985;54:350-4. 25. Castellino P, Simonson DC, DeFronzo RA. Adrenergic modulation of potassium metabolism during exercise in normal and diabetic humans. Am J Physiol 1987;252:E68-E76. 26. Rasmussen HS, Larsen OG, Meier K, Larsen J. Hemodynamic effects of intravenously administered magnesium on patients with ischemic heart disease. Clin Cardiol 1988;11:824-8. 27. Miyagi H, Yasue H, Okumura K, Ogawa H, Goto K, Oshima S. Effect of magnesium on angina1 attack induced by hyperventilation in patients with variant angina. Circulation 1989;79:597-602. 24.
Angiographic contrast media interference with laser-induced fluorescence excitation and detection in atherosclerotic human coronary arteries Laser-induced fluorescence has been used in conjunction with angiography for laser angioplasty gutdance. the effect of radiopaque contrast media on the excitation and detection of arterial fluorescence has not been previously reported. Accordingly, fluorescence emission spectra from human coronary artery necropsy specimens (n = 7) during excitation with pulsed excimer laser excitation (308 nm) was examined before and after the addition of three different contrast media, sodium and meglumine diatriroate, sodium and meglumine ioxaglate, and iopamidol. A decrease in overall fluorescence intensity was observed at all wavelengths for each contrast agent examined. The decrease in intensity of fluorescence emission was more marked at wavelengths less than 410 nm than at wavelengths above 425 nm. Similar effects were observed for contrast media diluted with whole blood. Absorption spectra for all three contrast media demonstrated absorption in the ultraviolet centered around 240 nm. We conclude that preferential absorption in the ultraviolet range by contrast media interferes with the excitation and detection of laser-induced fluorescence; use of visible light excitation may obviate interference with laser-induced fluorescence analysis of plaque. (AM HEART J 1991;121:110.)
Alexandra R. Lucas, MD,” Thomas Gauthier Jeffrey M. Isner, MD.” Boston, Muss.
From *Tufts New England Medical Center, Division of Cardiology; University School of Medicine; and bDepartment of Chemistry, University.
PhD,b Richard H. Clarke, PhD,b and
CTufts Boston
This work was performed while Dr. Lucas was an Alberta Heritage Foundation for Medical Research (AHFMR) Clinical Research Fellow in the Division of Cardiology at Tufts New England Medical Center.
110
Received
for publication
March
1, 1990; accepted
Reprint requests: Dr. Alexandra R. Lucas, Division X2, Walter Mackenzie Center, University of Alberta Alberta, Canada T6G-2R7. 4/1/24851
July
9, 1990.
of Cardiology, Room Hospitals, Edmonton,