Inactivation of human muscle Na+-K+-ATPase in vitro during prolonged exercise is increased with hypoxia

2004 ◽  
Vol 96 (5) ◽  
pp. 1767-1775 ◽  
Author(s):  
S. D. Sandiford ◽  
H. J. Green ◽  
T. A. Duhamel ◽  
J. G. Perco ◽  
J. D. Schertzer ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Prolonged Exercise ◽  
Vastus Lateralis ◽  
Neuromuscular Fatigue ◽  
Peak Oxygen Consumption ◽  
Membrane Excitability ◽  
M Wave ◽  
Oxygen Fraction ◽  
Inspired Oxygen

This study investigated the effects of prolonged exercise performed in normoxia (N) and hypoxia (H) on neuromuscular fatigue, membrane excitability, and Na+-K+-ATPase activity in working muscle. Ten untrained volunteers [peak oxygen consumption (VV̇o2 peak) = 42.1 ± 2.8 (SE) ml·kg-1·min-1] performed 90 min of cycling during N (inspired oxygen fraction = 0.21) and during H (inspired oxygen fraction = 0.14) at ∼50% of normoxic VV̇o2 peak. During N, 3- O-methylfluorescein phosphatase activity (nmol·mg protein-1·h-1) in vastus lateralis, used as a measure of Na+-K+-ATPase activity, decreased ( P < 0.05) by 21% at 30 min of exercise compared with rest (101 ± 53 vs. 79.6 ± 4.3) with no further reductions observed at 90 min (72.8 ± 8.0). During H, similar reductions ( P < 0.05) were observed during the first 30 min (90.8 ± 5.3 vs. 79.0 ± 6.3) followed by further reductions ( P < 0.05) at 90 min (50.5 ± 3.9). Exercise in N resulted in reductions ( P < 0.05) in both quadriceps maximal voluntary contractile force (MVC; 633 ± 50 vs. 477 ± 67 N) and force at low frequencies of stimulation, namely 10 Hz (142 ± 16 vs. 86.7 ± 10 N) and 20 Hz (283 ± 32 vs. 236 ± 31 N). No changes were observed in the amplitude, duration, and area of the muscle compound action potential (M wave). Exercise in H was without additional effect in altering MVC, low-frequency force, and M-wave properties. It is concluded that, although exercise in H resulted in a greater inactivation of Na+-K+-ATPase activity compared with N, neuromuscular fatigue and membrane excitability are not differentially altered.

Human neuromuscular fatigue is associated with altered Na+-K+-ATPase activity following isometric exercise

2002 ◽  
Vol 92 (4) ◽  
pp. 1585-1593 ◽  
Author(s):  
J. R. Fowles ◽  
H. J. Green ◽  
R. Tupling ◽  
S. O'Brien ◽  
B. D. Roy
Keyword(s):  
Atpase Activity ◽  
Maximal Voluntary Contraction ◽  
Vastus Lateralis ◽  
Isometric Exercise ◽  
Voluntary Contraction ◽  
Neuromuscular Fatigue ◽  
Vastus Lateralis Muscle ◽  
M Wave ◽  
Leg Extension ◽  
Muscle Action Potential

The purpose of this study was to investigate the hypothesis that reductions in Na+-K+- ATPase activity are associated with neuromuscular fatigue following isometric exercise. In control (Con) and exercised (Ex) legs, force and electromyogram were measured in 14 volunteers [age, 23.4 ± 0.7 (SE) yr] before and immediately after (PST0), 1 h after (PST1), and 4 h after (PST4) isometric, single-leg extension exercise at ∼60% of maximal voluntary contraction for 30 min using a 0.5 duty cycle (5-s contraction, 5-s rest). Tissue was obtained from vastus lateralis muscle before exercise in Con and after exercise in both the Con (PST0) and Ex legs (PST0, PST1, PST4), for the measurements of Na+-K+-ATPase activity, as determined by the 3- O-methylfluorescein phosphatase (3- O-MFPase) assay. Voluntary (maximal voluntary contraction) and elicited (10, 20, 50, 100 Hz) force was reduced 30–55% ( P < 0.05) at PST0 and did not recover by PST4. Muscle action potential (M-wave) amplitude and area (measured in the vastus medialis) and 3- O-MFPase activity at PST0-Ex were less than that at PST0-Con ( P < 0.05) by 37, 25, and 38%, respectively. M-wave area at PST1-Ex was also less than that at PST1-Con ( P < 0.05). Changes in 3- O-MFPase activity correlated to changes in M-wave area across all time points ( r = 0.38, P < 0.05, n= 45). These results demonstrate that Na+-K+- ATPase activity is reduced by sustained isometric exercise in humans from that in a matched Con leg and that this reduction in Na+-K+-ATPase activity is associated with loss of excitability as indicated by M-wave alterations.

Chronic intermittent hypoxia and incremental cycling exercise independently depress muscle in vitro maximal Na+-K+-ATPase activity in well-trained athletes

2005 ◽  
Vol 98 (1) ◽  
pp. 186-192 ◽  
Author(s):  
R. J. Aughey ◽  
C. J. Gore ◽  
A. G. Hahn ◽  
A. P. Garnham ◽  
S. A. Clark ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Vastus Lateralis ◽  
Incremental Exercise ◽  
Peak Oxygen Consumption ◽  
Vastus Lateralis Muscle ◽  
Minor Effect ◽  
Moderate Altitude ◽  
Ouabain Binding ◽  
Before And After

Athletes commonly attempt to enhance performance by training in normoxia but sleeping in hypoxia [live high and train low (LHTL)]. However, chronic hypoxia reduces muscle Na+-K+-ATPase content, whereas fatiguing contractions reduce Na+-K+-ATPase activity, which each may impair performance. We examined whether LHTL and intense exercise would decrease muscle Na+-K+-ATPase activity and whether these effects would be additive and sufficient to impair performance or plasma K+ regulation. Thirteen subjects were randomly assigned to two fitness-matched groups, LHTL ( n = 6) or control (Con, n = 7). LHTL slept at simulated moderate altitude (3,000 m, inspired O2 fraction = 15.48%) for 23 nights and lived and trained by day under normoxic conditions in Canberra (altitude ∼600 m). Con lived, trained, and slept in normoxia. A standardized incremental exercise test was conducted before and after LHTL. A vastus lateralis muscle biopsy was taken at rest and after exercise, before and after LHTL or Con, and analyzed for maximal Na+-K+-ATPase activity [K+-stimulated 3- O-methylfluorescein phosphatase (3- O-MFPase)] and Na+-K+-ATPase content ([3H]ouabain binding sites). 3- O-MFPase activity was decreased by −2.9 ± 2.6% in LHTL ( P < 0.05) and was depressed immediately after exercise ( P < 0.05) similarly in Con and LHTL (−13.0 ± 3.2 and −11.8 ± 1.5%, respectively). Plasma K+ concentration during exercise was unchanged by LHTL; [3H]ouabain binding was unchanged with LHTL or exercise. Peak oxygen consumption was reduced in LHTL ( P < 0.05) but not in Con, whereas exercise work was unchanged in either group. Thus LHTL had a minor effect on, and incremental exercise reduced, Na+-K+-ATPase activity. However, the small LHTL-induced depression of 3- O-MFPase activity was insufficient to adversely affect either K+ regulation or total work performed.

Glucose supplements increase human muscle in vitro Na+-K+-ATPase activity during prolonged exercise

2007 ◽  
Vol 293 (1) ◽  
pp. R354-R362 ◽  
Author(s):  
H. J. Green ◽  
T. A. Duhamel ◽  
K. P. Foley ◽  
J. Ouyang ◽  
I. C. Smith ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Prolonged Exercise ◽  
Serum Insulin ◽  
Vastus Lateralis ◽  
Oral Glucose ◽  
Vastus Lateralis Muscle ◽  
Ouabain Binding ◽  
Similar Time ◽  
Phosphatase Assay

Regulation of maximal Na+-K+-ATPase activity in vastus lateralis muscle was investigated in response to prolonged exercise with (G) and without (NG) oral glucose supplements. Fifteen untrained volunteers (14 males and 1 female) with a peak aerobic power (V̇o2peak) of 44.8 ± 1.9 ml·kg−1·min−1; mean ± SE cycled at ∼57% V̇o2peak to fatigue during both NG (artificial sweeteners) and G (6.13 ± 0.09% glucose) in randomized order. Consumption of beverage began at 30 min and continued every 15 min until fatigue. Time to fatigue was increased ( P < 0.05) in G compared with NG (137 ± 7 vs. 115 ± 6 min). Maximal Na+-K+-ATPase activity (Vmax) as measured by the 3- O-methylfluorescein phosphatase assay (nmol·mg−1·h−1) was not different between conditions prior to exercise (85.2 ± 3.3 or 86.0 ± 3.9), at 30 min (91.4 ± 4.7 vs. 91.9 ± 4.1) and at fatigue (92.8 ± 4.3 vs. 100 ± 5.0) but was higher ( P < 0.05) in G at 90 min (86.7 ± 4.2 vs. 109 ± 4.1). Na+-K+-ATPase content (βmax) measured by the vanadate facilitated [3H]ouabain-binding technique (pmol/g wet wt) although elevated ( P < 0.05) by exercise (0<30, 90, and fatigue) was not different between NG and G. At 60 and 90 min of exercise, blood glucose was higher ( P < 0.05) in G compared with NG. The G condition also resulted in higher ( P < 0.05) serum insulin at similar time points to glucose and lower ( P < 0.05) plasma epinephrine and norepinephrine at 90 min of exercise and at fatigue. These results suggest that G results in an increase in Vmax by mechanisms that are unclear.

Effects of prior exercise and a low-carbohydrate diet on muscle sarcoplasmic reticulum function during cycling in women

2006 ◽  
Vol 101 (3) ◽  
pp. 695-706 ◽  
Author(s):  
T. A. Duhamel ◽  
H. J. Green ◽  
J. G. Perco ◽  
J. Ouyang
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Atpase Activity ◽  
Vastus Lateralis ◽  
Phase 1 ◽  
Vastus Lateralis Muscle ◽  
Low Carbohydrate Diet ◽  
Hill Slope ◽  
Low Carbohydrate ◽  
Exercise Induced

The effects of exercise and diet on sarcoplasmic reticulum Ca2+-cycling properties in female vastus lateralis muscle were investigated in two groups of women following four different conditions. The conditions were 4 days of a low-carbohydrate (Lo CHO) and glycogen-depleting exercise plus a Lo CHO diet (Ex + Lo CHO) ( experiment 2) and 4 days of normal CHO (Norm CHO) and glycogen-depleting exercise plus Norm CHO (Ex + Norm CHO) ( experiment 1). Peak aerobic power (V̇o2peak) was 38.1 ± 1.4 (SE); n = 9 and 35.6 ± 1.4 ml·kg−1·min−1; n = 9, respectively. Sarcoplasmic reticulum properties measured in vitro in homogenates (μmol·g protein−1·min−1) indicated exercise-induced reductions ( P < 0.05) in maximal Ca2+-ATPase activity (0 > 30, 60 min > fatigue), Ca2+ uptake (0 > 30 > 60 min, fatigue), and Ca2+ release, both phase 1 (0, 30 > 60 min, fatigue) and phase 2 (0 > 30, 60 min, fatigue; 30 min > fatigue) in Norm CHO. Exercise was without effect in altering the Hill slope ( nH), defined as the slope of relationship between Ca2+-ATPase activity and Ca2+ concentration. No differences were observed between Norm CHO and Ex+Norm CHO. Compared with Norm CHO, Lo CHO resulted in a lower ( P < 0.05) Ca2+ uptake, phase 1 Ca2+ release (30 min), and nH. Ex + Lo CHO resulted in a greater ( P < 0.05) Ca2+ uptake and nH compared with Lo CHO. The results demonstrate that Lo CHO alone can disrupt SR Ca2+ cycling and that, with the exception of Ca2+ release, a glycogen-depleting session of exercise before Lo CHO can reverse the effects.

Fatigue depresses maximal in vitro skeletal muscle Na+-K+-ATPase activity in untrained and trained individuals

2002 ◽  
Vol 93 (5) ◽  
pp. 1650-1659 ◽  
Author(s):  
Steve F. Fraser ◽  
Jia L. Li ◽  
Michael F. Carey ◽  
Xiao N. Wang ◽  
Termboon Sangkabutra ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Phosphatase Activity ◽  
Important Determinant ◽  
Vastus Lateralis ◽  
Ouabain Binding ◽  
Isokinetic Contractions ◽  
Lower Ratio ◽  
Muscle Biopsies ◽  
Training State

This study investigated whether fatiguing dynamic exercise depresses maximal in vitro Na+-K+-ATPase activity and whether any depression is attenuated with chronic training. Eight untrained (UT), eight resistance-trained (RT), and eight endurance-trained (ET) subjects performed a quadriceps fatigue test, comprising 50 maximal isokinetic contractions (180°/s, 0.5 Hz). Muscle biopsies (vastus lateralis) were taken before and immediately after exercise and were analyzed for maximal in vitro Na+-K+-ATPase (K+-stimulated 3- O-methylfluoroscein phosphatase) activity. Resting samples were analyzed for [3H]ouabain binding site content, which was 16.6 and 18.3% higher ( P < 0.05) in ET than RT and UT, respectively (UT 311 ± 41, RT 302 ± 52, ET 357 ± 29 pmol/g wet wt). 3- O-methylfluoroscein phosphatase activity was depressed at fatigue by −13.8 ± 4.1% ( P < 0.05), with no differences between groups (UT −13 ± 4, RT −9 ± 6, ET −22 ± 6%). During incremental exercise, ET had a lower ratio of rise in plasma K+ concentration to work than UT ( P < 0.05) and tended ( P = 0.09) to be lower than RT (UT 18.5 ± 2.3, RT 16.2 ± 2.2, ET 11.8 ± 0.4 nmol · l−1 · J−1). In conclusion, maximal in vitro Na+-K+-ATPase activity was depressed with fatigue, regardless of training state, suggesting that this may be an important determinant of fatigue.

Effects of progressive exercise and hypoxia on human muscle sarcoplasmic reticulum function

2004 ◽  
Vol 97 (1) ◽  
pp. 188-196 ◽  
Author(s):  
T. A. Duhamel ◽  
H. J. Green ◽  
S. D. Sandiford ◽  
J. G. Perco ◽  
J. Ouyang
Keyword(s):  
Sarcoplasmic Reticulum ◽  
G Protein ◽  
Power Output ◽  
Maximal Activity ◽  
Peak Oxygen Consumption ◽  
Hill Coefficient ◽  
Oxygen Fraction ◽  
Mechanical Power Output ◽  
Progressive Exercise ◽  
Inspired Oxygen

This study examined the effects of progressive exercise to fatigue in normoxia (N) on muscle sarcoplasmic reticulum (SR) Ca2+ cycling and whether alterations in SR Ca2+ cycling are related to the blunted peak mechanical power output (POpeak) and peak oxygen consumption (V̇o2 peak) observed during progressive exercise in hypoxia (H). Nine untrained men (20.7 ± 0.42 yr) performed progressive cycle exercise to fatigue on two occasions, namely during N (inspired oxygen fraction = 0.21) and during H (inspired oxygen fraction = 0.14). Tissue extracted from the vastus lateralis before exercise and at power output corresponding to 50 and 70% of V̇o2 peak (as determined during N) and at fatigue was used to investigate changes in homogenate SR Ca2+-cycling properties. Exercise in H compared with N resulted in a 19 and 21% lower ( P < 0.05) POpeak and V̇o2 peak, respectively. During progressive exercise in N, Ca2+-ATPase kinetics, as determined by maximal activity, the Hill coefficient, and the Ca2+ concentration at one-half maximal activity were not altered. However, reductions with exercise in N were noted in Ca2+ uptake (before exercise = 357 ± 29 μmol·min−1·g protein−1; at fatigue = 306 ± 26 μmol·min−1·g protein−1; P < 0.05) when measured at free Ca2+ concentration of 2 μM and in phase 2 Ca2+ release (before exercise = 716 ± 33 μmol·min−1·g protein−1; at fatigue = 500 ± 53 μmol·min−1·g protein−1; P < 0.05) when measured in vitro in whole muscle homogenates. No differences were noted between N and H conditions at comparable power output or at fatigue. It is concluded that, although structural changes in SR Ca2+-cycling proteins may explain fatigue during progressive exercise in N, they cannot explain the lower POpeak and V̇o2 peak observed during H.

Muscle sarcoplasmic reticulum Ca2+ cycling adaptations during 16 h of heavy intermittent cycle exercise

2005 ◽  
Vol 99 (3) ◽  
pp. 836-843 ◽  
Author(s):  
G. P. Holloway ◽  
H. J. Green ◽  
T. A. Duhamel ◽  
S. Ferth ◽  
J. W. Moule ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Atpase Activity ◽  
Vastus Lateralis ◽  
Phase 1 ◽  
Hill Coefficient ◽  
Kinetic Properties ◽  
Cycle Exercise ◽  
Tissue Samples ◽  
The Hill

The repetition-dependent effects of a repetitive heavy exercise protocol previously shown to alter muscle mechanic behavior (Green HJ, Duhamel TA, Ferth S, Holloway GP, Thomas MM, Tupling AR, Rich SM, and Yau JE. J Appl Physiol 97: 2166–2175, 2004) on muscle sarcoplasmic reticulum (SR) Ca2+-transport properties, measured in vitro, were examined in 12 untrained volunteers [peak aerobic power (V̇o2 peak) = 44.3 ± 0.66 ml·kg−1·min−1]. The protocol involved 6 min of cycle exercise performed at ∼91% V̇o2 peak once per hour for 16 h. Tissue samples were obtained from the vastus lateralis before (B) and after (A) exercise at repetitions 1 (R1), 2 (R2), 9 (R9), and 16 (R16). Reductions ( P < 0.05) in maximal Ca2+-ATPase activity ( Vmax) of 26 and 12% with exercise were only observed at R1 and R16, respectively. Vmax remained depressed ( P < 0.05) at R2 (B) but not at R9 (B) and R16 (B). No changes were observed in two other kinetic properties of the enzyme, namely the Hill coefficient (defined as the slope of the relationship between Ca2+-ATPase activity and free Ca2+ concentration) and the Ca50 (defined as the free Ca2+ concentration needed to elicit 50% Vmax). Changes in Ca2+ uptake (measured at 2,000 nM) with exercise and recovery generally paralleled Vmax. The apparent coupling ratio, defined as the ratio between Ca2+ uptake and Vmax, was unaffected by the intermittent protocol. Reductions ( P < 0.05) in phase 1 Ca2+ release (32%) were only observed at R1. No differences were observed between B and A for R2, R9, and R16 or between B and B for R1, R2, R9, and R16. The changes in phase 2 Ca2+ release were as observed for phase 1 Ca2+ release. It is concluded that the SR Ca2+-handling properties, in general, display rapid adaptations to repetitive exercise.

Prolonged exercise to fatigue in humans impairs skeletal muscle Na+-K+-ATPase activity, sarcoplasmic reticulum Ca2+ release, and Ca2+ uptake

2004 ◽  
Vol 97 (4) ◽  
pp. 1414-1423 ◽  
Author(s):  
James A. Leppik ◽  
Robert J. Aughey ◽  
Ivan Medved ◽  
Ian Fairweather ◽  
Michael F. Carey ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Atpase Activity ◽  
G Protein ◽  
Uptake Rate ◽  
Prolonged Exercise ◽  
Transport Processes ◽  
Vastus Lateralis Muscle ◽  
Ouabain Binding ◽  
Exercise In Humans

Prolonged exhaustive submaximal exercise in humans induces marked metabolic changes, but little is known about effects on muscle Na+-K+-ATPase activity and sarcoplasmic reticulum Ca2+ regulation. We therefore investigated whether these processes were impaired during cycling exercise at 74.3 ± 1.2% maximal O2 uptake (mean ± SE) continued until fatigue in eight healthy subjects (maximal O2 uptake of 3.93 ± 0.69 l/min). A vastus lateralis muscle biopsy was taken at rest, at 10 and 45 min of exercise, and at fatigue. Muscle was analyzed for in vitro Na+-K+-ATPase activity [maximal K+-stimulated 3- O-methylfluorescein phosphatase (3- O-MFPase) activity], Na+-K+-ATPase content ([3H]ouabain binding sites), sarcoplasmic reticulum Ca2+ release rate induced by 4 chloro- m-cresol, and Ca2+ uptake rate. Cycling time to fatigue was 72.18 ± 6.46 min. Muscle 3- O-MFPase activity (nmol·min−1·g protein−1) fell from rest by 6.6 ± 2.1% at 10 min ( P < 0.05), by 10.7 ± 2.3% at 45 min ( P < 0.01), and by 12.6 ± 1.6% at fatigue ( P < 0.01), whereas 3[H]ouabain binding site content was unchanged. Ca2+ release (mmol·min−1·g protein−1) declined from rest by 10.0 ± 3.8% at 45 min ( P < 0.05) and by 17.9 ± 4.1% at fatigue ( P < 0.01), whereas Ca2+ uptake rate fell from rest by 23.8 ± 12.2% at fatigue ( P = 0.05). However, the decline in muscle 3- O-MFPase activity, Ca2+ uptake, and Ca2+ release were variable and not significantly correlated with time to fatigue. Thus prolonged exhaustive exercise impaired each of the maximal in vitro Na+-K+-ATPase activity, Ca2+ release, and Ca2+ uptake rates. This suggests that acutely downregulated muscle Na+, K+, and Ca2+ transport processes may be important factors in fatigue during prolonged exercise in humans.

Etiology of Neuromuscular Fatigue After Repeated Sprints Depends on Exercise Modality

2017 ◽  
Vol 12 (7) ◽  
pp. 878-885 ◽  
Author(s):  
Katja Tomazin ◽  
Jean-Benoit Morin ◽  
Guillaume Y. Millet
Keyword(s):  
Vastus Lateralis ◽  
Knee Extensor ◽  
Compound Action Potential ◽  
Neuromuscular Fatigue ◽  
Voluntary Activation ◽  
Peak Power Output ◽  
Peripheral Fatigue ◽  
M Wave ◽  
Sprint Running ◽  
Repeated Sprint

Purpose:To compare neuromuscular fatigue induced by repeated-sprint running vs cycling.Methods:Eleven active male participants performed 2 repeated-maximal-sprint protocols (5×6 s, 24-s rest periods, 4 sets, 3 min between sets), 1 in running (treadmill) and 1 in cycling (cycle ergometer). Neuromuscular function, evaluated before (PRE); 30 s after the first (S1), the second (S2), and the last set (LAST); and 5 min after the last set (POST5) determined the knee-extensor maximal voluntary torque (MVC); voluntary activation (VA); single-twitch (Tw), high- (Db100), and low- (Db10) frequency torque; and maximal muscle compound action potential (M-wave) amplitude and duration of vastus lateralis.Results:Peak power output decreased from 14.6 ± 2.2 to 12.4 ± 2.5 W/kg in cycling (P < .01) and from 21.4 ± 2.6 to 15.2 ± 2.6 W/kg in running (P < .001). MVC declined significantly from S1 in running but only from LAST in cycling. VA decreased after S2 (~–7%, P < .05) and LAST (~–9%, P < .01) set in repeated-sprint running and did not change in cycling. Tw, Db100, and Db10/Db100 decreased to a similar extent in both protocols (all P < .001 post-LAST). Both protocols induced a similar level of peripheral fatigue (ie, low-frequency peripheral fatigue, no changes in M-wave characteristics), while underlying mechanisms probably differed. Central fatigue was found only after running.Conclusion:Findings about neuromuscular fatigue resulting from RS cycling cannot be transferred to RS running.

4-Chloro-m-cresol is a Trigger of Malignant Hyperthermia in Susceptible Swine

1999 ◽  
Vol 90 (6) ◽  
pp. 1733-1740. ◽  
Author(s):  
Frank Wappler ◽  
Jens Scholz ◽  
Marko Fiege ◽  
Kerstin Kolodzie ◽  
Christiana Kudlik ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Malignant Hyperthermia ◽  
Carbon Dioxide Concentration ◽  
Central Venous ◽  
Mechanically Ventilated ◽  
Oxygen Fraction ◽  
Animal Care ◽  
Inspired Oxygen

Background 4-Chloro-m-cresol (4-CmC) induces marked contractures in skeletal muscle specimens from individuals susceptible to malignant hyperthermia (MHS). In contrast, 4-CmC induces only small contractures in specimens from normal (MHN) patients. 4-CmC is a preservative within a large number of commercially available drug-preparations (e.g., insulin, heparin, succinylcholine), and it has been suggested that 4-CmC might trigger malignant hyperthermia. This study was designed to investigate the effects of 4-CmC in vivo and in vitro in the same animals. Methods After approval of the animal care committee, six Pietrain MHS and six control (MHN) swine were anesthetized with azaperone 4 mg/kg intramuscularly and metomidate 10 mg/kg intraperitoneally. After endotracheal intubation, lungs were mechanically ventilated (inspired oxygen fraction 0.3) and anesthesia was maintained with etomidate 2.5 mg x kg(-1) x h(-1) and fentanyl 50 microg x kg(-1) x h(-1). Animals were surgically prepared with arterial and central venous catheters for measurement of hemodynamic parameters and to obtain blood samples. Before exposure to 4-CmC in vivo, muscle specimens were excised for in vitro contracture tests with 4-CmC in concentrations of 75 and 200 microM. Subsequently, pigs were exposed to cumulative administration of 3, 6, 12, 24, and 48 mg/kg 4-CmC intravenously. If an unequivocal episode of malignant hyperthermia occurred, as indicated by venous carbon dioxide concentration &gt; or = 70 mmHg, pH &lt; or = 7.25, and an increase of temperature &gt; or = 2 degrees C, the animals were treated with dantrolene, 3.5 mg/kg. Results All MHS swine developed malignant hyperthermia after administration of 4-CmC in doses of 12 or 24 mg/kg. Venous carbon dioxide concentration significantly increased and pH significantly decreased. Temperature increased in all MHS animals more than 2 degrees C. Blood lactate concentrations and creatine kinase levels were significantly elevated. All MHS swine were treated successfully with dantrolene. In contrast, no MHN swine developed signs of malignant hyperthermia. After receiving 4-CmC in a concentration of 48 mg/kg, however, all MHN animals died by ventricular fibrillation. The in vitro experiments showed that both concentrations of 4-CmC produced significantly greater contractures in MHS than in MHN specimens. Conclusions 4-CmC is in vivo a trigger of malignant hyperthermia in swine. However, the 4-CmC doses required for induction of malignant hyperthermia were between 12 and 24 mg/kg, which is about 150-fold higher than the 4-CmC concentrations within clinically used preparations.

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