N-acetylcysteine attenuates the decline in muscle Na+,K+-pump activity and delays fatigue during prolonged exercise in humans.

Reactive oxygen species (ROS) have been linked with both depressed Na(+),K(+)-pump activity and skeletal muscle fatigue. This study investigated N-acetylcysteine (NAC) effects on muscle Na(+),K(+)-pump activity and potassium (K(+)) regulation during prolonged, submaximal endurance exercise. Eight well-trained subjects participated in a double-blind, randomised, crossover design, receiving either NAC or saline (CON) intravenous infusion at 125 mg kg(-1) h(-1) for 15 min, then 25 mg kg(-1) h(-1) for 20 min prior to and throughout exercise. Subjects cycled for 45 min at 71% , then continued at 92% until fatigue. Vastus lateralis muscle biopsies were taken before exercise, at 45 min and fatigue and analysed for maximal in vitro Na(+),K(+)-pump activity (K(+)-stimulated 3-O-methyfluorescein phosphatase; 3-O-MFPase). Arterialized venous blood was sampled throughout exercise and analysed for plasma K(+) and other electrolytes. Time to fatigue at 92% was reproducible in preliminary trials (c.v. 5.6 +/- 0.6%) and was prolonged with NAC by 23.8 +/- 8.3% (NAC 6.3 +/- 0.5 versus CON 5.2 +/- 0.6 min, P < 0.05). Maximal 3-O-MFPase activity decreased from rest by 21.6 +/- 2.8% at 45 min and by 23.9 +/- 2.3% at fatigue (P < 0.05). NAC attenuated the percentage decline in maximal 3-O-MFPase activity (%Deltaactivity) at 45 min (P < 0.05) but not at fatigue. When expressed relative to work done, the %Deltaactivity-to-work ratio was attenuated by NAC at 45 min and fatigue (P < 0.005). The rise in plasma [K(+)] during exercise and the Delta[K(+)]-to-work ratio at fatigue were attenuated by NAC (P < 0.05). These results confirm that the antioxidant NAC attenuates muscle fatigue, in part via improved K(+) regulation, and point to a role for ROS in muscle fatigue.

Alkalosis increases muscle K+ release, but lowers plasma [K+] and delays fatigue during dynamic forearm exercise.

Alkalosis enhances human exercise performance, and reduces K+ loss in contracting rat muscle. We investigated alkalosis effects on K+ regulation, ionic regulation and fatigue during intense exercise in nine untrained volunteers. Concentric finger flexions were conducted at 75% peak work rate (3 W) until fatigue, under alkalosis (Alk, NaHCO3, 0.3 g kg(-1)) and control (Con, CaCO3) conditions, 1 month apart in a randomised, double-blind, crossover design. Deep antecubital venous (v) and radial arterial (a) blood was drawn at rest, during exercise and recovery, to determine arterio-venous differences for electrolytes, fluid shifts, acid-base and gas exchange. Finger flexion exercise barely perturbed arterial plasma ions and acid-base status, but induced marked arterio-venous changes. Alk elevated [HCO3-] and PCO2, and lowered [H+] (P < 0.05). Time to fatigue increased substantially during Alk (25 +/- 8%, P < 0.05), whilst both [K+]a and [K+]v were reduced (P < 0.01) and [K+]a-v during exercise tended to be greater (P= 0.056, n= 8). Muscle K+ efflux at fatigue was greater in Alk (21.2+/- 7.6 micromol min(-1), 32 +/- 7%, P < 0.05, n= 6), but peak K+ uptake rate was elevated during recovery (15 +/- 7%, P < 0.05) suggesting increased muscle Na+,K+-ATPase activity. Alk induced greater [Na+]a, [Cl-]v, muscle Cl- influx and muscle lactate concentration ([Lac-]) efflux during exercise and recovery (P < 0.05). The lower circulating [K+] and greater muscle K+ uptake, Na+ delivery and Cl- uptake with Alk, are all consistent with preservation of membrane excitability during exercise. This suggests that lesser exercise-induced membrane depolarization may be an important mechanism underlying enhanced exercise performance with Alk. Thus Alk was associated with improved regulation of K+, Na+, Cl- and Lac-.

Pharmacokinetics of intravenous N-acetylcysteine in men at rest and during exercise.

OBJECTIVE: We aimed to determine the pharmacokinetics (PK) of N-acetylcysteine (NAC) at rest and during exercise when given by continuous intravenous infusion intended to maintain relatively constant plasma concentrations. METHODS: Plasma concentrations of NAC were measured in 24 healthy male subjects during and after a two-stage intravenous infusion designed to provide constant NAC concentrations during cycling exercise, including intense exercise to fatigue. RESULTS: A three-compartment, open PK model was the best fit using population PK analysis with NONMEM. Whole-body clearance (CL) was 0.58 l kg(-1) h(-1) (95% CI 0.44-0.72) for reduced NAC (NACR) and 0.16 (0.13-0.20) l kg(-1) h(-1) for total NAC (NACT). The central volume of distribution (V1) was 0.064 (0.008-0.12) l kg(-1) for NACR and 0.037 (0.02-0.06) l kg(-1) for NACT. Exercise was a significant covariate in the model, resulting in a 25 and 23% reduction in CL of NACR and NACT, respectively. V1 in our subjects was smaller than expected, resulting in higher-than-anticipated initial concentrations of NAC. Despite these findings, the incidence of adverse effects attributable to NAC was minimal without using prophylactic or concomitant drug therapy. CONCLUSIONS: NAC can be given to healthy exercising men by intravenous infusion and to the plasma concentrations seen in this study with minimal adverse effects due to the drug. The PK parameters of NAC at rest in volunteers are consistent with previously reported values and are significantly altered by vigorous cycling exercise.

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

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.

Effects of intravenous N-acetylcysteine infusion on time to fatigue and potassium regulation during prolonged cycling exercise.

The production of reactive oxygen species in skeletal muscle is linked with muscle fatigue. This study investigated whether the antioxidant compound N-acetylcysteine (NAC) augments time to fatigue during prolonged, submaximal cycling exercise. Seven men completed a double-blind, crossover study, receiving NAC or placebo before and during cycling exercise, comprising 45 min at 70% of peak oxygen consumption (Vo2 peak) and then to fatigue at 90% Vo2 peak. NAC was intravenously infused at 125 mg.kg-1.h-1 for 15 min and then 25 mg.kg-1.h-1 for 20 min before and throughout exercise, which was continued until fatigue. Arterialized venous blood was analyzed for NAC concentration, hematology, and plasma electrolytes. NAC induced no serious adverse reactions and did not affect hematology, acid-base status, or plasma electrolytes. Time to fatigue was reproducible in preliminary trials (coefficient of variation 7.4 +/- 1.2%) and was not augmented by NAC (NAC 14.6 +/- 4.5 min; control 12.8 +/- 5.4 min). However, time to fatigue during NAC trials was correlated with Vo2 peak (r = 0.78; P < 0.05), suggesting that NAC effects on performance may be dependent on training status. The rise in plasma K+ concentration at fatigue was attenuated by NAC (P < 0.05). The ratio of rise in K+ concentration to work and the percentage change in time to fatigue tended to be inversely related (r = -0.71; P < 0.07). Further research is required to clarify a possible training status-dependent effect of NAC on muscle performance and K+ regulation.