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Intense interval training in healthy older adults increases skeletal muscle [3H]ouabain-binding site content and elevates Na+,K+-ATPase α2 isoform abundance in Type II fibers.
Wyckelsma, VL, Levinger, I, Murphy, RM, Petersen, AC, Perry, BD, Hedges, CP, Anderson, MJ, McKenna, MJ
Physiological reports. 2017;(7)
Abstract
Young adults typically adapt to intense exercise training with an increased skeletal muscle Na+,K+-ATPase (NKA) content, concomitant with reduced extracellular potassium concentration [K+] during exercise and enhanced exercise performance. Whether these changes with longitudinal training occur in older adults is unknown and was investigated here. Fifteen older adults (69.4 ± 3.5 years, mean ± SD) were randomized to either 12 weeks of intense interval training (4 × 4 min at 90-95% peak heart rate), 3 days/week (IIT, n = 8); or no exercise controls (n = 7). Before and after training, participants completed an incremental cycle ergometer exercise test until a rating of perceived exertion of 17 (very hard) on a 20-point scale was attained, with measures of antecubital venous [K+]v Participants underwent a resting muscle biopsy prior to and at 48-72 h following the final training session. After IIT, the peak exercise work rate (25%), oxygen uptake (16%) and heart rate (6%) were increased (P < 0.05). After IIT, the peak exercise plasma [K+]v tended to rise (P = 0.07), while the rise in plasma [K+]v relative to work performed (nmol.L-1J-1) was unchanged. Muscle NKA content increased by 11% after IIT (P < 0.05). Single fiber measurements, increased in NKA α2 isoform in Type II fibers after IIT (30%, P < 0.05), with no changes to the other isoforms in single fibers or homogenate. Thus, intense exercise training in older adults induced an upregulation of muscle NKA, with a fiber-specific increase in NKA α2 abundance in Type II fibers, coincident with increased muscle NKA content and enhanced exercise performance.
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Modulation of (Na,K)-ATPase activity by membrane fatty acid composition: therapeutic implications in human hypertension.
Rodrigo, R, Miranda-Merchak, A, Valenzuela Grau, R, Bachler, JP, Vergara, L
Clinical and experimental hypertension (New York, N.Y. : 1993). 2014;(1):17-26
Abstract
Abstract Oxidative stress (OS) plays a key role in the pathophysiology of essential hypertension and is associated with changes in the cell membrane fatty acid composition and fluidity. As (Na,K)-ATPase is modulated by the surrounding lipid microenvironment, lipid peroxidation could alter the interactions of this enzyme with the membrane components. Thus, modifications in the membrane fatty acid profile will translate into effects on (Na,K)-ATPase activity. Accordingly, a decrease in this enzyme activity has been reported in hypertensive patients. The aim of this study was to evaluate the relationship between membrane fluidity and fatty acid composition and (Na,K)-ATPase activity in erythrocytes of essential hypertensive patients supplemented with antioxidant vitamins C and E. A double-blind, randomized, placebo-controlled study was conducted in 120 men with essential hypertension assigned to receive vitamin C (1 g/day) +E (400 IU/day) or placebo for 8 weeks. Measurements included OS related parameters: GSH/GSSG ratio, F2-isoprostanes and antioxidant capacity of plasma, (Na,K)-ATPase activity and erythrocytes membrane fatty acid composition (PUFA, polyunsaturated fatty acids; SAFA, saturated fatty acids). Associations were assessed by Pearson correlation and the differences by Student t-test (p<0.05). Supplemented hypertensive patients showed higher activity of (Na,K)-ATPase and proportion of PUFA, and lower blood pressure, OS markers and proportion of SAFA, versus placebo. The activity of (Na,K)-ATPase correlated negatively with the proportion of SAFA, but positively with that of PUFA in both groups. Supplementation with vitamins C+E resulted in decreased OS and increased fluidity and PUFA proportion in the membrane, both of which positively modulate (Na,K)-ATPase activity, accounting for the blood pressure reduction.
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Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: results from the Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: a Randomized Controlled Trial in Patients Hospitalized with Heart Failure (HORIZON-HF) trial.
Shah, SJ, Blair, JE, Filippatos, GS, Macarie, C, Ruzyllo, W, Korewicki, J, Bubenek-Turconi, SI, Ceracchi, M, Bianchetti, M, Carminati, P, et al
American heart journal. 2009;(6):1035-41
Abstract
BACKGROUND Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of the Na+/K+ adenosine triphosphatase and stimulation of sarcoplasmic reticulum calcium adenosine triphosphatase activity. We analyzed data from HORIZON-HF, a randomized, controlled trial evaluating the short-term effects of istaroxime in patients hospitalized with heart failure and left ventricular ejection fraction < or = 35% to test the hypothesis that istaroxime improves diastolic stiffness in acute heart failure syndrome. METHODS One hundred twenty patients were randomized 3:1 (istaroxime/placebo) to a continuous 6-hour infusion of 1 of 3 doses of istaroxime or placebo. All patients underwent pulmonary artery catheterization and comprehensive 2-dimensional/Doppler and tissue Doppler echocardiography at baseline and at the end of the 6-hour infusion. We quantified diastolic stiffness using pressure-volume analysis and tissue Doppler imaging of the lateral mitral annulus (E'). RESULTS Baseline characteristics were similar among all groups, with mean age 55 +/- 11 years, 88% men, left ventricular ejection fraction 27% +/- 7%, systolic blood pressure (SBP) 116 +/- 13 mm Hg, and pulmonary capillary wedge pressure (PCWP) 25 +/- 5 mm Hg. Istaroxime administration resulted in an increase in E' velocities, whereas there was a decrease in E' in the placebo group (P = .048 between groups). On pressure-volume analysis, istaroxime decreased end-diastolic elastance (P = .0001). On multivariate analysis, increasing doses of istaroxime increased E' velocity (P = .043) and E-wave deceleration time (P = .001), and decreased E/E' ratio (P = .047), after controlling for age, sex, baseline ejection fraction, change in PCWP, and change in SBP. CONCLUSIONS Istaroxime decreases PCWP, increases SBP, and decreases diastolic stiffness in patients with acute heart failure syndrome.
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Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure.
Gheorghiade, M, Blair, JE, Filippatos, GS, Macarie, C, Ruzyllo, W, Korewicki, J, Bubenek-Turconi, SI, Ceracchi, M, Bianchetti, M, Carminati, P, et al
Journal of the American College of Cardiology. 2008;(23):2276-85
Abstract
OBJECTIVES We examined the hemodynamic, echocardiographic, and neurohormonal effects of intravenous istaroxime in patients hospitalized with heart failure (HF). BACKGROUND Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation of sarcoplasmic reticulum calcium ATPase. METHODS One hundred twenty patients admitted with HF and reduced systolic function were instrumented with a pulmonary artery catheter within 48 h of admission. Three sequential cohorts of 40 patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h infusion. The first cohort received 0.5 microg/kg/min, the second 1.0 microg/kg/min, and the third 1.5 microg/kg/min istaroxime or placebo. RESULTS All doses of istaroxime lowered pulmonary capillary wedge pressure (PCWP), the primary end point (mean +/- SD: -3.2 +/- 6.8 mm Hg, -3.3 +/- 5.5 mm Hg, and -4.7 +/- 5.9 mm Hg compared with 0.0 +/- 3.6 mm Hg with placebo; p < 0.05 for all doses). Istaroxime significantly decreased heart rate (HR) and increased systolic blood pressure (SBP). Cardiac index increased and left ventricular end-diastolic volume decreased significantly only with 1.5 microg/kg/min. On echocardiography, left ventricular end diastolic volume and deceleration time improved with 1.5 microg/kg/min. There were no changes in neurohormones, renal function, or troponin I. Adverse events were not life threatening and were dose related. CONCLUSIONS In patients hospitalized with HF, istaroxime improved PCWP and possibly diastolic function. In contrast to available inotropes, istaroxime increased SBP and decreased HR. (A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Pts With Worsening HF and Reduced LV Systolic Function [HORIZON-HF]; NCT00616161).
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Effect of dexamethasone on skeletal muscle Na+,K+ pump subunit specific expression and K+ homeostasis during exercise in humans.
Nordsborg, N, Ovesen, J, Thomassen, M, Zangenberg, M, Jøns, C, Iaia, FM, Nielsen, JJ, Bangsbo, J
The Journal of physiology. 2008;(5):1447-59
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Abstract
The effect of dexamethasone on Na(+),K(+) pump subunit expression and muscle exchange of K(+) during exercise in humans was investigated. Nine healthy male subjects completed a randomized double blind placebo controlled protocol, with ingestion of dexamethasone (Dex: 2 x 2 mg per day) or placebo (Pla) for 5 days. Na(+),K(+) pump catalytic alpha1 and alpha2 subunit expression was approximately 17% higher (P < 0.05) and the structural beta1 and beta2 subunit expression was approximately 6-8% higher (P < 0.05) after Dex compared with Pla. During one-legged knee-extension for 10 min at low intensity (LI; 18.6 +/- 1.0 W), two moderate intensity (51.7 +/- 2.4 W) exercise bouts (MI(1): 5 min; 2 min recovery; MI(2): exhaustive) and two high-intensity (71.7 +/- 2.5 W) exercise bouts (HI(1): 1 min 40 s; 2 min recovery; HI(2): exhaustive), femoral venous K(+) was lower (P < 0.05) in Dex compared with Pla. Thigh K(+) release was lower (P < 0.05) in Dex compared with Pla in LI and MI, but not in HI. Time to exhaustion in MI(2) tended to improve (393 +/- 50 s versus 294 +/- 41 s; P = 0.07) in Dex compared with Pla, whereas no difference was detected in HI(2) (106 +/- 10 s versus 108 +/- 9 s). The results indicate that an increased Na(+),K(+) pump expression per se is of importance for thigh K(+) reuptake at the onset of low and moderate intensity exercise, but less important during high intensity exercise.
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Glucose supplements increase human muscle in vitro Na+-K+-ATPase activity during prolonged exercise.
Green, HJ, Duhamel, TA, Foley, KP, Ouyang, J, Smith, IC, Stewart, RD
American journal of physiology. Regulatory, integrative and comparative physiology. 2007;(1):R354-62
Abstract
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 (Vo(2)(peak)) of 44.8 +/- 1.9 ml.kg(-1).min(-1); mean +/- SE cycled at approximately 57% Vo(2)(peak) 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 (V(max)) 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 (beta(max)) measured by the vanadate facilitated [(3)H]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 V(max) by mechanisms that are unclear.
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K+ channel activation with minoxidil stimulates nasal-epithelial ion transport and blunts exaggerated hypoxic pulmonary hypertension.
Peth, S, Karle, C, Dehnert, C, Bärtsch, P, Mairbäurl, H
High altitude medicine & biology. 2006;(1):54-63
Abstract
Increased pulmonary capillary pressure and inhibition of alveolar Na+ transport putatively contribute to the formation of pulmonary edema in alveolar hypoxia such as at high altitude. Since both events might be linked to the inhibition of K+ channels, we studied whether in vivo application of minoxidil, a stimulator of ATP-gated K channels (K+ ATP channel activator) prevents both effects. In a double- blind, placebo-controlled crossover study on 17 volunteers with no known susceptibility to high altitude pulmonary edema, we tested whether a single dose of minoxidil (5 mg) prevents pulmonary hypertension and inhibition of nasal-epithelial Na+ transport in normobaric hypoxia (12% O2, 2 h). In hypoxia, arterial SO2 was decreased to about 80%, and systolic pulmonary artery pressure (PAP) measured by Doppler echocardiography increased significantly from approximately 25 mmHg (normoxia) to approximately 38 mmHg (hypoxia; range 22 to 61 mmHg). Minoxidil decreased PAP in hypoxia in those individuals who had the highest increase in PAP in hypoxia when taking placebo. Nasal potentials decreased by about 10% in hypoxia. Although minoxidil had no effect on nasal potentials in normoxia, it increased nasal potentials significantly above normoxic control values after 2-h hypoxia. These results show that the K+ ATP activator minoxidil prevents the decrease in nasal-epithelial potential by hypoxia and seems to blunt an exaggerated increase in PAP in acute hypoxia.
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Muscle Na-K-pump and fatigue responses to progressive exercise in normoxia and hypoxia.
Sandiford, SD, Green, HJ, Duhamel, TA, Schertzer, JD, Perco, JD, Ouyang, J
American journal of physiology. Regulatory, integrative and comparative physiology. 2005;(2):R441-R449
Abstract
To investigate the effects of hypoxia and incremental exercise on muscle contractility, membrane excitability, and maximal Na(+)-K(+)-ATPase activity, 10 untrained volunteers (age = 20 +/- 0.37 yr and weight = 80.0 +/- 3.54 kg; +/- SE) performed progressive cycle exercise to fatigue on two occasions: while breathing normal room air (Norm; Fi(O(2)) = 0.21) and while breathing a normobaric hypoxic gas mixture (Hypox; Fi(O(2)) = 0.14). Muscle samples extracted from the vastus lateralis before exercise and at fatigue were analyzed for maximal Na(+)-K(+)-ATPase (K(+)-stimulated 3-O-methylfluorescein phosphatase) activity in homogenates. A 32% reduction (P < 0.05) in Na(+)-K(+)-ATPase activity was observed (90.9 +/- 7.6 vs. 62.1 +/- 6.4 nmol.mg protein(-1).h(-1)) in Norm. At fatigue, the reductions in Hypox were not different (81 +/- 5.6 vs. 57.2 +/- 7.5 nmol.mg protein(-1).h(-1)) from Norm. Measurement of quadriceps neuromuscular function, assessed before and after exercise, indicated a generalized reduction (P < 0.05) in maximal voluntary contractile force (MVC) and in force elicited at all frequencies of stimulation (10, 20, 30, 50, and 100 Hz). In general, no differences were observed between Norm and Hypox. The properties of the compound action potential, amplitude, duration, and area, which represent the electromyographic response to a single, supramaximal stimulus, were not altered by exercise or oxygen condition when assessed both during and after the progressive cycle task. Progressive exercise, conducted in Hypox, results in an inhibition of Na(+)-K(+)-ATPase activity and reductions in MVC and force at different frequencies of stimulation; these results are not different from those observed with Norm. These changes occur in the absence of reductions in neuromuscular excitability.
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Chronic intermittent hypoxia and incremental cycling exercise independently depress muscle in vitro maximal Na+-K+-ATPase activity in well-trained athletes.
Aughey, RJ, Gore, CJ, Hahn, AG, Garnham, AP, Clark, SA, Petersen, AC, Roberts, AD, McKenna, MJ
Journal of applied physiology (Bethesda, Md. : 1985). 2005;(1):186-92
Abstract
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 O(2) fraction = 15.48%) for 23 nights and lived and trained by day under normoxic conditions in Canberra (altitude approximately 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 ([(3)H]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; [(3)H]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.
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Inactivation of human muscle Na+-K+-ATPase in vitro during prolonged exercise is increased with hypoxia.
Sandiford, SD, Green, HJ, Duhamel, TA, Perco, JG, Schertzer, JD, Ouyang, J
Journal of applied physiology (Bethesda, Md. : 1985). 2004;(5):1767-75
Abstract
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 (Vo2peak) = 42.1 +/- 2.8 (SE) ml x kg(-1) x min(-1)] performed 90 min of cycling during N (inspired oxygen fraction = 0.21) and during H (inspired oxygen fraction = 0.14) at approximately 50% of normoxic Vo2peak. During N, 3-O-methylfluorescein phosphatase activity (nmol x mg protein(-1) x 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.