Effects of erythropoietin on muscle O2 transport during exercise in patients with chronic renal failure.

Erythropoietin (rHuEPO) has proven to be effective in the treatment of anemia of chronic renal failure (CRF). Despite improving the quality of life, peak oxygen uptake after rHuEPO therapy is not improved as much as the increase in hemoglobin concentration ([Hb)] would predict. We hypothesized that this discrepancy is due to failure of O2 transport rates to rise in a manner proportional to [Hb]. To test this, eight patients with CRF undergoing regular hemodialysis were studied pre- and post-rHuEPO ([Hb] = 7.5 +/- 1.0 vs. 12.5 +/- 1.0 g x dl-1) using a standard incremental cycle exercise protocol. A group of 12 healthy sedentary subjects of similar age and anthropometric characteristics served as controls. Arterial and femoral venous blood gas data were obtained and coupled with simultaneous measurements of femoral venous blood flow (Qleg) by thermodilution to obtain O2 delivery and oxygen uptake (VO2). Despite a 68% increase in [Hb], peak VO2 increased by only 33%. This could be explained largely by reduced peak leg blood flow, limiting the gain in O2 delivery to 37%. At peak VO2, after rHuEPO, O2 supply limitation of maximal VO2 was found to occur, permitting the calculation of a value for muscle O2 conductance from capillary to mitochondria (DO2). While DO2 was slightly improved after rHuEPO, it was only 67% of that of sedentary control subjects. This kept maximal oxygen extraction at only 70%. Two important conclusions can be reached from this study. First, the increase in [Hb] produced by rHuEPO is accompanied by a significant reduction in peak blood flow to exercising muscle, which limits the gain in oxygen transport. Second, even after restoration of [Hb], O2 conductance from the muscle capillary to the mitochondria remains considerably below normal.     

Muscle metabolism in patients with polymyositis simultaneously evaluated by using 31P-magnetic resonance spectroscopy and near-infrared spectroscopy

Simultaneous measurements of muscle energy metabolism using (31)P-magnetic resonance spectroscopy ((31)P-MRS) and the kinetics of muscular oxygen metabolism using near-infrared spectroscopy (NIRS) were conducted in polymyositis (PM) patients. The subjects were 12 PM patients (age 45 +/- 12 years) and 12 normal controls (age 41 +/- 12 years). The muscle phosphocreatine (PCr) index and intracellular pH (pHi) were determined with (31)P-MRS and the changes in intramuscular oxygenated (oxy-Hb), deoxygenated (deoxy-Hb), and total haemoglobin (total Hb) were evaluated with NIRS . The pHi and PCr index before steroid therapy in PM patients were significantly lower during exercise than in normal controls, and their recovery was statistically significantly delayed compared with the controls. The pattern of changes in NIRS over time before steroid therapy in PM patients differed from that in normal controls. There were smaller changes in deoxy-Hb and oxy-Hb during exercise, and total Hb decreased during exercise. In contrast, the kinetics of muscular metabolism after steroid therapy showed changes similar to those seen in normal controls. Simultaneous (31)P-MRS and NIRS measurements to determine the kinetics of muscular metabolism are expected to be useful as a noninvasive approach for the evaluation of treatment effects in PM patients.     

Contribution of intramuscular oxidative metabolism to total ATP production during forearm isometric exercise at varying intensities

It is not fully clear whether intramuscular oxidative metabolism contributes to total adenosine triphosphate (ATP) production during forearm isometric exercise at varying intensities. We tested hypothesis that oxidative metabolism with intramuscular O2 contributes to lessen the dependence on anaerobic metabolism, in particular phosphocreatine (PCr) breakdown. Seven male subjects were tested for changes in muscle oxygenation (MO2) and high-energy phosphates in forearm flexor muscles at rest and during exercise under arterial occlusion by 31-phosphorus magnetic resonance spectroscopy (31P-MRS) and near infrared spectroscopy (NIRS). Isometric wrist flexion exercise was performed for 1 min or until exhaustion at intensities corresponding to 30%, 50% and 70% of maximal voluntary contraction (MVC) under intramuscular O2 (Intramuscular O2-Ex) and anaerobic (Anaero-Ex) conditions. Oxidative ATP production in Intramuscular O2-Ex was calculated as 0.05 +/- 0.01 mM/s for 30%MVC, 0.08 +/- 0.01 mM/s for 50%MVC and 0.11 +/- 0.01 mM/s for 70%MVC. At a lower intensity (30%MVC), PCr breakdown rate (0.17 +/- 0.02 mM/s) of Anaero-Ex was significantly higher than the rate (0.13 +/- 0.01 mM/s) of Intramuscular O2-Ex (p < 0.05). There was no significant difference in ATP production rates through PCr breakdown and glycolysis between Intramuscular O2-Ex and Anaero-Ex at the higher intensities (50% and 70%MVC). In conclusion, intramuscular oxidative metabolism plays a significant role in reducing the dependence on PCr breakdown during isometric exercise at a lower intensity (30%MVC).     

Skeletal muscle metabolism in the leg during exercise in patients with congestive heart failure

1. Using 31P nuclear magnetic resonance, it has previously been demonstrated that patients with congestive heart failure exhibit a greater than normal phosphocreatine (PCr) depletion in the working skeletal muscles of the arm. We have studied the importance of the work necessary to reach a similar PCr depletion ([PCr]/([PCr] + [Pi]) = 0.5) in calf muscle. Our results show significantly lower values for patients with congestive heart failure in both aerobic and ischaemic conditions (respectively: 0.009 +/- 0.007 vs 0.026 +/- 0.013 W/kg body weight, P less than 0.01; 0.29 +/- 0.16 vs 0.90 +/- 0.25 J/kg body weight, P less than 0.01). 2. This original model of skeletal muscle exercise facilitates a comparison of PCr recovery rate due to a similarity in the PCr depletion and intracellular pH in the two series at the start of recovery. However, the PCr recovery rate is similar after both normoxic and ischaemic exercise, i.e. respective percentages of PCr increase in the first 25 s recovery spectrum were: (a) aerobic exercise, congestive heart failure 133 +/- 18%, control series 138 +/- 18%; (b) ischaemic exercise, congestive heart failure 114 +/- 13%, control series 118 +/- 12%. The absence of a difference in PCr recovery rate and the greater PCr depletion by ischaemic work in patients with congestive heart failure suggest modifications that cannot be explained by a reduced blood flow to the muscle. 3. When comparing the two series, intracellular pH evolved similarly in normoxia and ischaemia during both work and recovery. Thus, no increase in anaerobic glycolytic activity appears when equivalent PCr depletion has occurred.     

Non-invasive measurement of stroke volume during exercise in heart failure patients

The objective of the present study was to determine the variability of the arterio-venous O(2) concentration difference [C(a-v)O(2)] at anaerobic threshold and at peak oxygen uptake (VO(2)) during a progressively increasing cycle ergometer exercise test, with the purpose of assessing the possible error in estimating stroke volume from measurements of VO(2) alone. We sampled mixed venous and systemic arterial blood every 1 min during a progressively increasing cycle ergometer exercise test and measured, in each blood sample, haemoglobin concentration and blood gas data. Ventilation, VO(2) and CO(2) uptake were also measured continuously. We studied 40 patients with normal haemoglobin concentrations and with stable heart failure due to ischaemic or idiopathic cardiomyopathy. Mean values (+/-S.D.) for C(a-v)O(2) were 7.8+/-2.6, 13.0+/-2.4 and 15. 0+/-2.7 ml/100 ml at rest, anaerobic threshold and peak VO(2) respectively. The patients with heart failure were divided into classes according to their peak VO(2). Classes A, B and C contained patients with peak VO(2) values of>20, 15-20 and 10-15 ml.min(-1). kg(-1) respectively. At anaerobic threshold, C(a-v)O(2) was 12.3+/-1. 3, 13.1+/-2.7 and 13.5+/-2.6 ml/100 ml for classes A, B and C respectively (class A significantly different from classes B and C; P<0.05). At peak exercise C(a-v)O(2) was 13.6+/-1.4, 15.6+/-2.5 and 15.4+/-3.2 ml/100 ml for classes A, B and C respectively (class A significantly different from classes B and C; P<0.05). Stroke volume was estimated for each subject using the mean values of the measured C(a-v)O(2) in each functional class and individual values of VO(2) and heart rate using the Fick formulation. The average difference between the stroke volume estimated from mean C(a-v)O(2) and that obtained using the patient's actual C(a-v)O(2) value was 9.2+/-9.7, 1.0+/-8.8 and -0.2+/-6.1 ml at anaerobic threshold, and -1.9+/-11.3, 0.9+/-10.0 and -2.3+/-8.5 ml at peak exercise, in classes A, B and C respectively. Among the various classes, the most precise estimation of stroke volume was observed for class C patients. We conclude that stroke volume during exercise can be estimated with the accuracy needed for most purposes from measurement of VO(2) at the anaerobic threshold and at peak exercise, and from population-estimated mean values for C(a-v)O(2) in heart failure patients.     

Analysis of factors limiting maximal exercise performance in cystic fibrosis.

1. Maximal exercise capacity in cystic fibrosis is influenced by both pulmonary and nutritional factors: lung disease by limiting maximal achievable ventilation, and malnutrition through a loss of muscle mass. The associated reduction in everyday activities may result in peripheral muscle deconditioning. 2. We studied 14 stable patients with cystic fibrosis (six males, eight females) and 14 healthy control subjects (seven males, seven females) in order to assess the influence of these factors on exercise performance. Subjects underwent anthropometry to estimate muscle mass, spirometry to assess ventilatory capacity, a 30 s sprint on an isokinetic cycle ergometer to assess maximal leg muscle performance, and progressive cycle ergometry to assess overall exercise capacity. 3. Compared with control subjects, the patients with cystic fibrosis were of similar age and height but weighed proportionately less [% ideal weight (mean +/- SD): 94.3 +/- 9.64 versus 109.5 +/- 11.82] and showed evidence of airflow limitation [forced expiratory volume in 1.0 s (FEV1.0) 72.5 +/- 24.78 versus 112.6 +/- 14.25% of predicted]. 4. The patients with cystic fibrosis did less absolute (5.1 +/- 1.89 versus 7.3 +/- 1.97 kJ) but similar relative maximal (11.5 +/- 3.41 versus 13.1 +/- 3.55 kJ/kg lean body mass) sprint work. During progressive exercise, the group with cystic fibrosis achieved lower absolute [maximal O2 consumption (VO2max.) 1.8 +/- 0.527 versus 3.0 +/- 0.655 litres/min] and relative (VO2max./kg lean body mass: 40.5 +/- 9.23 versus 53.0 +/- 11.62 ml min-1 kg-1) work levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral oxygenation responses to standing in elderly patients with predominantly diastolic dysfunction

Patients with left ventricular dysfunction may have different orthostatic responses of blood pressure (BP) and cerebral oxygenation than healthy elderly subjects. We investigated orthostatic changes in systemic haemodynamic variables and cerebral oxygenation in 21 elderly patients with heart failure New York Heart Association class I-III in stable condition (age 70-83 years) after withdrawal of furosemide and captopril for 2 weeks, and in 18 healthy elderly subjects (age 70-84 years). Frontal cortical concentration changes of oxyhaemoglobin ([O2Hb]) and deoxyhaemoglobin ([HHb]) were continuously measured by near-infrared spectrophotometry and BP changes by Finapres before and during 10 min of standing. Upon standing [O2Hb] reflecting blood flow, changed by -1.2 +/- 0.9 micromol L-1 (mean +/- SEM) in the patients, whereas it decreased by -4.5 +/- 0.6 micromol L-1 (P<0.01) in the healthy subjects after standing (P<0.05 between groups). [HHb] reflecting the sum of cerebral blood flow, arterial oxygen saturation and cerebral oxygen uptake, increased by 1.5 +/- 0.5 micromol L-1 (P<0.05) and 1.7 +/- 0.6 micromol L-1 (P<0.05), respectively. Compared with healthy elderly subjects, elderly patients with left ventricular dysfunction showed smaller orthostatic [O2Hb] decreases (P<0.01), in relation to higher orthostatic BP rises (P<0.05). These findings indicate that BP changes and an altered cardiovascular balance may influence orthostatic cortical haemodynamic responses in elderly subjects.     

Dose-dependent effect of caffeine on reducing leg muscle pain during cycling exercise is unrelated to systolic blood pressure

This double-blind, within-subjects experiment examined the effects of ingesting two doses of caffeine on perceptions of leg muscle pain and blood pressure during moderate intensity cycling exercise. Low caffeine consuming college-aged males (N=12) ingested one of two doses of caffeine (5 or 10 mg.kg(-1) body weight) or placebo and 1 h later completed 30 min of moderate intensity cycling exercise (60% VO2peak). The order of drug administration was counter-balanced. Resting blood pressure and heart rate were recorded immediately before and 1 h after drug administration. Perceptions of leg muscle pain as well as work rate, blood pressure, heart rate, and oxygen uptake (VO2) were recorded during exercise. Caffeine increased resting systolic pressure in a dose-dependent fashion but these blood pressure effects were not maintained during exercise. Caffeine had a significant linear effect on leg muscle pain ratings [F(2,22)=14.06; P < 0.0001; eta2=0.56 ]. The mean (+/-SD) pain intensity scores during exercise after ingesting 10 mg.kg(-1) body weight caffeine, 5 mg.kg(-1) body weight caffeine, and placebo were 2.1+/-1.4, 2.6+/-1.5, and 3.5+/-1.7, respectively. The results support the conclusion that caffeine ingestion has a dose-response effect on reducing leg muscle pain during exercise and that these effects do not depend on caffeine-induced increases in systolic blood pressure during exercise.     

Aerobic capacity with two leg work versus one leg plus both arms work in men with peripheral vascular disease.

The purpose of this pilot study was to examine the correlation between ergometry in men with peripheral vascular disease exercising with both legs and with one leg and both arms. Fifteen men with peripheral vascular disease performed three symptom-limited exercise tests on an ergometer that could be operated from a wheelchair with both legs or with one leg and both arms. The three exercise conditions were both legs (arms stabilized), left leg plus both arms, and right leg plus both arms. The exercise parameters compared were maximum oxygen consumption, maximum heart rate, and duration of exercise. Blood pressure was monitored at two-minute intervals and oxygen saturation and electrocardiogram were monitored continuously. The mean VO2 max +/- standard deviation for both legs, right leg plus both arms, and left leg plus both arms were 14.36 +/- 6.15, 14.86 +/- 4.09, 14.01 +/- 4.14 ml O2/kg-min, respectively. The mean duration of exercise +/- standard deviation were 12.01 +/- 5.74, 10.94 +/- 4.68, and 9.81 +/- 4.70 minutes respectively. The mean maximum heart rate +/- standard deviation were 126 +/- 24, 137 +/- 23, 136 +/- 23, respectively for the same exercise conditions. The Pearson Correlation Coefficients for VO2 for both legs versus right leg plus both arms and left leg plus both arms were .639 and .873, respectively. The Pearson Correlation Coefficients for duration of exercise for both legs versus right leg plus both arms and left leg plus both arms were .837 and .877, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treadmill training improves fitness reserve in chronic stroke patients.

OBJECTIVE: To investigate the hypothesis that treadmill training will improve peak fitness, while lowering the energy cost of hemiparetic gait in chronic stroke patients. DESIGN: Noncontrolled exercise intervention study with repeated-measures analysis. SETTING: Hospital-based senior exercise research center. PARTICIPANTS: Twenty-three patients (mean age +/- standard deviation [SD] 67 +/- 8 yr) with chronic hemiparetic gait after remote (>6 mo) ischemic stroke. INTERVENTION: Three 40-minute sessions of treadmill exercise weekly for 6 months. MAIN OUTCOME MEASURES: Peak exercise capacity (VO2peak) and rate of oxygen consumption during submaximal effort treadmill walking (economy of gait) by open circuit spirometry and ambulatory workload capacity before and after 3 and 6 months of training. RESULTS: Patients who completed 3 months of training (n = 21) increased their VO2peak +/- SD from 15.4 +/- 2.9 mL x kg(-1) x min(-1) to 17.0 +/- 4.4 mL x kg(-1) x min(-1) (p <.02) and lowered their oxygen demands of submaximal effort ambulation from 9.3 +/- 2 mL x kg(-1) x min(-1) to 7.9 +/- 1.5 mL x kg(-1) x min(-1) (p =.002), which enabled them to perform the same constant-load treadmill task using 20% less of their peak exercise capacity (62.3% +/- 17.2% vs 49.9% +/- 19.3%, p <.002). Gains in VO2peak and economy of gait plateaued by 3 months, while peak ambulatory workload capacity progressively increased by 39% (p <.001) over 6 months. CONCLUSIONS: Treadmill training improves physiologic fitness reserve in chronic stroke patients by increasing VO2peak while lowering the energy cost of hemiparetic gait, and increases peak ambulatory workload capacity. These improvements may enhance functional mobility in chronic stroke patients.     

Oxygen Uptake to Work Rate Relation Throughout Peak Exercise in Normal Subjects: Relevance for Rate Adaptive Pacemaker Programming

The oxygen uptake to work rate (VO2/WR) relationship observed throughout peak exercise testing is already being applied for rate adaptive pacemaker programming. However, the detailed curve design of VO2/WR with respect to the anaerobic threshold (AT) has not yet been investigated. It was the purpose of this study to determine the VO2/WR slope below and above the AT in a healthy control group. Seventy-eight healthy control subjects (45.9 +/- 17.4 years; 34 women: 49.9 +/- 18.6 years 44 men: 43.6 +/- 16.6 years) were exercised on a treadmill with "breath-by-breath" gas exchange monitoring using the symptom limited "ramping incremental treadmill exercise" (RITE) protocol. The slope of the VO2/WR relationship from rest to peak exercise (r-p), rest to AT (slope A), and AT to peak exercise (slope B) in mL oxygen uptake per watt of external treadmill work was determined by linear regression analysis. [table: see text] The oxygen uptake to work rate relationship throughout peak exercise in the entire study group generated a significant slope change at the AT (31%, P < 0.0001) with a decreasing slope during higher work load intensities. Female subjects demonstrated a greater percentage of slope change at AT (43%), as compared to men (22%, P < 0.01). When using the oxygen uptake to work rate relationship for the programming of the pacemaker's rate response to exercise, the significant slope change at the AT should be considered to more appropriately pace during higher work intensities supported by anaerobic metabolism. Female pacemaker patients should be programmed to generate a steeper VO2/WR slope below AT with a greater slope change at AT, as compared to men. Abnormally high oxygen uptake to work rate ratios above the AT may be possibly used as an indicator of overpacing.     

Muscle creatine phosphate in gyrate atrophy of the choroid and retina with hyperornithinaemia–clues to pathogenesis

BACKGROUND: In gyrate atrophy of the choroid and retina with hyperornithinaemia (GA), inherited deficiency of ornithine-o-aminotransferase leads to progressive fundus destruction and atrophy of type II skeletal muscle fibres. Because high ornithine concentrations inhibit creatine biosynthesis, the ensuing deficiency of high-energy creatine phosphate may mediate the pathogenesis. MATERIALS AND METHODS: Relative concentrations of inorganic phosphate (Pi), creatine phosphate (PCr) and ATP in resting calf muscle were recorded in 23 GA patients and 33 control subjects using 31P-magnetic resonance spectroscopy (MRS). Eight patients with autosomal recessive retinitis pigmentosa with matched control subjects constituted an additional reference group. RESULTS: The PCr/Pi and PCr/ATP ratios (means +/- SD) were lower for the GA patients than for healthy control subjects [4.66 +/- 0.37 vs. 9.75 +/- 2.17 (P < 0.0001) and 2.85 +/- 0.37 vs. 3.70 +/- 0.50 (P < 0.05) respectively]. In retinitis pigmentosa the respective values were 9.12 +/- 2.57 and 4.25 +/- 0.45. Age and stage of the disease had no effect. CONCLUSION: Muscle 31P-MRS spectra were markedly abnormal in all GA patients.     

Haematological and hormonal responses to dynamic exercise in patients with chronic airway obstruction

The influence of exercise on hormonal and total white blood cells (WBC), lymphocytes (L). Granulocytes (GR), and platelet (P) count responses was studied in: twenty-five patients with chronic airway obstruction (CAO, 47 +/- 1.8 years, mean +/- SEM) and thirteen normal subjects (N, 36 +/- 2.6 years). They performed a submaximal (40 W) and a maximal exercise (VO2max). Arterial blood samples were taken at rest, 40 W, and VO2max. [H+], PaCO2, PaO2 haematocrit (Hct), [Hb], P, total platelet volume (TPV), WBC, GR, L, and total red blood cells (RBC) were measured. At rest, WBC, GR, P and TPV were higher in CAO patients, whilst PaO2 and cortisol were lower. At 40 W, when compared to values obtained at rest, WBC, GR, L, P and TPV were increased in both groups; WBC, GR, P and TPV were higher in CAO patients. VO2max of CAO patients represented 54% of that of controls. At VO2max, Hct, [Hb] and RBC were approximately 10% higher than at rest in both groups, whilst changes were more significant in normals for WBC (CAO = 55%, N = 76%), lymphocytes (CAO = 83%, N = 105%), GR, (CAO = 37%; N = 51%), platelets (CAO = 23%, N = 29%), TPV (CAO = 25.4%, N = 35%), [H+] (CAO = 43%, N = 38%) and ACTH (CAO = 82%, N = 139%). PaO2 and cortisol did not differ between groups. PaCO2 and platelets however, were higher in the CAO group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Importance of AV synchronous pacing during low intensity exercise evaluated by oxygen kinetics

It has been shown that dual chamber pacing with preservation of AV synchrony (DDD) is superior to fixed rate ventricular (VVI) or rate responsive ventricular (VVIR) pacing modes, as evaluated by ventilatory response to exercise. Previous studies have focused on the benefits of maintained AV synchrony at maximal exercise. However, there are limited data comparing O2 kinetics in different pacing modes during low intensity exercise, representing the majority of daily activities. This study aimed to provide an evaluation of different pacing modes using O2 kinetics during low intensity exercise. Nineteen patients (age 61 +/- 18 years) with complete AV block underwent low intensity treadmill exercise (35 W) with simultaneous evaluation of symptoms and O2 kinetics in three pacing modes. The first test was performed in DDD mode followed by a second test in VVIR mode with a programmed heart rate corresponding to the sinus rate during the first test. After 6 minutes of each test, the mode was switched from DDD to VVIR and vice versa. The third test was performed in VVI mode at 70 beats/min. O2 kinetics were defined as O2 deficit (time [rest to steady state] x delta VO2-sigma VO2 [rest to steady state]) and mean response time (MRT) of oxygen consumption (O2 deficit/delta VO2). The O2 deficit was 551 +/- 134 mL in DDD pacing, 634 +/- 139 mL in VVIR pacing, and 648 +/- 179 mL in VVI pacing (P = 0.001). MRT was 49 +/- 7.8 seconds in DDD pacing, 54.7 +/- 9.5 seconds in VVIR pacing, and 57.4 +/- 11.0 seconds in VVI pacing (P = 0.002). Ten (53%) patients developed symptoms during switch from DDD to VVIR mode whereas the switch from VVIR to DDD mode was not perceived by any patient (P < 0.001). In conclusion, our study shows an impact of AV synchronous pacing and heart rate adaptation on O2 kinetics during low intensity exercise that correspond to casual daily life activities. Our observations may have clinical implications for the management of patients with complete AV block.     

Ventilatory efficiency and rate of perceived exertion in obese and non-obese children performing standardized exercise

Sixty children, in the age span 6-17 years originally divided into two groups, matched by age, sex and height--30 obese subjects [15 girls/15 boys; body mass index (BMI) = 27.4 +/- 4.5 m kg-2; ideal body weight (IBW) range = 122-185%] and 30 controls (BMI = 18.8 +/- 2.7 m kg-2) performed incremental treadmill exercise test. Perceived exertion was assessed by means of Category-Ratio Borg scale. The duration of the exercise for the children in the obesity group was significantly shorter than controls (P = 0.010) but obese children have greater absolute values for oxygen uptake (VO2peak ml min-1 = 1907 +/- 671 versus 1495 +/- 562; P = 0.013) and ventilatory variables (VE, VT), which adjusted for body mass decrease significantly (VO2/kg ml min-1 kg-1 = 29.2 +/- 3.8 versus 33.6 +/- 3.5; P < 0.001). Among the various methods for 'normalizing' absolute values of VO2peak for body size, dividing it by body surface area (BSA) yielded the best results (VO2/BSA ml min-1 m-2 = 43.5 +/- 4.6 versus 44.7 +/- 5.6; P = 0.335). The ventilatory efficiency determined either as a slope of VE versus VCO2 or as a simple ratio at anaerobic threshold did not differ between obese and non-obese children in the incremental and recovery periods of exercise. There was a negative correlation of VE/VCO2 slope with age and anthropometric parameters. Obese children rated perceived exertion significantly higher than controls despite the standard workload (Borg score = 6.2 +/- 1.2 versus 5.2 +/- 1.1; P = 0.001). In conclusion, the absolute metabolic cost of exercise is higher in the obesity group compared with the control subjects. Both groups have similar ventilatory efficiency but an increased awareness of fatigue that furthermore limits their physical capacity.     

Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity.

We tested the hypothesis that endothelium-dependent vasodilatation is a determinant of insulin resistance of skeletal muscle glucose uptake in human obesity. Eight obese (age 26+/-1 yr, body mass index 37+/-1 kg/m2) and seven nonobese males (25+/-2 yr, 23+/-1 kg/m2) received an infusion of bradykinin into the femoral artery of one leg under intravenously maintained normoglycemic hyperinsulinemic conditions. Blood flow was measured simultaneously in the bradykinin and insulin- and the insulin-infused leg before and during hyperinsulinemia using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET). Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose ([18F]FDG) and PET. Whole body insulin-stimulated glucose uptake was lower in the obese (507+/-47 mumol/m2 . min) than the nonobese (1205+/-97 micromol/m2 . min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 micromol/kg muscle . min) than in the nonobese (56+/-9 micromol/kg muscle . min, P < 0.005) subjects. Bradykinin increased blood flow during hyperinsulinemia in the obese subjects by 75% from 16+/-1 to 28+/-4 ml/kg muscle . min (P < 0.05), and in the normal subjects by 65% from 23+/-3 to 38+/-9 ml/kg muscle . min (P < 0.05). However, this flow increase required twice as much bradykinin in the obese (51+/-3 microg over 100 min) than in the normal (25+/-1 mug, P < 0.001) subjects. In the obese subjects, blood flow in the bradykinin and insulin-infused leg (28+/-4 ml/kg muscle . min) was comparable to that in the insulin-infused leg in the normal subjects during hyperinsulinemia (24+/-5 ml/kg muscle . min). Despite this, insulin-stimulated glucose uptake remained unchanged in the bradykinin and insulin-infused leg (18+/-4 mumol/kg . min) compared with the insulin-infused leg (19+/-4 micromol/kg muscle . min) in the obese subjects. Insulin-stimulated glucose uptake also was unaffected by bradykinin in the normal subjects (58+/-10 vs. 56+/-9 micromol/kg . min, bradykinin and insulin versus insulin leg). These data demonstrate that obesity is characterized by two distinct defects in skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation. Since a 75% increase in blood flow does not alter glucose uptake, insulin resistance in obesity cannot be overcome by normalizing muscle blood flow.     

Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O]water, and [18F]fluoro-deoxy-glucose and positron emission tomography.

Defects in insulin stimulation of blood flow have been used suggested to contribute to insulin resistance. To directly test whether glucose uptake can be altered by changing blood flow, we infused bradykinin (27 microgram over 100 min), an endothelium-dependent vasodilator, into the femoral artery of 12 normal subjects (age 25+/-1 yr, body mass index 22+/-1 kg/m2) after an overnight fast (n = 5) and during normoglycemic hyperinsulinemic (n = 7) conditions (serum insulin 465+/-11 pmol/liter, 0-100 min). Blood flow was measured simultaneously in both femoral regions using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET), before and during (50 min) the bradykinin infusion. Glucose uptake was measured immediately after the blood flow measurement simultaneously in both femoral regions using [18F]-fluoro-deoxy-glucose ([18F]FDG) and PET. During hyperinsulinemia, muscle blood flow was 58% higher in the bradykinin-infused (38+/-9 ml/kg muscle x min) than in the control leg (24+/-5, P<0.01). Femoral muscle glucose uptake was identical in both legs (60.6+/-9.5 vs. 58.7+/-9.0 micromol/kg x min, bradykinin-infused vs control leg, NS). Glucose extraction by skeletal muscle was 44% higher in the control (2.6+/-0.2 mmol/liter) than the bradykinin-infused leg (1.8+/-0.2 mmol/liter, P<0.01). When bradykinin was infused in the basal state, flow was 98% higher in the bradykinin-infused (58+/-12 ml/kg muscle x min) than the control leg (28+/-6 ml/kg muscle x min, P<0.01) but rates of muscle glucose uptake were identical in both legs (10.1+/-0.9 vs. 10.6+/-0.8 micromol/kg x min). We conclude that bradykinin increases skeletal muscle blood flow but not muscle glucose uptake in vivo. These data provide direct evidence against the hypothesis that blood flow is an independent regulator of insulin-stimulated glucose uptake in humans.     

Assessment of exercise capacity in women with type 2 diabetes

The primary aim of this study was to compare the maximal oxygen uptake as evaluated from a submaximal exercise test (EVO2peak) to direct measurements of VO2peak during a maximal exercise test as means of monitoring the aerobic endurance capacity in women with type 2 diabetes (T2D). Twenty-seven women with T2D participated in the study. The program consisted of combined group training 1 h twice a week during 12 weeks and walks 1 h per week. EVO2 max was estimated using a submaximal exercise test on a bicycle ergometer ad modum Astrand. VO2peak and maximal work rate were measured using an incremental maximal exercise test on an electrically braked bicycle ergometer at baseline and after 6 and 12 weeks. EVO2peak was higher than VO2peak at baseline and significantly higher at 12 weeks (EVO2peak1.92+/-0.54 l min(-1), VO2peak 1.41+/-0.36, P<0.005). Maximal work rate increased significantly after 12 weeks (12+/-15, P<0.005) compared to baseline. The main finding of this study was that EVO2peak assessed using a submaximal exercise test, systematically overestimated VO2peak. The combined group training increased maximal work rate but not VO2peak. This is likely to reflect peripheral adaptation to exercise and/or improved mechanical efficiency.     

Halothane increases cytosolic Ca2+ and inhibits Na+/H+ exchange in L6 muscle cells

The effects of the general anesthetic halothane on the concentration of cytosolic free calcium ([Ca2+]i) and cytosolic pH (pHi), were investigated in L6 rat skeletal muscle cells. Basal [Ca2+]i was 169 +/- 8 nM, measured with the fluorescent Ca2(+)-indicator 1-[2-amino-5-(6-carboxyindol-2-yl)phenoxy]-2-(2'-amino-5- methylphenoxy)ethane-N,N,N',N'-tetra-acetate. Halothane (5.7 mM) increased [Ca2+]i to 225 +/- 15 nM in the presence of extracellular Ca2+, and from 137 +/- 6 nM to 179 +/- 9 nM in Ca2+ absence. This increase was dose-dependent. The anesthetic released about 50% of the releasable Ca2+ from intracellular stores. The resting pHi of L6 cells was 7.24 +/- 0.04, measured with the fluorescent pH indicator bis-carboxyethylcarboxyfluorescein. Halothane did not affect resting pHi, but inhibited cytoplasmic alkalinization by hypertonicity or cytoplasmic acidification: (1) The hypertonicity-induced alkalinization via activation of Na+/H+ exchange (to 7.50 +/- 0.08, initial rate 0.10 +/- 0.02 pH U/min) was inhibited with 5.7 mM halothane by 67%. (2) Acid-loaded cells (pHi 6.43 +/- 0.01 in cells) recovered towards neutrality via activation of Na+/H+ exchange (rate 0.47 pH U/min), and halothane inhibited the rate of pHi recovery by 50%. The halothane-mediated inhibition of alkalinizations after hypertonic exposure or acid-loading was also observed in bis-(o-amino-phenoxy)ethane-N,N,N',N'-tetra-acetate-loaded cells in Ca2(+)-free medium. Therefore, halothane increases [Ca2+]i and in parallel inhibits Na+/H+ exchange, compromising the ability of muscle cells to recover from imposed acidification.     

Effects of exercise training on aerobic and functional capacity of end-stage renal disease patients

The aim was to assess the effects of exercise training on aerobic and fuctional capacity of patients with end-stage renal disease (ESRD). Patients completed an incremental exercise test on a cycle ergometer to determine VO2 peak and VO2 at ventilatory threshold (VT; V-slope). On a separate day they performed two constant load exercise tests on a cycle ergometer at 90% of VT and at a workload of 33 W, to determine VO2 kinetics. Functional capacity was assessed using measurements of sit-to-stands (STS-5, STS-60) and a walk test. Dialysis patients were randomly allocated to an exercise (ET: n = 18, age = 57.3 years) or control (C: n = 15, age = 50.5 - 5 years) group. The ET group participated in an exercise training programme involving cycling for 3 months. Repeated measures ANOVA revealed significant time by group interactions (P < 0.05) following training for VO2 peak (ET: 17 +/- 6.1 versus 19.9 +/- 6-3, C: 19.5 +/- 4.7 versus 188 +/- 4.9 ml kg min(-1)) and VO2-VT (ET: 10.7 +/- 3.5 versus 11.8 +/- 3.3, C:12.9 +/- 3.2 versus 119 +/- 3.5 ml kg min(-10). VO2 kinetics remained unchanged in both groups at 90% -VT, but a trend (P = 0.059) towards faster kinetics at the 33 W was observed (ET: 49.6 +/- 19.5 versus 37.8 +/- 12.7, C: 42.8 +/- 13 versus 49.4 +/- 20.2 s). Significant time by group interactions (P < 0.05) were also observed for STS-5 (ET: 14.7 +/- 6.2 versus 11.0 +/- 3.3, C: 12.8 +/- 4.4 versus 12.7 +/- 4.8 s) and STS-60 measurements (ET: 21.2 + 7.2 versus 26.9 +/- 6.2, C: 23.7 +/- 6.8 versus 24.1 +/- 7.2). Three months of exercise rehabilitation significantly improves peak exercise capacity of patients with ESRD. Measurements of VO2 kinetics and functional capacity suggest that longer time might be needed to induce peripheral adaptations.