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Objective: to investigate the feasibility of using microdialysate glucose, lactate and pyruvate concentrations for grading the severity of blood flow reduction in patients with critical limb ischaemia., Patients and Methods: microdialysis catheters were inserted (two subcutaneously and one intramuscularly) in the symptomatic limb of ten patients. To further reduce limb perfusion, the lower leg was elevated during part of the experiment., Results: elevation reduced ankle and toe blood pressure and transcutaneous oxygen tension. Microdialysate glucose concentration decreased at all three catheter sites, while lactate increased in the intramuscular catheter. Two patients interrupted the elevated position prematurely due to severe pain in the foot. They had among the highest lactate levels in the horizontal position and the most marked increases following provocation. Neither initial metabolite concentrations nor concentration changes during elevation were shown to correlate to conventional methods used to assess limb perfusion., Conclusions: in patients with critical limb ischaemia microdialysis can be used without complications. A significant decrease in glucose concentration may reflect lowered blood flow in the elevated position. Metabolic response, i.e. increase in lactate concentration during profoundly reduced limb perfusion was heterogeneous, indicating an overestimation of the presence of ischaemia in some patients using current diagnostic methods., (Copyright 2000 Harcourt Publishers Ltd.)

The effect of training under conditions of local leg ischaemia on muscle area and fibre dimensions was studied in nine males. Leg ischaemia was induced by enclosing the legs in a pressure chamber and sealing the opening with a rubber membrane at the level of the crotch. Air pressure over the legs was 50 mmHg. The subjects performed 16 sessions (45 min) of one-legged supine strenuous ischaemic training during 4 weeks. Exercise intensity was maintained as high as possible during the whole session. The contralateral leg served as a control leg and remained passive during exercise. Before and after the training period, muscle fibre dimensions were determined from biopsy samples taken from the m. vastus lateralis, and leg muscle dimensions were assessed by magnetic resonance imaging (MRI). In the trained leg, mean fibre area increased by 12% (P < 0.05). The MRI-assessed cross-sectional area of the vastus group increased by 4% (P = 0.01). In the control leg, mean fibre area and the cross-sectional area of the vastus group were unchanged, while those of the adductor muscle group decreased by 4% (P < 0.05). It is concluded that a short period of strenuous ischaemic endurance training increases the cross-sectional area of the ischaemically trained muscle group, as measured both by MRI and from muscle biopsy samples. In contrast, the adductor muscles in the contralateral thigh showed a decreased cross-sectional area (as assessed by MRI), possibly due to the effects of the strenuous contralateral training, by mechanisms that have yet to be identified.

To test the influence of the accumulation of metabolites on exercise-induced hormone responses, plasma concentrations of cortisol, growth hormone (GH), insulin, testosterone, thyrotropin (TSH), free thyroxine (fT4) and triiodothyronine (T3) were compared during exercise performed under normal conditions (control) and under conditions of restricted blood flow of exercising leg muscles (ischaemia) in nine healthy young men. Blood supply was reduced by 15%-20% by the application of 50 mmHg external pressure over the exercising leg. During 45-min cycling exercise during ischaemia the increase in GH concentration was twice as large as under normal conditions. Despite the below-threshold exercise intensity for activation of the pituitary-adrenocortical system under normal exercise conditions ischaemic exercise elicited cortisol and T3 responses (concentration increases of 83% and 9.5%, respectively). Ischaemic exercise attenuated the decrease of plasma insulin concentration found under normal conditions. The concentrations of testosterone, TSH and fT4 were not changed significantly during exercise performed in either condition. The results support the suggested essential role of muscle metaboreceptors in the control of hormone responses during muscle activity.

The influence of graded leg muscle ischaemia on the adaptation to training and on the acute response to exercise was studied in healthy subjects. Graded ischaemia during supine exercise was induced by application of 50 mmHg external pressure on the legs. This procedure reduced leg blood flow by 16%, venous oxygen saturation by 12 percentage units, and markedly increased lactate release (p < 0.05 for all). One-legged training was performed during four weeks, 4 sessions per week. Each session started with one leg training for 45 min with reduced blood flow (ischaemic training). The contralateral leg, serving as a control, was then trained with an identical power-output profile for 45 min but without flow restriction (non-ischaemic training). Ischaemic training enhanced the adaptation to training. Peak oxygen uptake and time to fatigue increased more (p < 0.05) with ischaemic than with non-ischaemic training. Citrate synthase activity, capillaries per fibre, and glycogen content were greater (p < 0.05) in the trained than in the detrained state. In the ischaemically trained leg, the type IIb fibre proportion was lower (p < 0.05) and the I fibre proportion tended to be higher (p = 0.06) in the trained than in the detrained state. Maximum voluntary dynamic strength was decreased by 8% (p < 0.01) in the ischaemically trained leg, but was unaffected in the non-ischaemically trained leg. During acute ischaemic exercise, as compared to non-ischaemic exercise, there was a higher degree of glycogen depletion, a greater depletion of type II, but not of type I fibres, a greater electromyographic activity, higher catecholamine concentrations, lower intramuscular ATP and creatine phosphate content, and an increased nitric oxide formation as estimated by increased plasma nitrate content. In conclusion, the mechanisms underlying the potentiation of the adaptation to training by ischaemia are assumed to depend on the operation of stimuli which were amplified during acute ischaemic exercise.

Eight healthy men performed supine one-legged training on a bicycle ergometer 45 min per leg four times per week for 4 week. The ergometer and lower body were inside a pressure chamber, the opening of which was sealed at the level of the crotch. One leg trained with impeded leg blood flow (I-leg), induced by an increased (50 mmHg) chamber pressure, at the highest tolerable intensity. The contralateral leg trained at the same power under normal pressure (N-leg). Before and after training biopsies were taken from the vastus lateralis of both legs and maximal one-legged exercise tests were executed with both legs. Biopsies were repeated when the subjects had been back to their habitual physical activity for 3 months. Training increased exercise time to exhaustion, but more in the I-leg than in the N-leg. After training, the I-leg had higher activity of citrate synthase (CS), a marker of oxidative capacity, and lower activity of the M-subunit of lactate dehydrogenase isoenzymes. It also had a higher percentage of type-I fibres and a lower percentage of IIB fibres, larger areas of all fibre types and a greater number of capillaries per fibre. It is concluded that ischaemic training changes the muscle metabolic profile in a direction facilitating aerobic metabolism. An altered fibre-type composition may contribute, but is not enough prerequisite for the change.

The aim of the study was to compare the effects of ischaemic and non-ischaemic training on aerobic performance. In 10 subjects, peak oxygen uptake (peak VO2) and time to fatigue (TTF) for one-legged exercise were measured before and after 4 weeks (4 times week-1) of one-legged training. Each training session started with one leg training for 45 min with 20% blood-flow reduction induced by local application of a supra-atmospheric external pressure of 50 mmHg (ischaemic leg; I-leg). We have previously shown that this decreases leg blood flow by about 20%. The contralateral leg (non-restricted-flow leg; N-leg), serving as a control, then trained with an identical power-output profile for 45 min but without flow restriction. In the I-leg the average training-induced increments in TTF and peak VO2 were 27 and 24%, respectively. In the N-trained leg TTF and peak-VO2 increased 10 and 14%, respectively. Both increments were significantly greater (P < 0.05) in the I-trained leg. Moreover, the performance increase in the I-trained leg was exaggerated (P < 0.05) in the ischaemic test condition, i.e. there was a specificity in the training response. In conclusion, ischaemia acts as an additive stimulus to training leading to an exaggerated increase in endurance and peak-VO2 compared to identical training without blood-flow restriction. The main explanation is probably an enhanced local adaptation in the I-trained leg.

An experimental model used with the intention of mimicking the ischaemic condition in patients with arterial obliterative disease was evaluated. The influence of reduced effective perfusion pressure by increased external pressure on leg blood flow and metabolism was determined during exercise in 10 healthy subjects. Catheters were inserted into the right femoral artery and vein and into the left femoral vein. Supine one-legged (n = 5) or two-legged (n = 5) cycle exercise was performed with the subject's legs in a pressure chamber. Zero and three different levels of local supra-atmospheric pressure were applied over the legs: 30, 50 and 60 mmHg. Three submaximal work loads were used: 24, 48 and 72 W/leg. Leg blood flow was measured by the constant-infusion dye-dilution technique. Samples were also drawn from the femoral artery and vein for oxygen saturation and lactate determinations and arterial pressure was recorded. Exercise blood flow decreased progressively with increasing chamber pressure (P less than 0.001). Exposure to 50 mmHg over the working leg led to a mean reduction of blood flow by 16% and venous oxygen saturation by 12 percentage units (P less than 0.05). Lactate release increased with increasing pressure (P less than 0.05). In summary, local application of moderate positive external pressure over the working leg reduces blood flow in a 'dose-dependent' manner, and as a consequence, femoral venous oxygen saturation decreases and lactate release increases. Thus, this method makes it possible to induce graded ischaemia in human skeletal muscle during exercise in a controlled fashion.

Healthy young men executed supine one-legged cycle training four times per week for 4 wk with legs and the cycle ergometer inside a pressure chamber, the opening of which was sealed by a rubber membrane at the level of the crotch. Each training session started by training one leg under ischemic conditions induced by increased chamber pressure (50 mmHg) at the highest intensity tolerable for 45 min. Then the other leg was trained with the same power profile but normal atmospheric chamber pressure. Before and after the training period, both legs executed one-legged exercise tests under both normal and increased chamber pressure and muscle biopsies were taken from the vastus lateralis. Ischemic training increased performance more than normal training, the difference being greater for exercise executed under ischemic conditions. The difference in performance increase between the legs was paralleled by a greater muscle citrate synthase activity in the ischemically than in the normally trained leg.

Eleven subjects performed one-legged exercise four times per week for 5 wk. The subjects exercised one leg for 45 mm with restricted blood flow (R leg), followed by exercise with the other leg at the same absolute workload with unrestricted blood flow (UR leg). mRNA and protein expression were measured in biopsies from the vastus lateralis muscle obtained at rest before the training period, after 10 days, and after 5 wk of training, as well as 120 mm after the first and last exercise bouts. Basal Ang-2 and Tie- 1 mRNA levels increased in both legs with training. The Ang-2-to-Ang- 1 ratio increased to a greater extent in the R leg. The changes in Ang-2 mRNA were followed by similar changes at the protein level. In the R leg, VEGF-A mRNA expression responded transiently after acute exercise both before and after the 5-wk training program. Over the course of the exercise program, there was a concurrent increase in basal VEGF-A protein and VEGFR-2 mRNA in the R leg. Ki-67 mRNA showed a greater increase in the R leg and the protein was localized to the endothelial cells. In summary, the increased translation of VEGF-A is suggested to be caused by the short mRNA burst induced by each exercise bout. The concurrent increase in the Ang-2-to-Ang- 1 ratio and the VEGF-expression combined with the higher level of Ki-67 mRNA in the R leg indicate that changes in these systems are of importance also in nonpathological angiogenic condition such as voluntary exercise in humans. It further establish that hypoxialischemia-related metabolic perturbation is likely to be involved as stimuli in this process in human skeletal muscle. [ABSTRACT FROM AUTHOR]

VEGF-A contributes lo muscle tissue angiogenesis following aerobic exercise training. The temporal response of the VEGF-A isoforms and their target receptors has not been comprehensively profiled in human skeletal muscle. We combined submaximal exercise with and without reduced leg blood flow to establish whether ischemia-induced metabolic stress was an important physiological stimuli responsible for regulating the VEGF-A system in humans. Nine healthy men performed two 45-min bouts of one-leg knee-extension exercise, with and without blood flow restriction. Muscle biopsies were obtained at rest and 2 and 6 h after exercise. Expression (mRNA) of the VEGF-A splice variants and related receptors [VEGF receptor (VEGFR)-1, VEGFR-2, and neuropilin-1] was determined by using qPCR. VEGF-Atotal expression increased more robustly after exercise with reduced blood flow, and initially this principally reflected an increase in VEGF-A165. Six hours after exercise, there was a relatively greater increase in VEGF-A189, and this response was not influenced by blood flow conditions. VEGFR-1 mRNA expression increased 2 h after exercise, and neuropilin-1 expression was transiently reduced, while all three receptors increased by 6 h. There was no evidence for the expression of the inhibitory VEGF-A165B variant in human skeletal muscle. Our study, reflecting both VEGF-A ligand and receptors, implicates metabolic perturbation as a regulator of human muscle angiogenesis and demonstrates that VEGF-A splice variants are distinctly regulated. Our findings also indicate that all three receptor genes exhibit different pretranslational regulation, in response to exercise in humans. [ABSTRACT FROM AUTHOR]