Interstitial IGF-I in exercising skeletal muscle in women.

OBJECTIVE: To study interstitial IGF-I concentrations in resting and exercising skeletal muscle in relation to the circulating components of the IGF-IGF binding protein (IGFBP) system. DESIGN AND METHODS: Seven women performed endurance exercise with 1 leg (Ex-leg) for 1 h. The resting leg (Rest-leg) served as a control. IGF-I was determined in microdialysate (MD) and was compared with veno-arterial (v-a) concentrations of circulating IGF-IGFBP components. RESULTS: Median (range) basal MD-IGF-I was 0.87 (0.4-1.5) microg/l or 0.4 (0.2)% of total-IGF-I (t-IGF-I) determined in arterial serum and in the same concentration range as free dissociable IGF-I (f-IGF-I). Rest-leg MD-IGF-I decreased, reaching significance after exercise. Ex-leg MD-IGF-I was unchanged during exercise and declined after exercise at the level of significance (P = 0.05). There was a release of f-IGF-I from the Ex-leg into the circulation at the end of and shortly after exercise. A small but significant increase in circulating IGFBP-1 was detected at the end of exercise and IGFBP-1 increased further after exercise. Although interleukin-6 (IL-6) has been associated with IGFBP-3 proteolysis, the circulating molecular forms of IGFBP-3 remained unchanged in spite of an IL-6 release from the muscle compartment. CONCLUSIONS: Circulating IGFBP-1 is related to interstitial IGF-I in resting muscle although the temporal relationship may not be simple. Further studies should explore the role of local release of IGF-I and its impact on IGF-I activity during contraction.

Maximal oxygen uptake is not limited by a central nervous system governor.

We tested the hypothesis that the work of the heart was not a limiting factor in the attainment of maximal oxygen uptake (VO2 max). We measured cardiac output (Q) and blood pressures (BP) during exercise at two different rates of maximal work to estimate the work of the heart through calculation of the rate-pressure product, as a part of the ongoing discussion regarding factors limiting VO2 max. Eight well-trained men (age 24.4 +/- 2.8 yr, weight 81.3 +/- 7.8 kg, and VO2 max 59.1 +/- 2.0 ml x min(-1) x kg(-1)) performed two maximal combined arm and leg exercises, differing 10% in watts, with average duration of time to exhaustion of 4 min 50 s and 3 min 40 s, respectively. There were no differences between work rates in measured VO2 max, maximal Q, and peak heart rate between work rates (0.02 l/min, 0.3 l/min, and 0.8 beats/min, respectively), but the systolic, diastolic, and calculated mean BP were significantly higher (19, 5, and 10 mmHg, respectively) in the higher than in the lower maximal work rate. The products of heart rate times systolic or mean BP and Q times systolic or mean BP were significantly higher (3,715, 1,780, 569, and 1,780, respectively) during the higher than the lower work rate. Differences in these four products indicate a higher mechanical work of the heart on higher than lower maximal work rate. Therefore, this study does not support the theory, which states that the work of the heart, and consequently VO2 max, during maximal exercise is hindered by a command from the central nervous system aiming at protecting the heart from being ischemic.

A comparison between three rating scales for perceived exertion and two different work tests.

In the present article, three scales developed by Borg are compared on bicycle ergometer work. In the first study, comparing the Borg Ratings of Perceived Exertion (RPE) and Category scales with Ratio properties (CR10) scales, 40 healthy subjects (12 men and eight women for each scale) with a mean age of about 30 years (SD approximately 6) participated. A work-test protocol with step-wise increase of work loads every minute was used (20 W increase for men and 15 W for women). Ratings and heart rates (HRs) were recorded every minute and blood lactates every third minute. Data obtained with the RPE scale were described with linear regressions, with individual correlations of about 0.98. Data obtained with the CR10 scale could also be described by linear regressions, but when described by power functions gave exponents of about 1.2 (SD approximately 0.4) (with one additional constant included in the power function). This was significantly lower than the exponent of between 1.5 and 1.9 that has previously been observed. Mean individual correlations were 0.98. Blood lactate concentration grew with monotonously increasing functions that could be described by power functions with a mean exponent of about 2.6 (SD approximately 0.6) (with two additional constants included in the power functions). In the second study, where also the more recently developed Borg CR100 scale (centiMax) was included, 24 healthy subjects (12 men and 12 women) with a mean age of about 29 years (SD approximately 3) participated in a work test with a step-wise increase of work loads (25 W) every third minute. Ratings and HRs were recorded. RPE values were described by linear regressions with individual correlations of about 0.97. Data from the two CR scales were described by power functions with mean exponents of about 1.4 (SD approximately 0.5) (with a-values in the power functions). Mean individual correlations were about 0.98. In both studies, a tendency for a deviation from linearity between RPE values and HRs was observed. The obtained deviations from what has previously been obtained for work of longer duration (4-6 min) points to a need for standardization of work-test protocols and to the advantage of using CR scales.

Increased expression of vascular endothelial growth factor in human skeletal muscle in response to short-term one-legged exercise training.

The effects of short-term exercise training on vascular endothelial growth factor (VEGF) and one of its regulatory transcription factors, the hypoxia inducible factor 1 (HIF-1) subunit, were studied in eight healthy males. Muscle and blood samples were obtained before the 1st, and 24 h after the 7th training session. VEGF and HIF-1 mRNA were analysed using RT-PCR, VEGF mRNA localization with in situ hybridization and VEGF protein with ELISA. Concurrent increases in VEGF mRNA and protein levels were observed in skeletal muscle, and the mRNA was expressed within the skeletal muscle fibres and in cells in the interstitium. These data support the idea of a pretranslational regulation of exercise-induced changes in VEGF mRNA, and indicate that increased VEGF protein expression is an early event in skeletal muscle adaptation to training. Furthermore, different cell types may act as sources for the production of angiogenic factors in response to exercise. The levels of HIF-1 mRNA subunits did not change, suggesting no change in HIF-1 mRNA transcript levels in the regulation of training-induced VEGF expression. In contrast to increased tissue VEGF expression, the arterial and femoral venous plasma levels of VEGF were decreased by training, which may indicate an exercise-induced enhancement of the peripheral uptake of VEGF.

Effect of glycogen loading on skeletal muscle cross-sectional area and T2 relaxation time.

This study was performed to investigate if glycogen loading of skeletal muscles, by binding water, would effect the cross-sectional area (CSA) and if an altered water content would alter the transverse relaxation time (T2) measured by magnetic resonance imaging (MRI). Five healthy volunteers participated in a programme with 4 days of extremely carbohydrate-restricted meals followed by 4 days of extremely high carbohydrate intake. The CSA and T2 of thigh and calf muscles were related to the intramuscular glycogen content evaluated at days 4 and 8. An increase in glycogen content from 281 to 634 mmol kg(-1) dry wt increased the CSA of the vastus muscles by 3.5% from 78 +/- 11 to 80 +/- 12 cm2 and the thigh circumference by 2.5% from 146 +/- 20 to 150 23 cm2. Calf circumference increased non-significantly by 4% from 78 +/- 15 to 82 +/- 19 cm2. Mono-exponential T2 decreased in m. tibialis anterior from 27.8 +/- 1.2 to 26.9 +/- 1.7 ms, did not change in m. vastus lateralis 26.5 +/- 1.9 ms/26.6 +/- 1.3 ms or in m. gastrocnemius 29.5 +/- 1.0 ms/29.8 +/- 1.9 ms. Glycogen loading increased the signal intensity mainly at different echo times (TE) 15 and 30 ms. The study shows that increased glycogen filling in the muscles increases muscle CSA and that this can be detected by MRI. The signal intensity increased the most at shorter TEs suggesting a more tight intracellular binding of water in glycogen loaded muscles.

Exercise induces isoform-specific increase in 5'AMP-activated protein kinase activity in human skeletal muscle.

The 5'AMP-activated protein kinase (AMPK) is stimulated by contractile activity in rat skeletal muscle. AMPK has emerged as an important signaling intermediary in the regulation of cell metabolism being linked to exercise-induced changes in muscle glucose and fatty acid metabolism. In the present study, we determined the effects of exercise on isoform-specific AMPK activity (alpha1 and alpha2) in human skeletal muscle. Needle biopsies of vastus lateralis muscle were obtained from seven healthy subjects at rest, after 20 and 60 min of cycle ergometer exercise at 70% of VO(2)max, and 30 min following the 60 min exercise bout. In comparison to the resting state, AMPK alpha2 activity significantly increased at 20 and 60 min of exercise, and remained at a higher level with 30 min of recovery. AMPK alpha1 activity tended to slightly decrease with 20 min of exercise at 70%VO(2)max; however, the change was not statistically significant. AMPK alpha1 activities were at basal levels at 60 min of exercise and 30 min of recovery. On a separate day, the same subjects exercised for 20 min at 50% of VO(2)max. Exercise at this intensity did not change alpha2 activity, and similar to exercise at 70% of VO(2)max, there was no significant change in alpha1 activity. In conclusion, exercise at a higher intensity for only 20 min leads to increases in AMPK alpha2 activity but not alpha1 activity. These results suggest that the alpha2-containing AMPK complex, rather than alpha1, may be involved in the metabolic responses to exercise in human skeletal muscle.

Effects of dynamic ischaemic training on human skeletal muscle dimensions.

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.

Coping with anger-provoking situations, psychosocial working conditions, and ECG-detected signs of coronary heart disease.

This study explored the association among coping, psychosocial work factors, and signs of coronary heart disease (CHD) among prison staff (777 men, 345 women). Electrocardiogram (ECG) recordings at rest, health examinations, and a questionnaire were used. A high level of covert coping in men and a low level of open coping in women showed the strongest association with signs of CHD. Among several traditional biological and lifestyle risk factors, only age and systolic blood pressure in men and none in the case of women were significantly associated with CHD signs in the final multivariate regression analyses. A coping style of repressed emotions and actions in anger-provoking situations, independent of traditional risk factors, seems to be associated with a prevalence of ECG signs in male and female prison staff.

Changes in cross-sectional area in human exercising and non-exercising skeletal muscles.

This research was performed to study how the cross-sectional area (CSA) changes in the skeletal muscles of exercising (E-leg) and contralateral non-exercising (N-leg) legs and to evaluate to what extent changes in CSA mirror changes in blood flow or extravascular water displacement. Seven healthy volunteers performed plantar flexion exercise at three different exercise intensities for 10 min each. Six plantar flexions followed by a 2-s rest in between allowed repeated measurement of the blood flow to the lower limbs by duplex ultrasonography in the popliteal artery and CSA by magnetic resonance imaging. The CSA was measured using manual planimetry at rest and after 3 and 9 min of the exercise periods. The CSA increased in the E-leg by 4.5% and decreased in the N-leg by -2.4%, from rest to highest exercise intensity. Post-exercise imaging of the E-leg showed a bi-phasic recovery of CSA with a rapid phase followed by a slower phase while the blood flow very rapidly returned almost to basal. The time course of the post-exercise decrease indicated that about 50% of the increase in CSA at the highest exercise intensity might have been a result of extravascular water displacement and 50% of an increase in the vasculature volume related to the flow increase. The CSA reduction in N-leg seems to have been related to vasoconstriction, probably mainly of the capacitance vessels since blood flow was not reduced.

Skeletal muscle perfusion during exercise using Gd-DTPA bolus detection.

The study was performed to evaluate if skeletal muscle perfusion can be determined during exercise using an IV bolus injection of Gd-DTPA. A fast spoiled gradient echo sequence (T1 weighted) was used with intermittent imaging during one-legged plantar flexion at different workloads. Between repetitive flexions, a 2-sec rest allowed magnetic resonance imaging (MRI) of the lower legs and measurements of the blood flow in the popliteal artery by ultrasonography for subsequent calculation of muscle perfusion. Maximal signal intensity, upslope and downslope of the bolus, mean transit time, and integrated curve area were measured within regions of interest bilaterally. The skeletal muscle perfusion estimated by ultrasonography increased in the exercising leg from 4 ml x 100 g(-1) x min(-1) at rest to 38 ml at low, 86 ml at medium, and 110 ml x 100 g(-1) x min(-1) at high workload. The SImax increased from 1.38 +/- 0.12 to 1.58 +/- 0.15 and the negative slope of the peak nonsignificantly from - 2.38 +/- 1.75 to - 12.05 +/- 9. 71. All obtained MRI parameters could visually separate the muscles into exercising, nonexercising, and presumably low active muscles. It is concluded that the signal intensity curve using a fast spoiled gradient echo sequence did not overall quantitatively mirror the perfusion, evaluated as the blood flow measured by ultrasonography. However, the signal intensity seemed to follow the blood flow velocity within a limited range of 15-60 cm x sec(-1), corresponding to 35-90 ml x 100 g(-1) x min(-1). Nonetheless, it might be useful when studying ischemia or endothelial dysfunction in skeletal muscles during exercise.

Beneficial effects of exercise training in heart failure patients with low cardiac output response to exercise - a comparison of two training models.

BACKGROUND: Exercise capacity of patients with chronic heart failure (CHF) correlates poorly with estimates of cardiac function. Yet, it has been suggested that only patients without severely impaired cardiac output (CO) benefit from exercise training. Comparisons of different training models have not been made in the same study. AIMS: To evaluate whether the response to different training models diverges according to the cardiac output response to exercise in patients with chronic heart failure. METHODS: Sixteen CHF patients (63 +/- 11 years) with an ejection fraction of 30 +/- 11% underwent a baseline cardiopulmonary exercise test, right heart catheterization and leg muscle biopsy. Cardiac output (CO) response to exercise was defined as the ratio between CO increase and the increase in oxygen uptake (CO response index) during exercise. Patients were randomized into two training regimens, differing with regard to active muscle mass, i.e. whole body and one-legged exercise. RESULTS: Baseline exercise capacity expressed as W kg-1 correlated with the CO response index (r = 0.51, P < 0.05). Exercise capacity on the cycle ergometer increased in both groups but more in the one-legged than in the two-legged training group (P < 0.05). The improvement in exercise capacity did not correlate with base-line exercise capacity. It correlated with CO response index in the one-legged (r = 0.75, P < 0.01) but not in the two-legged training group. CO response index correlated negatively with the pulmonary capillary wedge pressure at peak exercise (r = - 0.60, P < 0.05). The increase in leg muscle citrate synthase activity after training correlated negatively with the baseline CO response index (r = - 0. 50, P < 0.05). CONCLUSIONS: The improvement of exercise capacity after one-legged training correlates with the CO increase in relation to the O2 uptake before training. In patients with low CO response, individualization of the exercise regimen is needed and the benefits of training a limited muscle mass at a time deserve further study.

Impaired exercise performance but normal skeletal muscle characteristics in female syndrome X patients.

Pathophysiologic mechanisms in syndrome X (anginal chest pain, positive exercise stress test, and angiographically normal coronary arteries) have been extensively studied. Recent reports suggest an ischemic origin of the pain to be less probable. Other contributing mechanisms that have been hypothesized are enhanced sympathetic drive or sensitivity or an abnormal muscle metabolism. Our aim in this study was to characterize exercise performance, skeletal muscle characteristics, and sympathetic control of blood flow in patients with syndrome X. Seven female patients aged 50 to 65 years and 5 matched controls were tested. Exercise test was performed according to clinical routine. Plasma catecholamine and blood lactate levels were measured before, during, and after exercise. Autonomic blood flow control was measured plethysmographically in the resting contralateral forearm during isometric handgrip. Muscle biopsy specimens were obtained at rest from the lateral part of Musculus vastus at midthigh. The biopsy samples were investigated for the relative number of different fiber types, phosphagen content, and energy charge, calculated as (adenosine triphosphate +/- 1/2 adenosine diphosphate)/[adenosine triphosphate +/- adenosine diphosphate +/- adenosine monophosphate]). Exercise capacity was markedly decreased in syndrome X compared with controls (85 +/- 14 vs 156 +/- 11 W, p <0.0005) and all patients discontinued exercise because of chest pain (Borg CR-10, 5 +/- 3). Peak heart rate was lower in syndrome X (150 +/- 18 vs 176 +/- 7 beats/min, p <0.01), whereas systolic blood pressure and double product did not differ. Peak norepinephrine plasma levels were lower than in controls (11 +/- 6 vs 24 +/- 13 nmol/L, p <0.04), whereas peak blood lactate levels did not differ. Blood flow increase in the resting forearm during isometric handgrip was similar to that in controls. The proportion of different fiber types, phosphagen content, and energy charge were normal. Thus, patients with syndrome X have a reduced physical exercise capacity but no skeletal muscle abnormalities. Catecholamine hypersensitivity may contribute to their condition.

Exercise-induced expression of angiogenesis-related transcription and growth factors in human skeletal muscle.

mRNA expression of vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and hypoxia-inducible factor (HIF) subunits HIF-1alpha and HIF-1beta in human skeletal muscle was studied during endurance exercise at different degrees of oxygen delivery. Muscle biopsies were taken before and after 45 min of one-legged knee-extension exercise performed under conditions of nonrestricted or restricted blood flow (approximately 15-20% lower) at the same absolute workload. Exercise increased VEGF mRNA expression by 178% and HIF-1beta by 340%, but not HIF-1alpha and FGF-2. No significant differences between the restricted and nonrestricted groups were observed. The exercise-induced increase in VEGF mRNA was correlated to the exercise changes in HIF-1alpha and HIF-1beta mRNA. The changes in VEGF, HIF-1alpha, and HIF-1beta mRNAs were correlated to the exercise-induced increase in femoral venous plasma lactate concentration. It is concluded that 1) VEGF but not FGF-2 gene expression is upregulated in human skeletal muscle by a single bout of dynamic exercise and that there is a graded response in VEGF mRNA expression related to the metabolic stress and 2) the increase in VEGF mRNA expression correlates to the changes in both HIF-1alpha and HIF-1beta mRNA.

The ability of non-invasive physiological tests to detect arterial occlusions in the lower extremity. An ROC study with particular regard to recruitment of patients for clinical trials.

In the prerandomization phase of a clinical trial it is essential to be able to exclude, in a non-invasive way, patients who cannot be randomized into the trial. The ability of routine non-invasive physiological examinations to detect arterial occlusion in the lower extremities was investigated in 182 patients with hypercholesterolaemia. Ankle blood pressure measurement, pulse oscillometry, digital pulse plethysmography and treadmill and cycle exercise tests were performed as part of the prerandomization phase of the Probucol Quantitative Regression Swedish Trial (PQRST). The PQRST was designed to compare the antiatherosclerotic effect of two different lipid-lowering regimens. Before randomization the patients also underwent aorto-femoral arteriography, which was used as 'gold standard'. The results were analysed with ROC methodology. Ankle blood pressure measurement (ABP) and inclination time (IT), measured with digital pulse plethysmography, without significant mutual difference, were the variables, best able to detect occlusions. For ABP, the AZ-values were 0.85, 0.82 and 0.94 in detection of right-sided, left-sided and bilateral occlusion, respectively. The corresponding figures for IT were AZ = 0.86, 0.91 and 0.93. If a bilateral occlusion was predicted in a patient with an ABP value of < = or 0.98, a specificity of 0.90 and a sensitivity of 0.87 were obtained, using arteriography as reference method. For IT, with a critical value of 320 ms, sensitivity and specificity were 0.83 and 0.90, respectively.

Substrate availability limits human skeletal muscle oxidative ATP regeneration at the onset of ischemic exercise.

We have demonstrated previously that dichloroacetate can attenuate skeletal muscle fatigue by up to 35% in a canine model of peripheral ischemia (Timmons, J.A., S.M. Poucher, D. Constantin-Teodosiu, V. Worrall, I.A. Macdonald, and P.L. Greenhaff. 1996. J. Clin. Invest. 97:879-883). This was thought to be a consequence of dichloroacetate increasing acetyl group availability early during contraction. In this study we characterized the metabolic effects of dichloroacetate in a human model of peripheral muscle ischemia. On two separate occasions (control-saline or dichloroacetate infusion), nine subjects performed 8 min of single-leg knee extension exercise at an intensity aimed at achieving volitional exhaustion in approximately 8 min. During exercise each subject's lower limbs were exposed to 50 mmHg of positive pressure, which reduces blood flow by approximately 20%. Dichloroacetate increased resting muscle pyruvate dehydrogenase complex activation status by threefold and elevated acetylcarnitine concentration by fivefold. After 3 min of exercise, phosphocreatine degradation and lactate accumulation were both reduced by approximately 50% after dichloroacetate pretreatment, when compared with control conditions. However, after 8 min of exercise no differences existed between treatments. Therefore, it would appear that dichloroacetate can delay the accumulation of metabolites which lead to the development of skeletal muscle fatigue during ischemia but does not alter the metabolic profile when a maximal effort is approached.

High proportion of type I fibres in thigh muscle of young dancers.

A previous study showed that adult female dancers have a high percentage of type I fibres in vastus lateralis, similar to that of endurance-trained female runners or female cross-country skiers. It is not known if dancers already at an early age are characterized by a high percentage of type I fibres or develop a high percentage of type I fibres as a consequence of dance training. Furthermore, the muscle fibre composition of male dancers has not previously been studied. Therefore the aim of the study was to analyse skeletal muscle fibre characteristics in 10-year-old and 20-year-old dancers of both sexes. Age-matched boys and girls whose physical activity was average for their age groups served as controls. Muscle biopsies for histochemical analysis were obtained from vastus lateralis using the percutaneous needle technique. The major finding of the present study was that the vastus lateralis of young dancers of both sexes had a higher percentage of type I fibres than that of controls. Moreover, the higher type I percentage was seen not only in 20 year olds, but also in 10 year olds, who had begun their dance training at a professional level only a few weeks earlier. No significant difference in this respect was found between female and male dancers. In conclusion, the muscle fibre type composition in young dancers of both sexes differs from that of the average individual of the same age and is characterized by a high percentage of type I fibres.

Improved ventilation and decreased sympathetic stress in chronic heart failure patients following local endurance training with leg muscles.

BACKGROUND: Two-legged knee extensor training activates only about half the muscle mass used in traditional cycle ergometer training. With such an exercise model it is possible to achieve a substantial local training effect in spite of a restricted circulatory capacity. The present study sought to investigate the systemic effects of such local training on ventilation and neurohumoral activity in patients with moderate heart failure. METHODS AND RESULTS: Thirteen male patients with chronic heart failure (age 56 +/- 3 years, EF 28 +/- 3%) performed two-legged knee extensor exercises (about 4 kg of working muscle) for 15 minutes 3 times a week during 8 weeks at 65-75% of peak VO2 of a two-legged kick and were compared to a non-training control group (n = 7, age 62 +/- 3, EF 27 +/- 3%). Before and after the training period VO2, VCO2 and the minute ventilation (1/min) were determined at rest and at submaximal and maximal workloads. Also measured before and after training were two-legged knee extensor peak exercise capacity (W), strength (Nm), a 6-minute walking test (m), quadriceps femoris citrate synthase activity, plasma catecholamines, vasoactive amines and blood lactate during submaximal knee extension exercise, and perceived health-related quality of life. After training, VO2 and VCO2 were reduced at submaximal exercise by 20-30% (P < .01) but were unchanged at peak exercise. With training, the two-legged knee extensor peak exercise capacity increased by 38% (P < .01). The 6-minute walking gait velocity increased by 12% (P < .01) and skeletal muscle citrate synthase activity by 28% (P < .01). Training improved the quality of life (P < .01). After training, VO2 (P < .001), VCO2 (P < .001) and minute ventilation (P < .001) were reduced at the workload corresponding to the maximal workload before training. The ratio minute ventilation/VO2 was reduced (P < .05) after training at the before-training maximal workload. No change was observed in the control group with regard to two-legged peak exercise capacity or peak VO2. Plasma NPY was reduced both at rest and at submaximal exercise by 35% (P < .01), whereas noradrenaline was reduced only during exercise (P < .05). CONCLUSIONS: Local muscle training is effective in stable chronic heart failure and can improve, in addition to exercise capacity and quality of life, the ventilatory response, and decrease the sympathetic stress.

Long-lasting coronary vasoconstrictor effects and myocardial uptake of endothelin-1 in humans.

The effect of intravenous administration of the endothelium derived vasoconstrictor peptide endothelin-1 (ET-1 0.2. 1 and 8 pmol kg-1 min-1) on coronary blood flow in relation to plasma ET-1 as well as blood lactate and glucose levels were investigated in six healthy volunteers. Coronary sinus blood flow was measured by thermodilution. Administration of ET-1 elevated arterial plasma ET 35-fold, dose-dependently increased mean arterial blood pressure from 95 +/- 5 mmHg to 110 +/- 6 mmHg (P < 0.01) and reduced heart rate from 64 +/- 4 beats min-1 to 58 +/- 4 beats min-1 (P < 0.05) at 8 pmol kg-1 min-1. Coronary sinus blood flow was reduced maximally by 23 +/- 4% (P < 0.01) and coronary vascular resistance increased by 48 +/- 11% (P < 0.01). Coronary sinus oxygen saturation decreased from 35 +/- 1% to 22 +/- 2% at 2 min after the infusion (P < 0.01). A coronary constrictor response was observed at a 4-fold elevation in plasma ET. The reduction is coronary sinus blood flow lasted 20 min and coronary sinus oxygen saturation was still reduced 60 min after the infusion. Myocardial oxygen uptake or arterial oxygen saturation were not affected by ET-1. Myocardial lactate net uptake decreased by 40% whereas glucose uptake was unaffected. At the highest infusion rate there was a net removal of plasma ET by 24 +/- 3% over the myocardium (P < 0.05). The results show that ET-1 induces long-lasting reduction in coronary sinus blood flow via a direct coronary vasoconstrictor effect in healthy humans observable at a 4-fold elevation in plasma ET-1. Furthermore, there is a net removal of circulating ET-1 by the myocardium.

Peak skeletal muscle perfusion is maintained in patients with chronic heart failure when only a small muscle mass is exercised.

OBJECTIVES: The issue to be resolved was whether peripheral leg blood flow in patients with chronic heart failure (CHF) is reduced by low local flow capacity or as a function of the amount of muscle mass activated during exercise. METHODS AND RESULTS: In ten CHF patients (ejection fraction 26 (9)%), and 12 healthy controls central and peripheral circulatory responses were assessed during dynamic one- and two-legged knee extensor work. The patients reached a peak perfusion of 234 (16) ml 100 g-1 min-1 in the one-legged mode, which was similar to the controls (244 (11) ml 100 g-1 min-1). At peak two-legged work muscle perfusion was reduced in the patients by 24% (P < 0.05). In contrast the controls maintained their peak muscle perfusion. The mass of the quadriceps femoris muscle and peak leg blood flow correlated closely for both groups at peak one-legged work (r = 0.85, P < 0.001). Peak oxygen uptake in the active limb during one-legged exercise was similar for patients and controls (0.52 (0.06) vs. 0.63 (0.06) l min-1), but it was 38% lower (P < 0.05) in patients than controls during exhaustive two-legged exercise. Arterial systemic oxygen delivery (cardiac output x arterial oxygen content), at peak exercise was highly correlated with peak one- and two-legged workload for both groups, explaining 70% of the difference in peak workload attained (P < 0.001). At peak two-legged exercise non-exercising tissues of the body in the male CHF patients with the largest limb muscle mass, received a blood flow of only 1.2 (0.7) 1 min-1. Mean arterial blood pressure at peak work in both test conditions was significantly lower for the patients than the controls. A higher sympathetic nerve activity in the patients, as evaluated by arterial noradrenaline concentration (NA) and leg NA spillover, contributed to maintain the perfusion pressure. CONCLUSIONS: Patients with moderate CHF can reach a peak skeletal muscle perfusion and a leg oxygen uptake comparable to that of healthy individuals when a sufficiently small muscle mass is activated. Exercise involving a larger muscle mass, for the patients in this study about 4 kg, markedly reduces peak leg blood flow, perfusion and oxygen uptake as well as blood flow to non-exercising organs and tissues.

Comparable potent coronary constrictor effects of endothelin-1 and big endothelin-1 in humans.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor produced from the precursor big ET-1 in endothelial cells. The coronary effects of these peptides in humans in vivo are unknown. Therefore, the effects of ET-1 and big ET-1 on coronary blood flow in relation to plasma ET-1 and big ET-1 levels were compared in healthy subjects. METHODS AND RESULTS: The peptides were infused intravenously at the rates of 0.2, 1, and 8 pmol/kg per minute. Each dose administered for 20 minutes except the highest dose of ET-1, which was administered for 10 minutes. ET-1 and big ET-1 evoked dose-related increases in mean arterial blood pressure from 93 +/- 4 to 107 +/- 4 mm Hg and from 89 +/- 2 to 122 +/- 5 mm Hg, respectively, at the highest dose. ET-1 and big ET-1 reduced coronary sinus blood flow, measured with thermodilution by a maximum of 25 +/- 4% and 28 +/- 8% and increased coronary vascular resistance by 50 +/- 9% and 107 +/- 26%, respectively. Coronary sinus, but not arterial, oxygen saturation was reduced in parallel with the coronary sinus blood flow. The effects of ET-1 and big ET-1 were similar at corresponding time points. During infusion of ET-1, a 19 +/- 5% extraction of ET-1 was observed over the coronary vascular bed (P < .05). Administration of big ET-1 elevated arterial plasma ET-1 levels by 2.4-fold, and after correction for the local extraction of ET-1, a myocardial production of ET-1 was observed. CONCLUSIONS: ET-1 and big ET-1 induce comparable increases in blood pressure and coronary constriction in humans in vivo. The results also suggest a net local removal of circulating ET-1 and big ET-1 and a local conversion of big ET-1 into ET-1 within the coronary vascular bed.