Eric van Breda

Nebivolol: A Third-Generation beta-Blocker That Augments Vascular Nitric Oxide Release : Endothelial beta(2)-Adrenergic Receptor-Mediated Nitric Oxide Production.

BACKGROUND Nebivolol is a beta(1)-selective adrenergic receptor antagonist with proposed nitric oxide (NO)-mediated vasodilating properties in humans. In this study, we explored whether nebivolol indeed induces NO production and, if so, by what mechanism. We hypothesized that not nebivolol itself but rather its metabolites augment NO production. METHODS AND RESULTS Mouse thoracic aorta segments were bathed in an organ chamber. Administration of nebivolol did not affect NO production. When nebivolol was allowed to metabolize in vivo in mice, addition of plasma of these mice caused a sustained 2-fold increase in NO release. Interestingly, coadministration of a selective beta(2)-adrenergic receptor antagonist (butoxamine) prevented the response. Immunohistochemistry and Western blot analysis demonstrated the presence of beta(2)- but not beta(1)-adrenergic receptors on endothelial cells. In the absence of calcium, metabolized nebivolol failed to increase NO production, suggesting a role for calcium-dependent NO synthase. With digital fluorescence imaging, a rapid and sustained rise in endothelial cytosolic free Ca(2+) concentration was observed after administration of metabolized nebivolol, which also was abrogated by butoxamine pretreatment. CONCLUSIONS In vivo metabolized nebivolol increases vascular NO production. This phenomenon involves endothelial beta(2)-adrenergic receptor ligation, with a subsequent rise in endothelial free [Ca(2+)](i) and endothelial NO synthase-dependent NO production. This may be an important mechanism underlying the nebivolol-induced, NO-mediated arterial dilation in humans.

Modulation of fatty-acid-binding protein content of rat heart and skeletal muscle by endurance training and testosterone treatment

The effects of training and/or testosterone treatment and its aromatization to oestradiol on fatty-acid-binding protein (FABP) content and cytochrome c oxidase activity in heart, soleus and extensor digitorum longus (EDL) muscles were studied in intact adult female rats. One group of rats remained sedentary, whereas the others were trained for 7 weeks. Thereafter the trained rats were divided into control and testosterone-treated groups, with or without an aromatase inhibitor. Testosterone was administered by a silastic implant. Training was continued for 2 weeks. In untreated sedentary rats the immunochemically assayed FABP contents were 497±28, 255±49 and 58±17 μg/g wet weight for the heart, soleus, and EDL respectively. In the heart the FABP content was increased after training (29%), testosterone treatment (33%) or both manipulations (53%). In soleus muscle FABP increased only after testosterone treatment (16%), whereas in EDL no changes were found. Inhibiting the aromatase enzyme complex abolished the testosterone-induced effect on FABP content in soleus (suggesting an oestradiol effect) but not in heart muscle. Among the three muscles studied the FABP content was found to be related to the cytochrome c oxidase activity in a non-linear way. In conclusion, it is shown that the FABP contents and mitochondrial activities of heart and skeletal muscle are affected by training and sex hormones and that these effects are different for heart and skeletal muscles.

High-intensity strength training improves quality of life in cancer survivors

Introduction. Cancer rehabilitation programs mainly involve endurance training, and little attention is paid to strength training. Cancer survivors are generally advised to train at much lower workloads than the standard guidelines for strength training suggest. The purpose of this study is to evaluate the effectiveness of an 18-week high-intensity strength training program in cancer survivors. Methods. Fifty-seven patients (age 24 to 73 years) who had received chemotherapy for lymphomas, breast, gynecologic, testicular, or colorectal cancer completed the program. Outcome measures were changes in muscular strength (one-repetition maximum), cardiopulmonary function (VO2 max), maximal short exercise capacity (MSEC), body composition and health-related quality of life (HRQOL) between baseline and follow-up. Discussion. The high-intensity strength training was well tolerated by all patients. Significant improvements in muscle strength were found, with effect sizes varying from 1.32 to 2.68. VO2 max increased significantly by 10% in men and by 13% in women. Different functional scales of HRQOL improved (p < 0.01), with effect sizes varying from 0.47 to 0.82. Muscle strength correlated significantly with physical functioning before and after the training program. Conclusion. We conclude that a supervised, high-intensity strength training program seems to be an effective means to improve muscle strength, cardiopulmonary function, and HRQOL and should be incorporated in cancer rehabilitation programs. Further randomized trials are needed to confirm the results.

Physical Activity during Cancer Treatment (PACT) Study: design of a randomised clinical trial

BackgroundFatigue is a major problem of cancer patients. Thirty percent of cancer survivors report serious fatigue three years after finishing treatment. There is evidence that physical exercise during cancer treatment reduces fatigue. This may also lead to an improvement of quality of life. Such findings may result in a decrease of healthcare related expenditures and societal costs due to sick leave. However, no studies are known that investigated these hypotheses. Therefore, the primary aim of our study is to assess the effect of exercise during cancer treatment on reducing complaints of fatigue and on reducing health service utilisation and sick leave.Methods/DesignThe Physical Activity during Cancer Treatment study is a multicentre randomised controlled trial in 150 breast and 150 colon cancer patients undergoing cancer treatment. Participants will be randomised to an exercise or a control group. In addition to the usual care, the exercise group will participate in an 18-week supervised group exercise programme. The control group will be asked to maintain their habitual physical activity pattern. Study endpoints will be assessed after 18 weeks (short term) and after 9 months (long term). Validated questionnaires will be used. Primary outcome: fatigue (Multidimensional Fatigue Inventory and Fatigue Quality List) and cost-effectiveness, health service utilisation and sick leave. Secondary outcome: health related quality of life (European Organisation Research and Treatment of Cancer-Quality of Life questionnaire-C30, Short Form 36 healthy survey), impact on functioning and autonomy (Impact on functioning and autonomy questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), physical fitness (aerobic peak capacity, muscle strength), body composition and cognitive-behavioural aspects. To register health service utilisation and sick leave, participants will keep diaries including the EuroQuol-5D. Physical activity level will be measured using the Short Questionnaire to Assess Health-Enhancing Physical Activity and will be monitored with an exercise log and a pedometer.DiscussionThis study investigates the (cost)-effectiveness of exercise during adjuvant treatment of patients with breast or colon cancer. If early physical exercise proves to be (cost) effective, establishing standardised physical exercise programmes during cancer treatment will be planned.Trial registrationCurrent Controlled trials ISRCTN43801571, Dutch Trial Register NTR2138

A Nonnatural Head–Neck Position(Rollkur) During Training Results in Less Acute Stress in Elite, Trained, Dressage Horses

This study measured parameters of stress in recreational, trained horses (REC; n = 7) and elite (International Grand Prix level) trained, dressage horses (DRES; n = 5). The training of the DRES horses uses an unnatural head–neck position (Rollkur), whereas in the REC horses such training techniques are not common. The study measured stress by using heart rate variability analysis for 30 min postfeeding in the morning and 30 min postexercise after a morning training session. The study found no significant difference at rest between the REC and DRES horses. During the posttraining measurements, however, the DRES horses showed, among others, a less sympathetic and increased parasympathetic dominance. These results suggest that DRES horses tend to have less acute stress than do REC horses postexercise. The findings of this study suggest maintaining the health and well-being of DRES horses despite nonnatural, biomechanical positions.

Intracellular Transport of Fatty Acids in Muscle

Long-chain fatty acids represent a major substrate for energy production in striated muscles, especially in those muscles which have a high oxidative enzymatic capacity. Following their uptake from the extracellular compartment the fatty acids have to translocate through the aqueous cytoplasm of the myocytes to reach the mitochondria where they undergo oxidative degradation. This intracellular transport is assisted by cytoplasmic fatty acid-binding protein (FABPc), a small (15 kD) protein which shows a high affinity for the non-covalent binding of long-chain fatty acids, and of which several types occur. So-called heart-type or muscle-type FABPc is found in muscle cells, and is abundant especially in oxidative fibers. The muscular FABPc content appears to relate to the rate of fatty acid utilization, and also changes in concert to modulations in fatty acid utilization induced by (patho)physiological stimuli (e. g. endurance training, diabetes). The facilitation of intracellular fatty acid transport by FABPc is accomplished by increasing the concentration of the diffusing fatty acids in the aqueous cytoplasm and, most likely, also by interacting directly with membranes to promote transfer of fatty acids to and from the cytosolic binding protein.

Modulation of glycogen metabolism of rat skeletal muscles by endurance training and testosterone treatment

The effects of training and/or testosterone treatment on glycogen content and the activities of glycogen synthase, glycogen phosphorylase, and fructose-6-phosphate kinase were studied in extensor digitorum longus (EDL) and soleus muscles of intact adult female rats. One group of rats remained sedentary, whereas another group was trained for 7 weeks. Thereafter, both the sedentary and trained rats were subdivided into two control and four testosterone-treated subgroups. Testosterone was administered by a silastic implant. Training was continued for 2 weeks. On the final day of the experiment rats from one trained control and one trained testosterone-treated subgroup ran for 60 min submaximally. Upon testosterone treatment of sedentary rats the glycogen concentration was not changed. However, in the soleus, but not in the EDL, the glycogen content was increased by training (P<0.05) which could, at least partly, be explained by a decrease in activity of active glycogen phosphorylase (P < 0.05). In the EDL of trained rats testosterone treatment increased glycogen content significantly by both an increase in activity of active glycogen synthase and a decrease in activity of active glycogen phosphorylase (P<0.05). In the EDL and soleus of testosterone-treated animals from the exercised subgroup a significant sparing of glycogen was observed, which could be explained by an increase in activity of active glycogen synthase and, in the soleus, could also be explained by a concerted decrease in active glycogen phosphorylase (P<0.05). In the two muscles studied, we also found that testosterone treatment in trained animals shifted the fibre type distribution towards more oxidative fibres in both types of muscle in comparison with the control animals. We conclude that testosterone, at a pharmacological dose, potentiates the training-induced increase in glycogen content of skeletal muscle and induces a glycogen-sparing effect after submaximal exercise.

Differential expression of equine muscle biopsy proteins during normal training and intensified training in young standardbred horses using proteomics technology

The major aim of the present study was to investigate the proteome of standardbred horses at different stages of training and intensified training. We searched for biomarkers using small skeletal muscle biopsies of live animals. 2D gel electrophoresis and mass spectrometry were successfully applied to investigate training-induced differential expression of equine muscle biopsy proteins. Despite the poor resolution of the equine genome and proteome, we were able to identify the proteins of 20 differential spots representing 16 different proteins. Evaluation of those proteins complies with adaptation of the skeletal muscle after normal training involving structural changes towards a higher oxidative capacity, an increased capacity to take up long-chain fatty acids, and to store energy in the form of glycogen. Intensified training leads to additional changed spots. Alpha-1-antitrypsin was found increased after intensified training but not after normal training. This protein may thus be considered as a marker for overtraining in horses and also linked to overtraining in human athletes.

Over)training effects on quantitative electromyography and muscle enzyme activities in standardbred horses.

Too intensive training may lead to overreaching or overtraining. To study whether quantitative needle electromyography (QEMG) is more sensitive to detect training (mal)adaptation than muscle enzyme activities, 12 standardbred geldings trained for 32 wk in age-, breed-, and sex-matched fixed pairs. After a habituation and normal training (NT) phase (phases 1 and 2, 4 and 18 wk, respectively), with increasing intensity and duration and frequency of training sessions, an intensified training (IT) group (phase 3, 6 wk) and a control group (which continued training as in the last week of phase 2) were formed. Thereafter, all horses entered a reduced training phase (phase 4, 4 wk). One hour before a standardized exercise test (SET; treadmill), QEMG analysis and biochemical enzyme activity were performed in muscle or in biopsies from vastus lateralis and pectoralis descendens muscle in order to identify causes of changes in exercise performance and eventual (mal)adaptation in skeletal muscle. NT resulted in a significant adaptation of QEMG parameters, whereas in muscle biopsies hexokinase activity was significantly decreased. Compared with NT controls, IT induced a stronger adaptation (e.g., higher amplitude, shorter duration, and fewer turns) in QEMG variables resembling potentially synchronization of individual motor unit fiber action potentials. Despite a 19% decrease in performance of the SET after IT, enzyme activities of 3-hydroxyacyl dehydrogenase and citrate synthase displayed similar increases in control and IT animals. We conclude that 1) QEMG analysis is a more sensitive tool to monitor training adaptation than muscle enzyme activities but does not discriminate between overreaching and normal training adaptations at this training level and 2) the decreased performance as noted in this study after IT originates most likely from a central (brain) rather than peripheral level.

Plasma acylcarnitine and fatty acid profiles during exercise and training in Standardbreds

OBJECTIVE To evaluate alterations in skeletal muscle carnitine metabolism during exercise and training by measuring changes in plasma acylcarnitine concentrations in Standardbreds. ANIMALS 10 Standardbred geldings with a mean +/- SD age of 20 +/- 2 months and weight of 384 +/- 42 kg. PROCEDURES In a 32-week longitudinal study, training on a treadmill was divided into 4 phases as follows: phase 1, acclimatization for 4 weeks; phase 2, 18 weeks with alternating endurance and high-intensity exercise training; phase 3, increased training volume and intensity for another 6 weeks; and phase 4, deconditioning for 4 weeks. In phase 3, horses were randomly assigned to 2 groups as follows: control horses (which continued training at the same level as in phase 2) and high-intensity exercise trained horses. At the end of each phase, a standardized exercise test (SET) was performed. Plasma acylcarnitine, fatty acids, and lactic acid and serum beta-hydroxybutyric acid (BHBA) concentrations were assessed before and at different time points after each SET. RESULTS Plasma lactic acid, total nonesterified fatty acids, 3-hydroxyisobutyric acid, and acetylcarnitine (C2-carnitine) concentrations significantly increased during SETs, whereas serum BHBA, plasma propionylcarnitine (C3-carnitine), and plasma butyryl- and isobutyrylcarnitine (C4-carnitine) concentrations decreased significantly, compared with those before SETs. CONCLUSIONS AND CLINICAL RELEVANCE Our findings indicated that the plasma acylcarnitine profile in horses likely reflects skeletal muscle carnitine metabolism following exercise, thereby providing a possible practical method to investigate potential disorders in carnitine metabolism in horses with myopathy.