Middle cerebral artery blood velocity during exercise with beta-1 adrenergic and unilateral stellate ganglion blockade in humans

A reduced ability to increase cardiac output (CO) during exercise limits blood flow by vasoconstriction even in active skeletal muscle. Such a flow limitation may also take place in the brain as an increase in the transcranial Doppler determined middle cerebral artery blood velocity (MCA V(mean)) is attenuated during cycling with beta-1 adrenergic blockade and in patients with heart insufficiency. We studied whether sympathetic blockade at the level of the neck (0.1% lidocaine; 8 mL; n=8) affects the attenuated exercise - MCA V(mean following cardio-selective beta-1 adrenergic blockade (0.15 mg kg(-1) metoprolol i.v.) during cycling. Cardiac output determined by indocyanine green dye dilution, heart rate (HR), mean arterial pressure (MAP) and MCA V(mean) were obtained during moderate intensity cycling before and after pharmacological intervention. During control cycling the right and left MCA V(mean) increased to the same extent (11.4 +/- 1.9 vs. 11.1 +/- 1.9 cm s(-1)). With the pharmacological intervention the exercise CO (10 +/- 1 vs. 12 +/- 1 L min(-1); n=5), HR (115 +/- 4 vs. 134 +/- 4 beats min(-1)) and delta MCA V(mean) (8.7 +/- 2.2 vs. 11.4 +/- 1.9 cm s(-1) were reduced, and MAP was increased (100 +/- 5 vs. 86 +/- 2 mmHg; P < 0.05). However, sympathetic blockade at the level of the neck eliminated the beta-1 blockade induced attenuation in delta MCA V(mean) (10.2 +/- 2.5 cm s(-1)). These results indicate that a reduced ability to increase CO during exercise limits blood flow to a vital organ like the brain and that this flow limitation is likely to be by way of the sympathetic nervous system.     

During hypoxic exercise some vasoconstriction is needed to match O2 delivery with O2 demand at the microcirculatory level.

To test the hypothesis that the increased sympathetic tonus elicited by chronic hypoxia is needed to match O(2) delivery with O(2) demand at the microvascular level eight male subjects were investigated at 4559 m altitude during maximal exercise with and without infusion of ATP (80 mug (kg body mass)(-1) min(-1)) into the right femoral artery. Compared to sea level peak leg vascular conductance was reduced by 39% at altitude. However, the infusion of ATP at altitude did not alter femoral vein blood flow (7.6 +/- 1.0 versus 7.9 +/- 1.0 l min(-1)) and femoral arterial oxygen delivery (1.2 +/- 0.2 versus 1.3 +/- 0.2 l min(-1); control and ATP, respectively). Despite the fact that with ATP mean arterial blood pressure decreased (106.9 +/- 14.2 versus 83.3 +/- 16.0 mmHg, P < 0.05), peak cardiac output remained unchanged. Arterial oxygen extraction fraction was reduced from 85.9 +/- 5.3 to 72.0 +/- 10.2% (P < 0.05), and the corresponding venous O(2) content was increased from 25.5 +/- 10.0 to 46.3 +/- 18.5 ml l(-1) (control and ATP, respectively, P < 0.05). With ATP, leg arterial-venous O(2) difference was decreased (P < 0.05) from 139.3 +/- 9.0 to 116.9 +/- 8.4(-1) and leg .VO(2max) was 20% lower compared to the control trial (1.1 +/- 0.2 versus 0.9 +/- 0.1 l min(-1)) (P = 0.069). In summary, at altitude, some degree of vasoconstriction is needed to match O(2) delivery with O(2) demand. Peak cardiac output at altitude is not limited by excessive mean arterial pressure. Exercising leg .VO(2peak) is not limited by restricted vasodilatation in the altitude-acclimatized human.     

Monitoring tissue oxygen availability with near infrared spectroscopy (NIRS) in health and disease

Near infrared spectroscopy (NIRS) is becoming a widely used research instrument to measure tissue oxygen (O2) status non-invasively. Continuous-wave spectrometers are the most commonly used devices, which provide semi-quantitative changes in oxygenated and deoxygenated hemoglobin in small blood vessels (arterioles, capillaries and venules). Refinement of NIRS hardware and the algorithms used to deconvolute the light absorption signal have improved the resolution and validity of cytochrome oxidase measurements. NIRS has been applied to measure oxygenation in a variety of tissues including muscle, brain and connective tissue, and more recently it has been used in the clinical setting to assess circulatory and metabolic abnormalities. Quantitative measures of blood flow are also possible using NIRS and a light-absorbing tracer, which can be applied to evaluate circulatory responses to exercise along with the assessment of tissue O2 saturation. The venular O2 saturation can be estimated with NIRS by applying venous occlusion and measuring changes in oxygenated vs. total hemoglobin. These various measurements provide the opportunity to evaluate several important metabolic and circulatory patterns in very localized regions of tissue and may be fruitful in the study of occupational syndromes and a variety of diseases.     

Interleukin-6 release is higher across arm than leg muscles during whole-body exercise

Exercising muscle releases interleukin-6 (IL-6), but the mechanisms controlling this process are poorly understood. This study was performed to test the hypothesis that the IL-6 release differs in arm and leg muscle during whole-body exercise, owing to differences in muscle metabolism. Sixteen subjects (10 men and six women, with body mass index 24 ± 1 kg m(-2) and peak oxygen uptake 3.4 ± 0.6 l min(-1)) performed a 90 min combined arm and leg cycle exercise at 60% of maximal oxygen uptake. The subjects arrived at the laboratory having fasted overnight, and catheters were placed in the femoral artery and vein and in the subclavian vein. During exercise, arterial and venous limb blood was sampled and arm and leg blood flow were measured by thermodilution. Lean limb mass was measured by dual-energy X-ray absorbtiometry scanning. Before and after exercise, biopsies were obtained from vastus lateralis and deltoideus. During exercise, IL-6 release was similar between men and women and higher (P < 0.05) from arms than legs (1.01 ± 0.42 and 0.33 ± 0.12 ng min(-1) (kg lean limb mass)(-1), respectively). Blood flow (425 ± 36 and 554 ± 35 ml min(-1) (kg lean limb mass)(-1)) and fatty acid uptake (26 ± 7 and 47 ± 7 μmol min(-1) (kg lean limb mass)(-1)) were lower, glucose uptake similar (51 ± 12 and 41 ± 8 mmol min(-1) (kg lean limb mass)(-1)) and lactate release higher (82 ± 32 and -2 ± 12 μmol min(-1) (kg lean limb mass)(-1)) in arms than legs, respectively, during exercise (P < 0.05). No correlations were present between IL-6 release and exogenous substrate uptakes. Muscle glycogen was similar in arms and legs before exercise (388 ± 22 and 428 ± 25 mmol (kg dry weight)(-1)), but after exercise it was only significantly lower in the leg (219 ± 29 mmol (kg dry weight)(-1)). The novel finding of a markedly higher IL-6 release from the exercising arm compared with the leg during whole-body exercise was not directly correlated to release or uptake of exogenous substrate, nor to muscle glycogen utilization.     

The effect of rowing on endothelial function and insulin action in healthy controls and in patients with type 2 diabetes

Patients with type 2 diabetes (T2DM) have an increased risk for cardiovascular disease. We examined the effects of 8 weeks of home‐based rowing training (heart rate corresponding to 65–70% of VO_{2 peak}) on endothelial function and glucose clearance (local and systemic effects) in male subjects with T2DM (n=9) and matched controls (n=8). Before and after training (30 min every other day), all subjects underwent sequential graded brachial artery infusions of non‐insulin vasodilators (acetylcholine; sodium nitroprusside; adenosine). Forearm blood flow was improved by training in controls (without and with insulin: P=0.003 and 0.05, respectively) but not in subjects with T2DM. Likewise, whole body glucose clearance increased in response to training in controls (P=0.05) but not in T2DM. However, in both groups, the capacity for local forearm glucose extraction (controls: P=0.001; T2DM: P=0.002) and clearance (controls: P<0.001; T2DM: P=0.01) were positively affected by exercise. While the subjects with T2DM did not respond to the same degree as controls to 8 weeks of home‐based exercise, there are clear benefits as illustrated by improvements in local glucose disposal. Training of higher intensity or duration may be required in order to elicit a response similar to controls.     

Combined inhibition of nitric oxide and prostaglandins reduces human skeletal muscle blood flow during exercise

The vascular endothelium is an important mediator of tissue vasodilatation, yet the role of the specific substances, nitric oxide (NO) and prostaglandins (PG), in mediating the large increases in muscle perfusion during exercise in humans is unclear. Quadriceps microvascular blood flow was quantified by near infrared spectroscopy and indocyanine green in six healthy humans during dynamic knee extension exercise with and without combined pharmacological inhibition of NO synthase (NOS) and PG by l -NAME and indomethacin, respectively. Microdialysis was applied to determine interstitial release of PG. Compared to control, combined blockade resulted in a 5- to 10-fold lower muscle interstitial PG level. During control incremental knee extension exercise, mean blood flow in the quadriceps muscles rose from 10 ± 0.8 ml (100 ml tissue)⁻¹ min⁻¹ at rest to 124 ± 19, 245 ± 24, 329 ± 24 and 312 ± 25 ml (100 ml tissue)⁻¹ min⁻¹ at 15, 30, 45 and 60 W, respectively. During inhibition of NOS and PG, blood flow was reduced to 8 ± 0.5 ml (100 ml tissue)⁻¹ min⁻¹ at rest, and 100 ± 13, 163 ± 21, 217 ± 23 and 256 ± 28 ml (100 ml tissue)⁻¹ min⁻¹ at 15, 30, 45 and 60 W, respectively ( P < 0.05 vs. control). In conclusion, combined inhibition of NOS and PG reduced muscle blood flow during dynamic exercise in humans. These findings demonstrate an important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction.     

Physiological,biochemical, anthropometric,and biomechanical influences on exercise economy in humans

Interindividual variation in running and cycling exercise economy (EE) remains unexplained although studied for more than a century. This study is the first to comprehensively evaluate the importance of biochemical, structural, physiological, anthropometric, and biomechanical influences on running and cycling EE within a single study. In 22 healthy males (VO₂max range 45.5‐72.1 mL·min^?1·kg^?1), no factor related to skeletal muscle structure (% slow‐twitch fiber content, number of capillaries per fiber), mitochondrial properties (volume density, oxidative capacity, or mitochondrial efficiency), or protein content (UCP3 and MFN2 expression) explained variation in cycling and running EE among subjects. In contrast, biomechanical variables related to vertical displacement correlated well with running EE, but were not significant when taking body weight into account. Thus, running EE and body weight were correlated (R²=.94; P<.001), but was lower for cycling EE (R²=.23; P<.023). To separate biomechanical determinants of running EE, we contrasted individual running and cycling EE considering that during cycle ergometer exercise, the biomechanical influence on EE would be small because of the fixed movement pattern. Differences in cycling and running exercise protocols, for example, related to biomechanics, play however only a secondary role in determining EE. There was no evidence for an impact of structural or functional skeletal muscle variables on EE. Body weight was the main determinant of EE explaining 94% of variance in running EE, although more than 50% of the variability of cycling EE remains unexplained.     

Erythropoietin treatment elevates haemoglobin concentration by increasing red cell volume and depressing plasma volume

Erythropoietin (Epo) has been suggested to affect plasma volume, and would thereby possess a mechanism apart from erythropoiesis to increase arterial oxygen content. This, and potential underlying mechanisms, were tested in eight healthy subjects receiving 5000 IU recombinant human Epo (rHuEpo) for 15 weeks at a dose frequency aimed to increase and maintain haematocrit at approximately 50%. Red blood cell volume was increased from 2933 ± 402 ml before rHuEpo treatment to 3210 ± 356 ( P < 0.01), 3117 ± 554 ( P < 0.05), and 3172 ± 561 ml ( P < 0.01) after 5, 11 and 13 weeks, respectively. This was accompanied by a decrease in plasma volume from 3645 ± 538 ml before rHuEpo treatment to 3267 ± 333 ( P < 0.01), 3119 ± 499 ( P < 0.05), and 3323 ± 521 ml ( P < 0.01) after 5, 11 and 13 weeks, respectively. Concomitantly, plasma renin activity and aldosterone concentration were reduced. This maintained blood volume relatively unchanged, with a slight transient decrease at week 11, such that blood volume was 6578 ± 839 ml before rHuEpo treatment, and 6477 ± 573 (NS), 6236 ± 908 ( P < 0.05), and 6495 ± 935 ml (NS), after 5, 11 and 13 weeks of treatment. We conclude that Epo treatment in healthy humans induces an elevation in haemoglobin concentration by two mechanisms: (i) an increase in red cell volume; and (ii) a decrease in plasma volume, which is probably mediated by a downregulation of the rennin–angiotensin–aldosterone axis. Since the relative contribution of plasma volume changes to the increments in arterial oxygen content was between 37.9 and 53.9% during the study period, this mechanism seems as important for increasing arterial oxygen content as the well-known erythropoietic effect of Epo.