SUMMARY1. Eight subjects performed one-legged, dynamic, knee-extensor exercise, first at 10 W followed by 10 min rest, then at an intense, exhaustive exercise load (65 W) lasting 3-2 min. After 60 min recovery, exercise was performed for 8-10 min each at 20, 30, 40 and 50 W. Measurements of pulmonary oxygen uptake, heart rate, blood pressure, leg blood flow, and femoral arterial-venous differences of oxygen content and lactate were performed as well as determination of ATP, creatine phosphate (CP) inosine monophosphate (IMP) and lactate concentrations on biopsy material from the quadriceps muscle before and immediately after the intense exercise, and at 3, 10 and 60 min into recovery.2. Individual linear relations (r = 0-95-1-00) between the power outputs for submaximal exercise and oxygen uptakes (leg and pulmonary) were used to estimate the energy demand during intense exercise. Pulmonary and leg oxygen deficits determined as the difference between energy demand and oxygen uptake were 0-46 and 0-48 1 (kg active muscle)-', respectively. Limb and pulmonary oxygen debts (oxygen uptake during 60 min of recovery -pre-exercise oxygen uptake) were 0-55 and 1P65 1 (kg active muscle)-', respectively. J. BANGSBO AND OTHERS for less than 10 % of the leg oxygen debt, and lactate elimination including resynthesis of glycogen for another 25 %. 5. The anaerobic energy contribution during the first half-minute of intense exercise accounted for 80 % of the total energy turnover and this decreased to 30 % during the last phase of the exercise. The mean anaerobic energy contribution was 45 % for the 3-2 min of exhaustive exercise.6. The maximal anaerobic capacity of human muscle amounted to the equivalent of close to 051 02 kg-1. An extrapolation to whole-body anaerobic capacity cannot be made, as the magnitude of neither [ATP] and [CP] reduction nor lactate release from the muscle is likely to be comparable in all muscles when the human performs whole-body exercise.7. When exercising with a small muscle group the measurements of (i) oxygen deficit and (ii) energy yield, based on metabolic alterations of the active muscle, give similar values for the anaerobic energy release. The dominant fraction of the elevation in recovery oxygen uptake (i.e. oxygen debt) is not accounted for, as normalization of nucleotides, CP, muscle and blood lactate only amounted to about 3 of the debt measurement. Elevation in hormones such as adrenaline and noradrenaline as well as temperature do not appear to play a role in the high recovery oxygen uptake in the present study.

Heart rate and blood pressure are elevated at the onset and throughout the duration of dynamic or static exercise. These neurally mediated cardiovascular adjustments to physical activity are regulated, in part, by a peripheral reflex originating in contracting skeletal muscle termed the exercise pressor reflex. Mechanically sensitive and metabolically sensitive receptors activating the exercise pressor reflex are located on the unencapsulated nerve terminals of group III and group IV afferent sensory neurons, respectively. Mechanoreceptors are stimulated by the physical distortion of their receptive fields during muscle contraction and can be sensitized by the production of metabolites generated by working skeletal myocytes. The chemical by-products of muscle contraction also stimulate metaboreceptors. Once activated, group III and IV sensory impulses are transmitted to cardiovascular control centers within the brain stem where they are integrated and processed. Activation of the reflex results in an increase in efferent sympathetic nerve activity and a withdrawal of parasympathetic nerve activity. These actions result in the precise alterations in cardiovascular hemodynamics requisite to meet the metabolic demands of working skeletal muscle. Coordinated activity by this reflex is altered after the development of cardiovascular disease, generating exaggerated increases in sympathetic nerve activity, blood pressure, heart rate, and vascular resistance. The basic components and operational characteristics of the reflex, the techniques used in human and animals to study the reflex, and the emerging evidence describing the dysfunction of the reflex with the advent of cardiovascular disease are highlighted in this review.

Non-technical summary The cardiovascular response to exercise is exaggerated in hypertension. This heightened circulatory responsiveness increases the risk of occurrence of an adverse cardiovascular event during and immediately following a bout of exercise. Accumulating evidence suggests the muscle metaboreflex, a chemically sensitive peripheral reflex originating in skeletal muscle, contributes significantly to this abnormal cardiovascular response to exercise. However, its role remains controversial. In addition, the receptor mechanisms underlying metaboreflex dysfunction in hypertension remain undetermined. To this end, the current investigation demonstrates that the metaboreflex is overactive in hypertensive rats eliciting exaggerated increases in sympathetic nerve activity and blood pressure. Importantly, the study shows, for the first time, that the metaboreflex dysfunction manifest in hypertension is mediated, in part, by activation of the skeletal muscle TRPv1 receptor. As such, the investigation identifies the muscle metaboreflex, specifically the TRPv1 receptor, as a potential target for the treatment of cardiovascular hyperexcitability during exercise in hypertension. AbstractThe circulatory response to exercise is exaggerated in hypertension potentially increasing the risk for adverse cardiovascular events. Evidence suggests the skeletal muscle metaboreflex contributes to this abnormal circulatory response. However, as the sensitivity of this reflex has been reported to be both reduced and potentiated in hypertension, its role remains controversial. In addition, the receptor mechanisms underlying muscle metaboreflex dysfunction in this disease remain undetermined. To address these issues, metaboreflex activity was assessed during 'supra-stimulation' of the reflex via ischaemic hindlimb muscle contraction. This manoeuvre evoked significantly larger increases in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in spontaneously hypertensive rats (SHR) compared to normotensive Wistar-Kyoto (WKY) rats. The skeletal muscle TRPv1 receptor was evaluated as a potential mediator of this metaboreflex response as it has been shown to contribute significantly to muscle reflex activation in healthy animals. Stimulation of the TRPv1 receptor by injection of capsaicin into the arterial supply of the hindlimb evoked significantly larger elevations in MAP and RSNA in SHR compared to WKY. The pressor and sympathetic responses to ischaemic muscle contraction in WKY and SHR were attenuated by the administration of the TRPv1 receptor antagonist capsazepine with the magnitude of the capsazepine-induced reductions being greater in SHR than WKY. TRPv1 protein expression in dorsal root ganglia, but not skeletal muscle, was significantly greater in SHR than WKY. The results suggest the muscle metaboreflex is overactive in hypertension. Further, this reflex overactivity can be partially normalized by antagonizing TRPv1 receptors in skeletal muscle.

SUMMARY1. In human subjects sustained static contractions of the quadriceps femoris in one leg were performed with the same absolute and the same relative intensity before and after partial neuromuscular blockade with either decamethonium or tubocurarine which reduced strength to about 50 % of the control value. During the contractions performed with the same absolute force, the magnitude of the cardiovascular responses (heart rate and blood pressure) was greater during neuromuscular blockade than during control contractions. During the contractions involving the same relative force the magnitude of the cardiovascular responses was almost the same with and without neuromuscular blockade. These findings were independent of the drug used.2. The metabolic part of the exercise pressor reflex was assessed by the application of an arterial cuff I min before cessation of exercise and for the following 3 min of rest. Although heart rate and blood pressure decreased after cessation of exercise, application of the tourniquet resulted in higher post-exercise values and this effect was seen both with and without neuromuscular blockade.3. Muscle biopsies from the subjects' m. vastus lateralis were analysed for fastand slow-twitch fibre composition showing 27-66 % slow-twitch fibres. No correlation was found between cardiovascular responses to static exercise, with or without neuromuscular blockade, and fibre type predominance. 4. The results suggest that the involvement of fast-or slow-twitch muscle fibres does not play a dominant role in the cardiovascular responses to static exercise in man. Both central command and reflex neural mechanisms are of importance, and it appears that these two control mechanisms are redundant and that neural occlusion may be operative. However, when partial neuromuscular blockade induces a disproportion between an increase in central command and a constant or decreasing muscle tension and metabolism, the larger signal arising from central command determines the magnitude of the cardiovascular responses.

In hypertension, the blood pressure response to exercise is exaggerated. We demonstrated previously that this heightened pressor response to physical activity is mediated by an overactive skeletal muscle exercise pressor reflex (EPR), with important contributions from its metaboreflex and mechanoreflex components. However, the mechanisms driving the abnormal blood pressure response to EPR activation are largely unknown. Recent evidence in humans suggests that the muscle metaboreflex partially mediates the enhanced EPR-induced pressor response via abnormally large changes in sympathetic nerve activity (SNA). Whether the muscle mechanoreflex induces similarly exaggerated alterations in SNA in hypertension remains unknown, as does the role of the mechanoreceptors mediating muscle reflex activity. To address these issues, the EPR was selectively activated by electrically inducing hindlimb muscle contraction in decerebrate normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Stimulation of the EPR evoked significantly larger increases in mean arterial pressure (MAP) and renal SNA (RSNA) in SHR compared with WKY (ΔRSNA from baseline: 140 ± 11 vs. 48 ± 8%). The mechanoreflex was stimulated by stretching hindlimb muscle which likewise elicited significantly greater elevations in MAP and RSNA in SHR than WKY (ΔRSNA from baseline: 105 ± 11 vs. 35 ± 7%). Blockade of mechanoreceptors in muscle with gadolinium significantly attenuated the MAP and RSNA responses to contraction and stretch in SHR. These data suggest that 1) the exaggerated pressor response to activation of the EPR and muscle mechanoreflex in hypertension is mediated by abnormally large reflex-induced augmentations in SNA and 2) this accentuated sympathetic responsiveness is evoked, in part, by stimulation of muscle mechanoreceptors.

Small for gestational age infants are known to develop hypertension in adulthood. This prenatal programming of hypertension (PPH) can result from several insults including maternal dietary protein deprivation, uteroplacental insufficiency and prenatal administration of glucocorticoids. The mechanisms underlying the development of hypertension remain unclear although the sympathetic nervous system has been indirectly implicated. This study was designed to directly measure renal sympathetic activity (RSNA) both at rest and during physical stress in an animal model of PPH. The adult male offspring of rats fed either a 6% (PPH) or 20% protein diet (control) were investigated. Conscious systolic blood pressure measured by tail cuff was significantly higher in PPH compared to control (140 ± 3 vs. 128 ± 3 mmHg, P < 0.05). Baseline mean arterial pressure (MAP), heart rate (HR) and RSNA were not different between groups during isoflurane anesthesia or after decerebration. Physical stress was induced in decerebrate animals by activating the exercise pressor reflex (EPR) during static muscle contraction. Stimulation of the EPR evoked significantly larger changes from baseline in MAP (40 ± 7 vs. 20 ± 4 mmHg, P < 0.05), HR (19 ± 3 vs. 5 ± 1 bpm, P < 0.05) and RSNA (198 ± 29 vs. 68 ± 14 %, P < 0.05) in PPH as compared to control. The data demonstrate that the sympathetic response to physical stress is markedly exaggerated in PPH and may play a significant role in the development of hypertension in adults born small for gestational age.

Insulin action was assessed in thighs of five healthy young males who had one knee immobilized for 7 days by a splint. The splint was not worn in bed. Subjects also used crutches to prevent weight bearing of the immobilized leg. Immobilization decreased the activity of citrate synthase and 3-OH-acyl-CoA-dehydrogenase in the vastus lateralis muscle by 9 and 14%, respectively, and thigh volume by 5%. After 7 days of immobilization, a two-step euglycemic hyperinsulinemic clamp procedure combined with arterial and bilateral femoral venous catheterization was performed. Insulin action on glucose uptake and tyrosine release of the thighs at mean plasma insulin concentrations of 67 (clamp step I) and 447 microU/ml (clamp step II) was decreased by immobilization, whereas immobilization did not affect insulin action on thigh exchange of free fatty acids, glycerol, O2, or potassium. Before and during the clamp step I, lactate release was significantly higher in the immobilized than in the control thigh. Seven days of one-legged immobilization causes local decreased insulin action on thigh glucose uptake and net protein degradation.

This investigation evaluated regional differences in blood flow and oxygen consumption and their relationship in exercised muscle during recovery from exhaustive exercise. Five healthy men performed exhaustive one-legged cycling exercise. Positron emission tomography was used to measure blood flow, oxygen uptake, and oxygen extraction in the quadriceps femoris muscle before and after exercise. Regions of interest included five areas of the muscle (two proximal, one central, and two distal), which were evenly spaced across the muscle. Before exercise, blood flow and oxygen consumption decreased significantly (P < 0.05) in the direction from the proximal to the distal portions; blood flow declined from 2.0 +/- 0.5 to 1.4 +/- 0.3 ml x 100 g-1 x min-1, and oxygen consumption decreased from 0.21 +/- 0.04 to 0.17 +/- 0.02 ml.100 g-1x min-1. In contrast, these gradients in blood flow and oxygen consumption diminished during recovery after exercise. Consequently, there was a positive relationship between changes in blood flow and oxygen consumption in an exercised muscle during recovery after exercise (r = 0.963, P < 0.01). These changes became larger in the direction from proximal to distal portions: blood flow increased from 2.9 +/- 0.7 to 3.9 +/- 0.8 and oxygen consumption from 1.4 +/- 0.1 to 1.8 +/- 0.4 times resting values. These results suggest that hemodynamic variables are heterogeneous within a muscle both at rest and during recovery from exercise and that there is a systematic difference in these variables in the direction from proximal to distal regions within the quadriceps femoris muscle.