Potential Local Mechanisms for Exercise-Induced Hypoalgesia in Response to Blood Flow Restriction Training.

Overall, there is a great need within sports medicine to ensure that athletes can return from injury in an efficient, yet thorough manner. It is crucial to not avoid necessary difficulties in this process but also to ensure time-efficient rehabilitation. One of the more promising techniques to achieve timely recovery is blood flow restriction (BFR) training. BFR training is a growing and novel development that could be a vital tool to lighten the burden of recovery from injury in athletes. BFR utilizes a pneumatic tourniquet to limit blood flow in specific areas of the body. The use of BFR has been shown to potentially enhance the analgesic effects of exercise-induced hypoalgesia (EIH). By limiting pain, athletes will be less burdened by mobility and loading exercises required for them to effectively return to play. In a field where time away from sports can have massive implications, the need for tools to assist in the acceleration of the rehabilitation process is vital. Much of the work that has already been done in the field has been able to exploit the benefits of EIH and further enhance the body's capabilities through BFR. Studies have compared EIH at low- and high-intensity settings utilizing BFR with both resistance and aerobic exercise. The results of these studies show comparable beta-endorphin levels with high-intensity exercise without BFR and low-intensity exercise with BFR. Low-intensity training with BFR had greater local pain relief, perhaps indicating the promising effects of BFR in enhancing EIH. By reviewing the current literature on this topic, we hope that further progress can be made to better understand the mechanism behind BFR and its ability to enhance EIH. Currently, local metabolites are a major focus for the potential mechanism behind these effects. Mas-related G-protein-coupled receptors (Mrgprs) contribute to local pain pathways via mast cell degranulation. Similarly, chemokine receptor 2/chemokine ligand 2 (CCR2/CCL2) triggers mast cell degranulation and inflammation-induced pain. Finally, pain-reducing effects have been linked to anti-inflammatory IL-10 signaling and anaerobic metabolites via transient receptor potential vanilloid 1 (TRPV1). Through a better understanding of these metabolites and their mechanisms, it is possible to further exploit the use of BFR to not only serve athletes recovering from injury but also apply this information to better serve all patients.

Arteriolar vasodilation involves actin depolymerization.

It is generally assumed that relaxation of arteriolar vascular smooth muscle occurs through hyperpolarization of the cell membrane, reduction in intracellular Ca2+ concentration, and activation of myosin light chain phosphatase/inactivation of myosin light chain kinase. We hypothesized that vasodilation is related to depolymerization of F-actin. Cremaster muscles were dissected in rats under pentobarbital sodium anesthesia (50 mg/kg). First-order arterioles were dissected, cannulated on glass micropipettes, pressurized, and warmed to 34°C. Internal diameter was monitored with an electronic video caliper. The concentration of G-actin was determined in flash-frozen intact segments of arterioles by ultracentrifugation and Western blot analyses. Arterioles dilated by ~40% of initial diameter in response to pinacidil (1 × 10-6 mM) and sodium nitroprusside (5 × 10-5 mM). The G-actin-to-smooth muscle 22α ratio was 0.67 ± 0.09 in arterioles with myogenic tone and increased significantly to 1.32 ± 0.34 ( P < 0.01) when arterioles were dilated with pinacidil and 1.14 ± 0.18 ( P < 0.01) with sodium nitroprusside, indicating actin depolymerization. Compared with control vessels (49 ± 5%), the percentage of phosphorylated myosin light chain was significantly reduced by pinacidil (24 ± 2%, P < 0.01) but not sodium nitroprusside (42 ± 4%). These findings suggest that actin depolymerization is an important mechanism for vasodilation of resistance arterioles to external agonists. Furthermore, pinacidil produces smooth muscle relaxation via both decreases in myosin light chain phosphorylation and actin depolymerization, whereas sodium nitroprusside produces smooth muscle relaxation primarily via actin depolymerization. NEW & NOTEWORTHY This article adds to the accumulating evidence on the contribution of the actin cytoskeleton to the regulation of vascular smooth muscle tone in resistance arterioles. Actin depolymerization appears to be an important mechanism for vasodilation of resistance arterioles to pharmacological agonists. Dilation to the K+ channel opener pinacidil is produced by decreases in myosin light chain phosphorylation and actin depolymerization, whereas dilation to the nitric oxide donor sodium nitroprusside occurs primarily via actin depolymerization.

A chronic physical activity treatment in obese rats normalizes the contributions of ET-1 and NO to insulin-mediated posterior cerebral artery vasodilation.

This study tested the hypotheses that obesity-induced decrements in insulin-stimulated cerebrovascular vasodilation would be normalized with acute endothelin-1a receptor antagonism and that treatment with a physical activity intervention restores vasoreactivity to insulin through augmented nitric oxide synthase (NOS)-dependent dilation. Otsuka Long-Evans Tokushima Fatty rats were divided into the following groups: 20 wk old food controlled (CON-20); 20 wk old free food access (model of obesity, OB-20); 40 wk old food controlled (CON-40); 40 wk old free food access (OB-40); and 40 wk old free food access+RUN (RUN-40; wheel-running access from 20 to 40 wk). Rats underwent Barnes maze testing and a euglycemic hyperinsulinemic clamp (EHC). In the 40-wk cohort, cerebellum and hippocampus blood flow (BF) were examined (microsphere infusion). Vasomotor responses (pressurized myography) to insulin were assessed in untreated, endothelin-1a receptor antagonism, and NOS inhibition conditions in posterior cerebral arteries. Insulin-stimulated vasodilation was attenuated in the OB vs. CON and RUN groups (P ≤ 0.04). Dilation to insulin was normalized with endothelin-1a receptor antagonism in the OB groups (between groups, P ≥ 0.56), and insulin-stimulated NOS-mediated dilation was greater in the RUN-40 vs. OB-40 group (P < 0.01). At 40 wk of age, cerebellum BF decreased during EHC in the OB-40 group (P = 0.02) but not CON or RUN groups (P ≥ 0.36). Barnes maze testing revealed increased entry errors and latencies in the RUN-40 vs. CON and OB groups (P < 0.01). These findings indicate that obesity-induced impairments in vasoreactivity to insulin involve increased endothelin-1 and decreased nitric oxide signaling. Chronic spontaneous physical activity, initiated after disease onset, reversed impaired vasodilation to insulin and decreased Barnes maze performance, possibly because of increased exploratory behavior.NEW & NOTEWORTHY The new and noteworthy findings are that 1) in rodents, obesity-related deficits in insulin-mediated vasodilation are associated with increased influence of insulin-stimulated ET-1 and depressed influence of insulin-stimulated NOS and 2) a physical activity intervention, initiated after the onset of disease, restores insulin-mediated vasodilation, likely by normalizing insulin-stimulated ET-1 and NOS balance. These data demonstrate that the treatment effects of chronic exercise on insulin-mediated vasodilation extend beyond active skeletal muscle vasculature and include the cerebrovasculature.

Positional differences in reactive hyperemia provide insight into initial phase of exercise hyperemia.

Studies have reported a greater blood flow response to muscle contractions when the limb is below the heart compared with above the heart, and these results have been interpreted as evidence for a skeletal muscle pump contribution to exercise hyperemia. If limb position affects the blood flow response to other vascular challenges such as reactive hyperemia, this interpretation may not be correct. We hypothesized that the magnitude of reactive hyperemia would be greater with the limb below the heart. Brachial artery blood flow (Doppler ultrasound) and blood pressure (finger-cuff plethysmography) were measured in 10 healthy volunteers. Subjects lay supine with one arm supported in two different positions: above or below the heart. Reactive hyperemia was produced by occlusion of arterial inflow for varying durations: 0.5 min, 1 min, 2 min, or 5 min in randomized order. Peak increases in blood flow were 77 ± 11, 178 ± 24, 291 ± 25, and 398 ± 33 ml/min above the heart and 96 ± 19, 279 ± 62, 550 ± 60, and 711 ± 69 ml/min below the heart (P < 0.05). Thus a standard stimulus (vascular occlusion) elicited different responses depending on limb position. To determine whether these differences were due to mechanisms intrinsic to the arterial wall, a second set of experiments was performed in which acute intraluminal pressure reduction for 0.5 min, 1 min, 2 min, or 5 min was performed in isolated rat soleus feed arteries (n = 12). The magnitude of dilation upon pressure restoration was greater when acute pressure reduction occurred from 85 mmHg (mimicking pressure in the arm below the heart; 28.3 ± 7.9, 37.5 ± 5.9, 55.1 ± 9.9, and 68.9 ± 8.6% dilation) than from 48 mmHg (mimicking pressure in the arm above the heart; 20.8 ± 4.8, 22.6 ± 4.4, 31.2 ± 5.8, and 49.2 ± 7.1% dilation). These data support the hypothesis that arm position differences in reactive hyperemia are at least partially mediated by mechanisms intrinsic to the arterial wall. Overall, these results suggest the need to reevaluate studies employing positional changes to examine muscle pump influences on exercise hyperemia.

Endothelial function and exercise training: evidence from studies using animal models.

This review summarizes and examines the evidence from experiments using animal models to determine the effect of endurance exercise training on endothelium-dependent dilation in the arterial circulation. The response of the endothelium to exercise training is complex and depends on a number of factors that include the duration of the training program, the size of the artery/arteriole, the anatomical location of the artery/arteriole, and the health of the individual. In healthy animals, short-term exercise training appears to cause enhanced endothelium-dependent dilation in some vascular beds, but it returns to normal levels as the duration of the training program increases. In general, evidence supports the notion that exercise training causes greater increases in endothelium-dependent dilation in various disease states than in healthy individuals. The evidence of a generalized effect of training on arterial endothelium in all regions of the body is inconsistent and appears to depend on the animal model used. Available results indicate that training duration, artery size, and anatomical location interact in ways not fully understood at this time to determine whether and to what extent endothelium-dependent dilation will be enhanced by exercise training.

Mechanical compression elicits vasodilatation in rat skeletal muscle feed arteries.

To date, no satisfactory explanation has been provided for the immediate increase in blood flow to skeletal muscles at the onset of exercise. We hypothesized that rapid vasodilatation is a consequence of release of a vasoactive substance from the endothelium owing to mechanical deformation of the vasculature during contraction. Rat soleus feed arteries were isolated, removed and mounted on micropipettes in a sealed chamber. Arteries were pressurized to 68 mmHg, and luminal diameter was measured using an inverted microscope. Pressure pulses of 600 mmHg were delivered for 1 s, 5 s, and as a series of five repeated 1 s pulses with 1 s between pulses. During application of external pressure the lumen of the artery was completely closed, but immediately following release of pressure the diameter was significantly increased. In intact arteries (series 1, n = 6) for the 1 s pulse, 5 s pulse and series of five 1 s pulses, the peak increases in diameter were, respectively, (mean +/-s.e.m.) 16 +/- 2, 14 +/- 2 and 27 +/- 3%, with respective times from release of pressure to peak diameter of 4.1 +/- 0.3, 4.6 +/- 0.7 and 2.8 +/- 0.4 s. In series 2 (n= 9) the arteries increased diameter by 15 +/- 2, 15 +/- 2 and 30 +/- 3% before and by 8 +/- 1, 8 +/- 1 and 21 +/- 2% after removal of the endothelium with air. The important new finding in these experiments is that mechanical compression caused dilatation of skeletal muscle feed arteries with a time course similar to the change in blood flow after a brief muscle contraction. The magnitude of dilatation was not affected by increasing the duration of compression but was enhanced by increasing the number of compressions. Since removal of the endothelium reduced but did not abolish the dilatation in response to mechanical compression, it appears that the dilatation is mediated by both endothelium-dependent and -independent signalling pathways.