Nitric oxide and prostaglandins influence local skeletal muscle blood flow during exercise in humans: coupling between local substrate uptake and blood flow

Synergic action of nitric oxide (NO) and prostaglandins (PG) in the regulation of muscle blood flow during exercise has been demonstrated. In the present study, we investigated whether these vasodilators also regulate local blood flow, flow heterogeneity, and glucose uptake within the exercising skeletal muscle. Skeletal muscle blood flow was measured in seven healthy young men using near-infrared spectroscopy and indocyanine green and muscle glucose uptake using positron emission tomography and 2-fluoro-2-deoxy-D-[(18)F]glucose without and with local blockade of NO and PG at rest and during one-legged dynamic knee-extension exercise. Local blockade was produced by infusing nitro-L-arginine methyl ester and indomethacin directly in the muscle via a microdialysis catheter. Blood flow and glucose uptake were measured in the region of blockade and in two additional regions of vastus lateralis muscle 1 and 4 cm away from the infusion of blockers. Local blockade during exercise at 25 and 40 watts significantly decreased blood flow in the infusion region and in the region 1 cm away from the site of infusion but not in the region 4 cm away. During exercise, muscle glucose uptake did not show any regional differences in response to blockade. These results show that NO and PG synergistically contribute to the local regulation of blood flow in skeletal muscle independently of muscle glucose uptake in healthy young men. Thus these vasodilators can play a role in regulating microvascular blood flow in localized regions of vastus lateralis muscle but do not influence regional glucose uptake. The findings suggest that local substrate uptake in skeletal muscle can be regulated independently of regional changes in blood flow.     

The response of muscle interstitial prostaglandin E(2)(PGE(2)), prostacyclin I(2)(PGI(2)) and thromboxane A(2)(TXA(2)) levels during incremental dynamic exercise in humans determined by in vivo microdialysis.

The microdialysis in vivo technique allows the isolation, purification and quantitative determination of bioactive molecules with low molecular weight (<20.000 Da) from interstitial fluid (IF) of the muscles. PGE(2)and PGI(2)are vasodilator local hormones, while the TXA(2)is a vasoconstrictor. PGI(2)and TXA(2)are unstable and convert to stable products 6-keto-PGF(1a)and TXB(2), respectively. The purpose of this study was to evaluate the response of PGE(2), PGI(2)and TXA(2)in the IF of human muscle (vastus lateralis) during dynamic exercise with a cycle ergometer. In this study two microdialysis probes were inserted with CMA-60 microdialysis catheters into the vastus lateralis muscle of the right leg of eight healthy volunteers aged 24.1+/-2.1 years, height 177.5+/-1.5 cm and body weight 78.1+/-2.4 kg. After insertion the microdialysis probes perfused at a rate of 3.0 microl/min with Ringer acetate solution. The dialysate fluid was collected a) during the 30' rest period, b) during the 30' exercise period at 100 watts, c) during the 30' exercise period at 150 watts and d) during the 30' rest period after exercise. Our measurements (by the RIA method) showed that the levels of PGE(2)and 6-keto-PGF(1a)in the I.F. of the vastus lateralis muscle increased significantly, while there was a significant decrease in TXB(2)during exercise. The changes in the above biomolecules were increased proportionately with the strain of the subject's muscle. Conclusion: Dynamic exercise of the muscles produces a local increase of the vasodilators PGE(2)and PGI(2)while the vasoconstrictor TXA(2)is reduced in the IF of the muscles. This is further evidence that exercise induces propitious biochemical changes. Furthermore, the muscle production of arachidonic acid metabolites during exercise depends on the intensity of the exercise.     

The role of the cyclooxygenase products in evoking sympathetic activation in exercise

Animal studies suggest that prostaglandins in skeletal muscles stimulate afferents and contribute to the exercise pressor reflex. However, human data regarding a role for prostaglandins in this reflex are varied, in part because of systemic effects of pharmacological agents used to block prostaglandin synthesis. We hypothesized that local blockade of prostaglandin synthesis in exercising muscles could attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing exercise. Blood pressure (Finapres), heart rate, and MSNA (microneurography) were assessed in 12 young healthy subjects during static handgrip and postexercise muscle ischemia (PEMI) before and after local infusion of 6 mg of ketorolac tromethamine in saline via Bier block (regional intravenous anesthesia). In the second experiment (n = 10), the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased the prostaglandins synthesis to approximately 33% of the baseline. After ketorolac Bier block, the increases in MSNA from the baseline during the fatiguing handgrip was significantly lower than that before the Bier block (before ketorolac: Delta502 +/- 111; post ketorolac: Delta348 +/- 62%, P = 0.016). Moreover, the increase in total MSNA during PEMI after ketorolac was significantly lower than that before the Bier block (P = 0.014). Saline Bier block had no similar effect. The observations indicate that blockade of prostaglandin synthesis attenuates MSNA responses seen during fatiguing handgrip and suggest that prostaglandins contribute to the exercise pressor reflex.     

The response of muscle interstitial F2-isoprostane (8-ISO-PGF2alpha) during dynamic muscle contractions in humans

8-Iso-prostaglandin F2alpha (8-iso-PGF2alpha) is a characteristic F2-isoprostane which is produced in humans via a free radical-catalysed lipid peroxidation mechanism of arachidonic acid, independent of the cycloxygenase pathway. The measurement of the plasma levels of 8-iso-PGF2alpha was shown to be the most reliable biochemical index of oxidant stress status in the human body. However, there is no reference in literature of local muscle interstitial 8-iso-PGF2alpha production during dynamic muscle contractions. The aim of the present study was to evaluate the response of 8-iso-PGF2alpha during intensive exercise with a cycle ergometer. Two microdialysis probes with CMA-60 microdialysis catheters were inserted into the vastus lateralis muscle of the right leg of six healthy male volunteers. After insertion, these microdialysis probes were attached to a perfusion pump that perfused ringer acetate solution at a rate of 0.3 microl/min. The dialysate fluid samples were collected: (a) during a 30 min rest period and (b) during a 30 min period of dynamic exercise with a cycle ergometer at 150 Watts. Our measurements showed that the levels of 8-iso-PGF2alpha in the interstitial fluid (IF) of the vastus lateralis muscle increase significantly during exercise (from 113.5 +/- 30.2 to 329.9 +/- 69.8 pg/ml, P = 0.05). In conclusion, dynamic muscle exercise produces a local increase of the IF levels of 8-iso-PGF2alpha due to local peroxidation injury of the contractive muscle. The microdialysis method is widely applied, easily repeated and it could contribute in evaluating the local lipid muscle peroxidation during intensive exercise.     

Bed rest attenuates sympathetic and pressor responses to isometric exercise in antigravity leg muscles in humans

Although spaceflight and bed rest are known to cause muscular atrophy in the antigravity muscles of the legs, the changes in sympathetic and cardiovascular responses to exercises using the atrophied muscles remain unknown. We hypothesized that bed rest would augment sympathetic responses to isometric exercise using antigravity leg muscles in humans. Ten healthy male volunteers were subjected to 14-day 6 degrees head-down bed rest. Before and after bed rest, they performed isometric exercises using leg (plantar flexion) and forearm (handgrip) muscles, followed by 2-min postexercise muscle ischemia (PEMI) that continues to stimulate the muscle metaboreflex. These exercises were sustained to fatigue. We measured muscle sympathetic nerve activity (MSNA) in the contralateral resting leg by microneurography. In both pre- and post-bed-rest exercise tests, exercise intensities were set at 30 and 70% of the maximum voluntary force measured before bed rest. Bed rest attenuated the increase in MSNA in response to fatiguing plantar flexion by approximately 70% at both exercise intensities (both P < 0.05 vs. before bed rest) and reduced the maximal voluntary force of plantar flexion by 15%. In contrast, bed rest did not alter the increase in MSNA response to fatiguing handgrip and had no effects on the maximal voluntary force of handgrip. Although PEMI sustained MSNA activation before bed rest in all trials, bed rest entirely eliminated the PEMI-induced increase in MSNA in leg exercises but partially attenuated it in forearm exercises. These results do not support our hypothesis but indicate that bed rest causes a reduction in isometric exercise-induced sympathetic activation in (probably atrophied) antigravity leg muscles.     

Changes in muscle size and architecture following 20 days of bed rest

Five healthy men carried out a program of head-down bed rest (BR) for 20 days. Before and after BR, a series of cross-sectional scans of the thigh were performed using magnetic resonance imaging, from which volumes of the quadriceps muscles were determined and physiological cross-sectional areas (PCSA) were calculated. Muscle thickness and pennation angles of the triceps brachii, vastus lateralis, and triceps surae muscles were also determined by ultrasonography. During BR, subjects performed unilateral isokinetic knee extension exercises every day. The contralateral limb served as a control. Decrease in PCSA after BR was greater in the control (-10.2 +/- 6.3%) than in the trained limb (-5.2 +/- 4.2%). Among the quadriceps, vastus intermedius in the control limb was predominantly atrophied by BR with respect to the volume and PCSA, and the rectus femoris showed the greatest training effect and retained its size in the trained limb. Decreases in muscle thicknesses in leg muscles were not prevented by the present exercise protocol, suggesting a need for specific exercise training for these muscles. Neither trained nor control muscles showed significant changes in pennation angles in any muscles after BR, suggesting that muscle architecture does not change remarkably by muscle atrophy by up to 10%.     

Local prostaglandin blockade attenuates muscle mechanoreflex-mediated renal vasoconstriction during muscle stretch in humans

During exercise, muscle mechanoreflex-mediated sympathoexcitation evokes renal vasoconstriction. Animal studies suggest that prostaglandins generated within the contracting muscle sensitize muscle mechanoreflexes. Thus we hypothesized that local prostaglandin blockade would attenuate renal vasoconstriction during ischemic muscle stretch. Eleven healthy subjects performed static handgrip before and after local prostaglandin blockade (6 mg ketorolac tromethamine infused into the exercising forearm) via Bier block. Renal blood flow velocity (RBV; Duplex Ultrasound), mean arterial pressure (MAP; Finapres), and heart rate (HR; ECG) were obtained during handgrip, post-handgrip muscle ischemia (PHGMI) followed by PHGMI with passive forearm muscle stretch (PHGMI + stretch). Renal vascular resistance (RVR, calculated as MAP/RBV) was increased from baseline during all paradigms except during PHGMI + stretch after the ketorolac Bier block trial where RVR did not change from baseline. Before Bier block, RVR rose more during PHGMI + stretch than during PHGMI alone (P < .01). Similar results were found after a saline Bier block trial (Delta53 +/- 13% vs. Delta35 +/- 10%; P < 0.01). However, after ketorolac Bier block, RVR was not greater during PHGMI + stretch than during PHGMI alone [Delta39 +/- 8% vs. Delta40 +/- 12%; P = not significant (NS)]. HR and MAP responses were similar during PHGMI and PHGMI + stretch (P = NS). Passive muscle stretch during ischemia augments renal vasoconstriction, suggesting that ischemia sensitizes mechanically sensitive afferents. Inhibition of prostaglandin synthesis eliminates this mechanoreceptor sensitization-mediated constrictor responses. Thus mechanoreceptor sensitization in humans is linked to the production of prostaglandins.     

The effect of unilateral isokinetic strength training on local adipose and muscle tissue morphology, thickness, and enzymes.

One-leg exercise of 5 weeks duration in 10 healthy middleaged women resulted in a significant increment of muscle force in the exercising leg and in a less, but at some angular velocities also significant, increase in the nonexercising leg. The thickness of subcutaneous tissue measured by ultrasound and skinfold caliper decreased, while muscle thickness increased in the exercising leg only. The increased thickness of muscle tissue was associated with an increase in the relative number and relative fiber area of type II fibers in the exercising leg. The mean fiber area of type IIB fibers increased significantly as well as the activity of lactate dehydrogenase and myokinase. The decrease of thickness of subcutaneous adipose tissue was not associated with a significant decrease in fat cell size and was probably due to geometrical factors secondary to hypertrophy of the underlying muscle. It is concluded that the relationship between lean and fat components of the human thigh is significantly influenced by changes in the activity of the thigh skeletal muscles, but a local dynamic strength training program can hardly be used for local emptying of the fat depot over the exercising muscles.     

Glutamate availability is important in intramuscular amino acid metabolism and TCA cycle intermediates but does not affect peak oxidative metabolism.

Muscle glutamate is central to reactions producing 2-oxoglutarate, a tricarboxylic acid (TCA) cycle intermediate that essentially expands the TCA cycle intermediate pool during exercise. Paradoxically, muscle glutamate drops approximately 40-80% with the onset of exercise and 2-oxoglutarate declines in early exercise. To investigate the physiological relationship between glutamate, oxidative metabolism, and TCA cycle intermediates (i.e., fumarate, malate, 2-oxoglutarate), healthy subjects trained (T) the quadriceps of one thigh on the single-legged knee extensor ergometer (1 h/day at 70% maximum workload for 5 days/wk), while their contralateral quadriceps remained untrained (UT). After 5 wk of training, peak oxygen consumption (VO2peak) in the T thigh was greater than that in the UT thigh (P<0.05); VO2peak was not different between the T and UT thighs with glutamate infusion. Peak exercise under control conditions revealed a greater glutamate uptake in the T thigh compared with rest (7.3+/-3.7 vs. 1.0+/-0.1 micromol.min(-1).kg wet wt(-1), P<0.05) without increase in TCA cycle intermediates. In the UT thigh, peak exercise (vs. rest) induced an increase in fumarate (0.33+/-0.07 vs. 0.02+/-0.01 mmol/kg dry wt (dw), P<0.05) and malate (2.2+/-0.4 vs. 0.5+/-0.03 mmol/kg dw, P<0.05) and a decrease in 2-oxoglutarate (12.2+/-1.6 vs. 32.4+/-6.8 micromol/kg dw, P<0.05). Overall, glutamate infusion increased arterial glutamate (P<0.05) and maintained this increase. Glutamate infusion coincided with elevated fumarate and malate (P<0.05) and decreased 2-oxoglutarate (P<0.05) at peak exercise relative to rest in the T thigh; there were no further changes in the UT thigh. Although glutamate may have a role in the expansion of the TCA cycle, glutamate and TCA cycle intermediates do not directly affect VO2peak in either trained or untrained muscle.     

Regulation of subcutaneous adipose tissue blood flow during exercise in humans

Regulation of subcutaneous adipose tissue blood flow (ATBF) remains poorly elucidated in humans, especially during exercise. In the present study we tested the role of adenosine in the regulation of ATBF adjacent to active and inactive thigh muscles during intermittent isometric knee-extension exercise (1 s contraction followed by 2 s rest with workloads of 50, 100, and 150 N) in six healthy young women. ATBF was measured using positron emission tomography (PET) without and with unspecific adenosine receptor inhibitor theophylline infused intravenously. Adipose regions were localized from fused PET and magnetic resonance images. Blood flow in subcutaneous adipose tissue adjacent to active muscle increased from rest (1.0 ± 0.3 ml·100 g(-1)·min(-1)) to exercise (P < 0.001) and along with increasing exercise intensity (50 N = 4.1 ± 1.4, 100 N = 5.4 ± 1.8, and 150 N = 6.9 ± 3.0 ml·100 g(-1)·min(-1), P = 0.03 for the increase). In contrast, ATBF adjacent to inactive muscle remained at resting levels with all intensities (～1.0 ± 0.5 ml·100 g(-1)·min(-1)). During exercise theophylline prevented the increase in ATBF adjacent to active muscle especially during the highest exercise intensity (50 N = 4.3 ± 1.8 ml·100 g(-1)·min(-1), 100 N = 4.0 ± 1.5 ml·100 g(-1)·min(-1), and 150 N = 4.9 ± 1.8 ml·100 g(-1)·min(-1), P = 0.06 for an overall effect) but had no effect on blood flow adjacent to inactive muscle or adipose blood flow in resting contralateral leg. In conclusion, we report in the present study that 1) blood flow in subcutaneous adipose tissue of the leg is increased from rest to exercise in an exercise intensity-dependent manner, but only in the vicinity of working muscle, and 2) adenosine receptor antagonism attenuates this blood flow enhancement at the highest exercise intensities.     

E and F alpha series prostaglandins in developing muscles

Prostaglandins are known to affect myoblast proliferation and fusion in vitro and are putative regulators of in vivo myogenesis. The levels of E and F alpha series prostaglandins in the thigh muscles of chicken embryos were measured by radioimmunoassays and correlated with indicators of muscle development. Just prior to the onset of secondary myogenesis, the amounts of PGE1, PGE2 and PGF1 alpha plus PGF2 alpha per mg of protein were high. In temporal association with myotube formation, the amount of PGE1 and PGE2 per mg of protein decreased. PGF alpha levels also fell, but at a slower rate than observed with the E series prostaglandins. The decreases in the amounts of prostaglandins per mg protein appeared to be due to a decline in the total amount of prostaglandin within each muscle. These observations are consistent with prostaglandins being one of the factors that controls in vivo muscle formation.     

Increase in interstitial interleukin-6 of human skeletal muscle with repetitive low-force exercise.

Interleukin (IL)-6, which is released from muscle tissue during intense exercise, possesses important metabolic and probably anti-inflammatory properties. To evaluate the IL-6 response to low-intensity exercise, we conducted two studies: 1) a control study with insertion of microdialysis catheters in muscle and determination of interstitial muscle IL-6 response over 2 h of rest and 2) an exercise study to investigate the IL-6 response to 20 min of repetitive low-force exercise. In both studies, a microdialysis catheter (cutoff: 3,000 kDa) was inserted into the upper trapezius muscle of six male subjects, and the catheters were perfused with Ringer-acetate at 5 microl/min. Venous plasma samples were taken in the exercise study. The insertion of microdialysis catheters into muscle resulted in an increase in IL-6 from 8 +/- 0 to 359 +/- 171 and 484 +/- 202 pg/ml after 65 and 110 min, respectively (P < 0.001). Similarly, in the exercise study, IL-6 increased to 289 +/- 128 pg/ml after a 55-min rest (P < 0.001). During the subsequent repetitive low-force exercise, muscle IL-6 further increased to 1,246 +/- 461 pg/ml and reached 2,132 +/- 477 pg/ml after a 30-min recovery (all P < 0.001). In contrast to this, plasma IL-6 did not significantly change in response to exercise. We conclude that upper extremity, low-intensity exercise results in a substantial increase in IL-6 in the interstitium of the stabilizing trapezius muscle, whereas no change is seen for plasma IL-6.     

Microdialysis and the measurement of muscle interstitial K+ during rest and exercise in humans.

The purpose of this study was to examine whether microdialysis and the internal reference thallium-201 ((201)Tl) could accurately measure muscle interstitial K+ (Ki+) before, during, and after exercise. The relative loss of (201)Tl and simultaneous relative recovery of K+ were measured in vitro for 12 microdialysis probes that were bathed in Ringer acetate medium and perfused at various flows (3-10 microl/min). (201)Tl loss was linearly related to K+ recovery, and their level of agreement was not different from zero. Microdialysis and (201)Tl were then used to measure Ki+ in the gastrocnemius medialis muscle of four humans during rest and static plantar flexion exercise. At rest, Ki+ was 3.9-4.3 mmol/l when the perfusate flow was 2 or 5 microl/min. During exercise, Ki+ increased from 6.9 +/- 0.4 to 7.5 +/- 0.3 mmol/l at low to high intensity and declined to 5.2 +/- 0.3 mmol/l after exercise. These results suggest that large changes in Ki+ in human skeletal muscle can be accurately measured by using microdialysis and (201)Tl.     

Two weeks of muscle immobilization impairs functional sympatholysis but increases exercise hyperemia and the vasodilatory responsiveness to infused ATP

During exercise, contracting muscles can override sympathetic vasoconstrictor activity (functional sympatholysis). ATP and adenosine have been proposed to play a role in skeletal muscle blood flow regulation. However, little is known about the role of muscle training status on functional sympatholysis and ATP- and adenosine-induced vasodilation. Eight male subjects (22 ± 2 yr, Vo(2max): 49 ± 2 ml O(2)·min(-1)·kg(-1)) were studied before and after 5 wk of one-legged knee-extensor training (3-4 times/wk) and 2 wk of immobilization of the other leg. Leg hemodynamics were measured at rest, during exercise (24 ± 4 watts), and during arterial ATP (0.94 ± 0.03 μmol/min) and adenosine (5.61 ± 0.03 μmol/min) infusion with and without coinfusion of tyramine (11.11 μmol/min). During exercise, leg blood flow (LBF) was lower in the trained leg (2.5 ± 0.1 l/min) compared with the control leg (2.6 ± 0.2 l/min; P < 0.05), and it was higher in the immobilized leg (2.9 ± 0.2 l/min; P < 0.05). Tyramine infusion lowers LBF similarly at rest, but, when tyramine was infused during exercise, LBF was blunted in the immobilized leg (2.5 ± 0.2 l/min; P < 0.05), whereas it was unchanged in the control and trained leg. Mean arterial pressure was lower during exercise with the trained leg compared with the immobilized leg (P < 0.05), and leg vascular conductance was similar. During ATP infusion, the LBF response was higher after immobilization (3.9 ± 0.3 and 4.5 ± 0.6 l/min in the control and immobilized leg, respectively; P < 0.05), whereas it did not change after training. When tyramine was coinfused with ATP, LBF was reduced in the immobilized leg (P < 0.05) but remained similar in the control and trained leg. Training increased skeletal muscle P2Y2 receptor content (P < 0.05), whereas it did not change with immobilization. These results suggest that muscle inactivity impairs functional sympatholysis and that the magnitude of hyperemia and blood pressure response to exercise is dependent on the training status of the muscle. Immobilization also increases the vasodilatory response to infused ATP.     

Skeletal muscle carnitine metabolism in patients with unilateral peripheral arterial disease.

Patients with peripheral arterial disease (PAD) have abnormalities of carnitine metabolism that may contribute to their functional impairment. To test the hypothesis that muscle acylcarnitine generation (intermediates in oxidative metabolism) in patients with PAD provides a marker of the muscle dysfunction, 10 patients with unilateral PAD and 6 age-matched control subjects were studied at rest, and the patients were studied during exercise. At rest, biopsies of the gastrocnemius muscle in the patients' nonsymptomatic leg revealed a normal carnitine pool and lactate content compared with control subjects. In contrast, the patients' diseased leg had higher contents of lactate and long-chain acylcarnitines than controls. The muscle short-chain acylcarnitine content in the patients' diseased leg at rest was inversely correlated with peak exercise performance (r = -0.75, P less than 0.05). With graded treadmill exercise, only patients who exceeded their individual lactate threshold had an increase in muscle short-chain acylcarnitine content in the nonsymptomatic leg, which was identical to the muscle carnitine response in normal subjects. In the patients' diseased leg, muscle short-chain acylcarnitine content increased with exercise from 440 +/- 130 to 900 +/- 200 (SE) nmol/g (P less than 0.05). In contrast to the nonsymptomatic leg, there was no increase in muscle lactate content in the diseased leg with exercise, and the change in muscle carnitine metabolism was correlated with exercise duration (r = 0.82, P less than 0.01) and not with the lactate threshold. We conclude that energy metabolism in ischemic muscle of patients with PAD is characterized by the accumulation of acylcarnitines.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibited skeletal muscle healing in cyclooxygenase-2 gene-deficient mice: the role of PGE2 and PGF2alpha.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat skeletal muscle injury. However, studies have shown that NSAIDs may be detrimental to the healing process. Mediated by prostaglandin F(2alpha) (PGF(2alpha)) and prostaglandin E(2) (PGE(2)), the cycloxygenase-2 (COX-2) pathway plays an important role in muscle healing. We hypothesize that the COX-2 pathway is important for the fusion of muscle cells and the regeneration of injured muscle. For the in vitro experiments, we isolated myogenic precursor cells from wild-type (Wt) and COX-2 gene-deficient (COX-2(-/-)) mice and examined the effect of PGE(2) and PGF(2alpha) on cell fusion. For the in vivo experiments, we created laceration injury on the tibialis anterior (TA) muscles of Wt and COX-2(-/-) mice. Five and 14 days after injury, we examined the TA muscles histologically and functionally. We found that the secondary fusion between nascent myotubes and myogenic precursor cells isolated from COX-2(-/-) mice was severely compromised compared with that of Wt controls but was restored by the addition of PGF(2alpha) or, to a lesser extent, PGE(2) to the culture. Histological and functional assessments of the TA muscles in COX-2(-/-) mice revealed decreased regeneration relative to that observed in the Wt mice. The findings reported here demonstrate that the COX-2 pathway plays an important role in muscle healing and that prostaglandins are key mediators of the COX-2 pathway. It suggests that the decision to use NSAIDs to treat muscle injuries warrants critical evaluation because NSAIDs might impair muscle healing by inhibiting the fusion of myogenic precursor cells.     

Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans

It is now generally accepted that alpha-adrenoreceptor-mediated vasoconstriction is attenuated during exercise, but the efficacy of nonadrenergic vasoconstrictor pathways during exercise remains unclear. Thus, in eight young (23 +/- 1 yr), healthy volunteers, we contrasted changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of the alpha(1)-adrenoreceptor agonist phenylephrine (PE) with that of the nonadrenergic endothelin A (ET(A))/ET(B) receptor agonist ET-1. Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20%, 40%, and 60% of maximal work rate (WR(max)). Drug infusion rates were adjusted for blood flow to maintain comparable doses across all subjects and conditions. At rest, PE infusion (8 ng x ml(-1) x min(-1)) provoked a rapid and significant decrease in leg blood flow (-51 +/- 3%) within 2.5 min. Resting ET-1 infusion (40 pg x ml(-1) x min(-1)) significantly decreased leg blood flow within 5 min, reaching a maximal vasoconstriction (-34 +/- 3%) after 25-30 min of continuous infusion. Compared with rest, an exercise intensity-dependent attenuation to PE-mediated vasoconstriction was observed (-18 +/- 5%, -7 +/- 2%, and -1 +/- 3% change in leg blood flow at 20%, 40%, and 60% of WR(max), respectively). Vasoconstriction in response to ET-1 was also blunted in an exercise intensity-dependent manner (-13 +/- 3%, -7 +/- 4%, and 2 +/- 3% change in leg blood flow at 20%, 40%, and 60% of WR(max), respectively). These findings support a significant contribution of ET-1 and alpha-adrenergic receptors in the regulation of skeletal muscle blood flow in the human leg at rest and suggest a similar, intensity-dependent "lysis" of peripheral ET and alpha-adrenergic vasoconstriction during dynamic exercise.     

Effects on Contralateral Muscles after Unilateral Electrical Muscle Stimulation and Exercise

It is well established that unilateral exercise can produce contralateral effects. However, it is unclear whether unilateral exercise that leads to muscle injury and inflammation also affects the homologous contralateral muscles. To test the hypothesis that unilateral muscle injury causes contralateral muscle changes, an experimental rabbit model with unilateral muscle overuse caused by a combination of electrical muscle stimulation and exercise (EMS/E) was used. The soleus and gastrocnemius muscles of both exercised and non-exercised legs were analyzed with enzyme- and immunohistochemical methods after 1, 3 and 6 weeks of repeated EMS/E. After 1 w of unilateral EMS/E there were structural muscle changes such as increased variability in fiber size, fiber splitting, internal myonuclei, necrotic fibers, expression of developmental MyHCs, fibrosis and inflammation in the exercised soleus muscle. Only limited changes were found in the exercised gastrocnemius muscle and in both non-exercised contralateral muscles. After 3 w of EMS/E, muscle fiber changes, presence of developmental MyHCs, inflammation, fibrosis and affections of nerve axons and AChE production were observed bilaterally in both the soleus and gastrocnemius muscles. At 6 w of EMS/E, the severity of these changes significantly increased in the soleus muscles and infiltration of fat was observed bilaterally in both the soleus and the gastrocnemius muscles. The affections of the muscles were in all three experimental groups restricted to focal regions of the muscle samples. We conclude that repetitive unilateral muscle overuse caused by EMS/E overtime leads to both degenerative and regenerative tissue changes and myositis not only in the exercised muscles, but also in the homologous non-exercised muscles of the contralateral leg. Although the mechanism behind the contralateral changes is unclear, we suggest that the nervous system is involved in the cross-transfer effects.     

Local sweating responses of different body areas in dehydration-hydration experiments

Five subjects performed intermittent exercise on a bicycle ergometer (25 min work, 5 min rest cycles for 2 hours, and 20 min work, 10 min rest cycles for a further hour) in a hot environment (air and wall temperatures = 36 degrees C; dew-point temperature = 10 degrees C; air velocity = 0.6 m.s-1). The relative mechanical work load was of 70 W (30% of the maximal aerobic capacity). Seven experimental tests were carried out in order to induce a plasma hypovolemia associated with either a plasma hypo- or hyperosmolarity. The preexercise level of body hydration was also manipulated by giving a diuretic, or by ingestion of 500 ml of isotonic electrolyte sucrose solution before the start of exercise. Continuous measurements were made of rectal and mean skin temperatures. The sweating responses of the chest and of the thigh (over the active muscles of the leg) were monitored from 4 sweat collection capsules highly ventilated. On each of these body areas, the local skin temperatures under one of the 2 capsules was kept at a constant level (37 degrees C). The effects of the level of body hydration on the sweating response only appear when a high local thermal clamp is imposed beneath the capsule. This local effect is particularly strong over the active muscles of the thigh. The influence of the preexercise hydration appears during dehydration tests. This effect is not significant when fluid is given to the subject during the exercise. The change in the sensitivity of the thermoregulatory system is more strongly associated with plasma osmolarity than hypovolemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of anti-inflammatory medication on the running-induced rise in patella tendon collagen synthesis in humans

NSAIDs are widely used in the treatment of inflammatory diseases as well as of tendon diseases associated with pain in sports and labor. However, the effect of NSAID intake, and thus blockade of PGE(2) production, on the tendon tissue adaptation is unknown. The purpose of the present study was to elucidate the possible effects of NSAID intake on healthy tendon collagen turnover in relation to a strenuous bout of endurance exercise. Fifteen healthy young men were randomly assigned into two experimental groups, with one group receiving indomethacin (oral 2 × 100 mg Confortid daily for 7 days; NSAID; n = 7) and a placebo group (n = 8). Both groups were exposed to a prolonged bout of running (36 km). The collagen synthesis NH?-terminal propeptide of type I (PINP) and PGE? concentrations were measured before and 72 h following the run in the patella tendon by microdialysis. The peritendinous concentrations of PINP increased significantly in the placebo group as a result of the run, as shown previously. PGE? levels were significantly decreased 72 h after the run compared with basal levels in the subjects treated with NSAID and unchanged in the placebo group. The NSAID intake abolished the adaptive increase in collagen synthesis in the patella tendon found in the placebo group in response to the prolonged exercise (P < 0.05). The present study demonstrates that intake of NSAID decreased interstitial PGE? and abolished the exercise-induced adaptive increase in collagen synthesis in human tendons.