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SYMPOSIUM REPORT |
1 Copenhagen Muscle Research Centre, University Hospital and Copenhagen University, Rigshospitalet 7652, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
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Abstract |
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(Received 11 May 2007;
accepted after revision 27 June 2007;
first published online 19 July 2007)
Corresponding author B. Saltin: CMRC, Rigshospitalet 7652, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Email: bengt.saltin{at}rh.regionh.dk
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Introduction |
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Muscle mass-dependent skeletal muscle hyperaemia
In a series of experiments Harms et al. (1997, 1998) induced a reduced leg blood flow by increasing the respiratory muscle work during bicycle exercise, similar to the findings of Secher et al. (1977). There is less of a consensus, however, when using the exercise model that combines arm and leg bicycling. In most studies there is a trend for a lowering of the blood flow to the legs when the arms are added, but not in all subjects (Strange et al. 1990; Richter et al. 1992; Richardson et al. 1995). A satisfactory explanation is not at hand, but variation in exercise protocols and, possibly more importantly, proper methods to measure limb blood flow may have contributed to the lack of confirmatory work. Another possible limitation with the arm–leg exercise model is that it is technically demanding for the subjects and that their exercise capacity in arms and legs is quite uneven. As a consequence, a study on cross-country skiers was designed. Upper and lower body are trained similarly in cross-country skiers and they can perform on their skies with ‘only’ their legs or arms (double pooling) as well as combining arm–leg exercise (classical skiing; Fig. 1). The arm–shoulder and the leg peak muscle blood flows were determined separately, after which the skiers performed to exhaustion using the classical technique. Peak values for cardiac output were the highest when arm and leg exercise were combined (classical skiing), but the blood flow in the muscles of both upper and lower body became reduced (Table 1). This reduction in muscle perfusion was similar in upper and lower limbs and in the order of up to 20–30%, thus confirming the earlier findings of Secher et al. of vasoconstriction in vessels of intensely contracting skeletal muscles (Secher et al. 1977).
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Muscle hyperaemia and its regulation
There are probably few areas within the physiological field in which the mismatch is larger between the number and depth of studies performed and the firm knowledge that has been gained. This relates both to a possible neurogenic component in the regulation of muscle perfusion as well as possible locally produced substances eliciting the vasodilatation (Saltin et al. 1998). It is agreed that there is an interplay between neurogenic and local factors, but through the years the level of knowledge has advanced to understanding the principle for the regulation rather than the specific details of which factor or substance that plays a role and at which time point during the exercise.
One feature that is crucial in muscle hyperaemia is functional sympatolysis (Remensnyder et al. 1962), i.e. an inhibition of the sympathetically mediated vasoconstrictor response in active muscles as long as blood pressure can be maintained. Its existence is well documented in humans (Savard et al. 1989; Rosenmeier et al. 2003). Evidence can be drawn from experiments using the knee extensor model, where keeping one leg kicking at a given power output and adding the other leg and the arms causes no drop in muscle perfusion in spite of a steadily increasing sympathetic activity to the contracting muscle as judged by noradrenaline spillover (Savard et al. 1989). Indeed, maximal isometric contraction with the arms which induces a very marked enhancement of the muscle sympathetic nerve activity (MSNA) in the legs do not affect one-legged knee extensor muscle perfusion (Strange, 1999). The mechanism behind this phenomenon is thought to be a substance produced in the contracting muscle that inhibits 
-1 and or -2 activation by the noradrenaline released from the nerve terminals. Some experimental proof exists for NO to be the blocker of the -receptors, and the use of blockers like L-NMMA and L-NAME has provided support for NO in playing a role in rat muscles (Thomas & Victor, 1998). In humans, support for NO in playing a role in eliciting functional sympatholysis comes from studies of Duchenne muscular dystrophy patients who are lacking n-NOS. In these patients, muscle contraction does not appear to block for a lower body negative pressure-induced enhancement of sympathetic activity (Sander et al. 2000). Lately ATP has been proposed to be a player in causing functional sympatholysis (Rosenmeier et al. 2004). In favour of such role for ATP and its binding to the P2
receptors is the fact that the effect of elevating the sympathetic activation with tyramine can be blocked by infusion of ATP in the artery feeding the muscle without ATP entering the interstitium of the muscle (J.B. Rosenmeier & J. González-Alonso, unpublished observations).
Data on human skeletal muscle vasodilator substances
In a review by Clifford and Hellsten, a comprehensive status was given for past and present experimental evidence of various substances by which muscle hyperaemia is induced locally (Clifford & Hellsten, 2004). In the present article, some recent work will be highlighted focusing on NO, prostaglandin, EDHF and ATP. In our hands, blocking NO with L-NMMA or L-NAME had no or minimal effects on the magnitude of the blood flow during exercise. At rest before the exercise and early in recovery these blockers have a profound effect, reducing blood flow to a half or two-thirds (Rådegran & Saltin, 1999). The lack of response during the exercise could be due to too low a dose of the blocker, but also to the fact that other vasodilatory substances are given a larger role in inducing the hyperaemia. This latter view is favoured in the review by Clifford & Hellsten (2004). However, the number of reports supporting this concept is limited (Frandsen et al. 2000), although support can be found for redundancy from the fact that when multiple blockers are used, exercise-induced hyperaemia can be significantly reduced (Hillig et al. 2003). In experiments where L-NMMA is combined with indomethacin and sulphaphenazole to impair prostaglandin (PG2) and EET production, muscle blood flow was reduced by up to 25–30%. There is a dose–response effect as shown by the fact that low responders had a more substantial blood flow reduction when, for example, the amount of sulphaphenozol was increased (Hillig et al. 2003). In more recent studies, again using L-NMMA and indomethacin, but exchanging the sulphaphenozol with tetraethylammoniumchloride (TEA), the latter blocker added no further to the blood flow reduction observed with L-NMMA and indomethacin (Mortensen et al. 2007). It could be a question of dose or subtle differences between sulphaphenazole and TEA in their effectiveness in regard to the blocking of cytochrome P450, and thereby which EETs that are not produced.
Recently, ATP as a vasodilatator in skeletal muscle has drawn further attention. Already in the 1960s, Forrester and Lind proposed this possibility (Forrester & Lind, 1969), but ATP did not actually come into focus until the more recent work by Ellsworth and colleagues (Ellsworth et al. 1995). What makes ATP or a nucleotide quite similar to ATP attractive is the notion that it may have this dual effect, i.e. impairing sympathetically mediated vasoconstriction as well as having a direct dilatory effect on the microcirculation. In Ellsworth's work she points at the red cells, acting as the provider of ATP (Sprague et al. 2001). One hypothesis is that the fewer O2 binding sites on the haemoglobin molecule that are being occupied, the larger is the ATP release. Some support for this suggestion has been provided by the work of Gonzalez et al. using the knee extensor model and a complex combination of normoxia, hypoxia and hyperoxia with different degrees of CO blocking of Hb binding sites for O2 (Gonzáles-Alonso et al. 2002, 2006). At a given submaximal power output, blood flow was closely related to femoral venous oxygen content (rather than oxygen tension). Moreover, femoral venous plasma ATP concentration was in a hyperbolic manner a function of femoral venous oxyhaemaglobin content, being highest the lower the PO2 value (Gonzáles-Alonso et al. 2002). These data provide support for the notion of a role of the red blood cells as oxygen sensors in the contracting skeletal muscles, and a release of ATP from the red cells and its binding to P2Y-receptors to be the mechanism by which vasodilatation is induced.
A reasonable summary of our present knowledge of the regulatory mechanisms for the cardiovascular response to exercise could be: (1) Very high peak muscle perfusion in the range of 250–400 ml (100 g)–1 min–1 is observed in the thigh muscle of humans during intense exercise; (2) Vasodilatation in skeletal muscle is closely regulated to match oxygen demand. This is accomplished by the combined effect of inhibiting the noradrenaline released from terminals of the sympathetic nerves (functional sympatolysis) and vasodilatation induced by locally produced or released vasoactive substances. Exactly which these substances are has not yet been identified, but NO or ATP are discussed as inhibitors of the noradrenaline binding to the -receptors and a multitude of substances are known to experimentally cause vasodilatation of which NO, prostaglandin, EETs and ATP have been assigned a role in this presentation; and (3) The human cardiovascular system is not capable of supporting all muscles with an ample blood flow during more vigorous exercise when a large muscle mass is active (perhaps due to evolution and possibly an effect of the erect homo sapiens). As a result sympathetically mediated vasoconstriction does occur in feeding arteries in active upper and lower limb muscles – to maintain blood pressure – in intense combined arm and leg exercise.
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Footnotes |
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References |
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difference).
2000 m above sea level; unpublished). When the arms are added to the ongoing leg exercise, leg NA spillover is markedly elevated and in part overrides the locally induced vasodilatation in the legs (limb blood flow).