Two major determinants control the distribution of blood flow: vascular structure and vascular control, or mechanisms that control vascular resistance by modulating smooth muscle contraction and, therefore, diameter of arte-rioles. Both capillary and arteriole densities are greater in muscle regions composed primarily of oxidative fibers than in those composed primarily of glycolytic fibers. This structural difference between the vascularization of different muscle fiber types allows oxidative regions to have a lower vascular resistance and a higher capacity for blood flow. Thus structural differences in the vasculature between oxidative and glycolytic regions of muscle at least partially explain the greater maximal blood flows measured in oxida-tive regions.
There are a number of vascular control mechanisms that contribute to exercise hyperemia in skeletal muscle. These include extrinsic (from outside the tissue) or central mechanisms such as neural and humoral control and intrinsic (or local) mechanisms such as metabolic or myogenic control mechanisms. In general, extrinsic control mechanisms are more concerned with systemic blood pressure regulation, whereas intrinsic control mechanisms are more concerned with control of oxygen delivery to local areas. There is much evidence that differences in vascular control exist in regions of different fiber type and that this may help determine the heterogeneous distribution of blood flow during exercise.
Extrinsic Vascular Control Mechanisms
Under resting conditions blood flow to skeletal muscle is limited by sympathetically mediated constriction of arteries and arterioles in the muscle. The involvement of a neural mechanism in mediating exercise hyperemia is attractive because it would help to explain the rapid increase in blood flow at the onset of exercise. Possible mechanisms for exercise hyperemia include either sympathetic withdrawal or a sympathetically mediated vasodilation. However, neither of these mechanisms appears to play a role in exercise hyperemia. While sympathetic cholinergic nerves have been found in some vascular beds and in some species, it does not appear that sympathetic cholinergic vasodilation contributes to increases in skeletal muscle blood flow during exercise. Additionally, sympathetic nerve activity to skeletal muscle is not reduced during exercise. On the contrary, sympathetic nerve activity appears to be increased during exercise [1, 4], and this vasoconstrictor influence is thought to limit the vasodilation of exercise in order to help maintain systemic blood pressure. Thus withdrawal of sympathetic nerve activity does not mediate increases in blood flow during exercise.
A number of hormones or other bloodborne agents can cause changes in vascular diameters and therefore could help to mediate changes in muscle blood flow during exercise. The concentrations of most of these agents do not change rapidly enough to explain the large increases in muscle blood flow that occur with the onset of exercise, and most also do not appear to have much effect on blood flow during sustained exercise. Vasopressin and angiotensin II are two vasoconstrictor hormones that appear to play a role in the distribution of blood flow during exercise, but their primary effect is in constricting resistance vessels in non-contracting tissues of the gut region. One substance that may have an effect is acetylcholine, the neurotransmitter of muscle contraction and a well-known vasodilator, as there is some evidence that acetylcholine spillover from the myoneural junction may increase muscle blood flow . This is an attractive hypothesis for two reasons. First, as acetylcholine release from motor nerves would presumably increase with the initiation of exercise, this would provide a mechanism for the immediate increase in blood flow that occurs at the commencement of exercise. Second, as acetyl-choline release from motor nerves would presumably increase as exercise intensity increases, this would provide a mechanism for relating increases in blood flow to the intensity of exercise. However, other studies using blockers of acetylcholine receptors have failed to show any effect on blood flow to exercising skeletal muscle ; therefore, the role of acetylcholine in helping mediate exercise hyperemia is presently in doubt.
Intrinsic Vascular Control Mechanisms
The most attractive hypotheses regarding the mechanisms mediating exercise hyperemia involve metabolic vasodilation. According to this idea, the rate of muscle metabolism and the rate of muscle blood flow are coupled, presumably by one or more metabolites produced by the exercising muscle. These metabolites diffuse to the neighboring arterioles and when, present in sufficient quantities, cause vasodilation. The resultant increase in blood flow will help to "wash out" or carry away the metabolites, which reduces the vasodilator stimulus. Thus the level of vascular tone is the result of a constant tension between metabolite production and metabolite "washout."
The identity of the substance or substances causing metabolic vasodilation is not currently known, though a host of substances have been proposed and studied. To contribute to metabolic vasodilation, the vasodilator substance must meet at least two criteria: It must increase in concentration at the vascular wall as exercise intensity increases, and it must have the ability to relax vascular smooth muscle, either directly or indirectly . The list of potential metabolites involved includes adenosine and/or adenine nucleotides, potassium, hydrogen, carbon dioxide, reduced oxygen levels, tissue osmolality, inorganic phosphate, prostaglandins, and histamine.
Adenosine is a known vasodilator that directly causes smooth muscle relaxation and also acts indirectly via its action on the endothelium [1, 3, 7]. It is an attractive candidate for metabolic vasodilation because its production should be directly related to the rate of muscle metabolism as adenine nucleotides are broken down for their energy-bearing phosphate bonds. Indeed, adenosine appears to play a major role in dilation of the coronary circulation. But studies examining the role of adenosine in skeletal muscle hyperemia have not been definitive, with the majority of studies showing no role for adenosine [1, 3, 8]. Studies measuring adenosine concentrations in contracting muscle have generally found levels lower than that which would cause vasodilation , suggesting that adenosine plays at most a minor role in mediating increased blood flow, but adenosine is rapidly degraded and accurate sampling of adenosine at the smooth muscle cell is difficult [7, 8]. It appears that the inconclusive results may result at least in part from a regional heterogeneity in the action of adenosine. Studies examining adenosine's role at moderate exercise intensities in cats and miniature swine have found no effect of adenosine in glycolytic muscle but that adenosine causes vasodilation in primarily oxidative regions of muscle
[1, 3, 8]. At high exercise intensities, adenosine appears to cause vasodilation in all skeletal muscle types [1, 3, 8]. Furthermore, vascular reactivity to adenosine is greater in smaller than larger arterioles, and this may also complicate data interpretation . Thus the effects of adenosine in mediating exercise hyperemia appear to depend both on fiber type composition of muscle and on exercise intensity.
Potassium is a vasodilator of the microcirculation in low concentrations and it is released from both motor neurons and myocytes during membrane repolarization [7, 8]. Venous potassium levels rise during exercise, and venous potassium concentrations have been reported to correlate well with the reduction in vascular resistance in contracting muscle. However, the dilatory effect of potassium is transient, and the increase in potassium during exercise appears to be transient as well [7, 8]. This evidence suggests that potassium contributes little if at all to prolonged increases in blood flow during steady-state exercise, but that it may play a role in the initiation of the increase in blood flow at the onset of exercise.
Because one of the major functions of increasing blood flow is to increase O2 delivery and CO2 clearance, the notion that concentrations of these gases may directly regulate vascular tone is appealing. It is well known that in skeletal muscle reduced arterial o2 concentration causes vasodilation while increased o2 concentration causes vasoconstriction. Arachidonic acid metabolites, via the action of various cytochrome P-450 enzymes, may mediate at least part of the response of arteriolar smooth muscle to o2. But the role of o2 in mediating exercise hyperemia is unclear for at least two reasons. First, while tissue and venous Po2 values are reduced during muscle contraction, periarteriolar Po2 values decrease only temporarily at the onset of muscle contraction and return to resting levels after a few minutes . Second, it has been difficult experimentally to measure periarteriolar Po2 values in small arterioles where oxygen may have its largest effect . Thus a direct role for O2 in regulating vascular diameters during exercise is uncertain. That does not necessarily rule out O2 as a mediator of exercise hyperemia. The correlation between reductions in tissue and venous Po2 and reductions in vascular resistance suggests that o2 may have an indirect effect on vascular diameters through production of a secondary signal that is dependent on oxygen levels .
Although Co2 production is increased and venous Co2 concentrations increase markedly during exercise, Co2 has generally been considered to be a fairly weak vasodilator. It is possible for two reasons that this idea should be reconsidered. First, the potency of Co2 as a vasodilator may be enhanced in conjunction with reduced O2 levels . This suggests that there is a synergistic effect of O2 and CO2 and that examining Co2 alone does not provide a full picture of its effects. Second, Duling and Dora have pointed out that the Co2 concentration around arterial smooth muscle is unknown . While experiments have generally altered arterial CO2, the effects of gas diffusion, of shunting into veins, and of CO2 buffering are unknown, and the CO2 concentration in the microenvironment of the vascular smooth muscle cells of small arterioles is not known in these experiments, even when arterial and venous CO2 concentrations can be measured. Thus CO2 may play a larger role than previously recognized.
A number of other potential vasodilatory metabolites have been studied, and clear evidence is lacking that any of them play a major role in metabolic vasodilation. Hydrogen ions appear to be produced by contracting muscle and venous and muscular pH is decreased during exercise . However, it is not clear that periarteriolar pH changes significantly during exercise, and experimentally reducing periarteriolar pH fails to cause significant increases in blood flow. Inorganic phosphate is also produced during muscle contraction, but if it causes vasodilation its role is relatively minor . Indeed, the available evidence does not point to any single metabolic product of exercise as the primary mediator of exercise hyperemia. However, this does not rule out metabolic vasodilation as a major contributor to exercise hyperemia. Rather, metabolic vasodilation probably results from the combined effect of many substances working in concert. Part of this effect is likely due in a small way to the effect of these metabolites on plasma osmolality. The osmolality of venous blood is increased during exercise, presumably because of the increased production of adenosine, H+, K+, and a number of other molecules during exercise, and increases in osmolality have been shown to elicit a small degree of vasodilation. But the majority of the metabolic vasodilation occurring during exercise is probably due to the combined effect of numerous vasodilatory metabolic products.
It should be noted that the previous discussion regarding metabolic vasodilation refers only to the sustained steady-state period of exercise. The immediate increase in blood flow at the onset of exercise is unlikely to be affected by metabolic factors for at least three reasons. First, the accumulation of metabolites occurs at a slower rate than the initial increase in blood flow. Second, measurements of arteriolar diameters during muscle contraction indicate that vasodilation occurs at a slower rate than the increase in blood flow, with blood flow increasing within the first seconds of exercise and dilation taking 5 to 20 seconds following onset . Third, there is a poor correlation between work rate (and the associated rate of metabolism) and dilation at the onset of exercise, as demonstrated by the fact that changes in work rate do not necessarily alter the magnitude of the initial increase in blood flow . Thus metabolic vasodilation is thought to be a major contributor to the blood flow response to sustained exercise, but it is unlikely to contribute to the initial hyperemia at the onset of exercise.
Sympathetic nerve activity (SNA) increases at the onset of exercise, and the magnitude of the increase during sus tained exercise is directly related to the exercise intensity . The increased SNA mediates a variety of cardiovascular responses necessary to continue exercise for more than a few seconds, including an increased heart rate and stroke volume, and a redistribution of blood flow from noncon-tracting tissues to active skeletal muscle. The fact that there is significant vasodilation in active muscle despite the increased SNA directed to the muscle vasculature has led to the concept of functional sympatholysis. According to this idea, metabolites produced by the contracting muscle interfere with sympathetic vasoconstriction and allow the metabolic vasodilation to prevail. The mechanism of this inhibition of sympathetic vasoconstriction by metabolic products is probably twofold. First, some metabolites likely inhibit the release of norepinephrine from sympathetic nerve endings at the vessel wall (prejunctional inhibition) [1, 4]. Second, there is good evidence that metabolic products decrease alpha-adrenergic receptor sensitivity to norepinephrine. Both a-1 and a-2 receptors are located in larger arterioles, but only a-2 receptors are present in smaller arte-rioles, and the a-2 receptors are more affected by metabolic inhibition than the a-1 receptors . The net result of functional sympatholysis is that sympathetically mediated vasoconstriction occurs in noncontracting muscle regions while it is overridden in active areas by metabolic vasodilation. This provides an efficient means of directing blood flow specifically to regions of muscle that are active during exercise. Additionally, because the muscle regions active at a given intensity of exercise are heavily influenced by the fiber type composition of the muscle, functional sympathol-ysis contributes to the fiber type dependence of blood flow distribution.
Despite the production of vasodilatory metabolites and the vasodilation that occurs in active regions of skeletal muscle, the overriding of SNA in these regions is not complete [1, 3, 5, 8]. Rather, there is a constant tension between metabolic vasodilation and sympathetically mediated vasoconstriction, and the level of vascular tone at any time is a result of this tension. The resulting vasomotor tone is important both for the maintenance of fluid balance in active muscle and for the maintenance of systemic blood pressure . Total vasodilation in active regions would outstrip cardiac output and baroreceptor reflexes would be unable to maintain systemic blood pressure.
Because the mechanism for the initial hyperemia at the onset of exercise must be rapidly acting and because neural factors do not play a role, it is likely that mechanical factors associated with muscle contraction are involved in the early response. One mechanical factor is the myogenic response, which refers to the intrinsic property of vascular smooth muscle that causes it to contract when it is stretched. The result is that increased arteriolar distending pressures cause arterioles to constrict and decreased distending pressures cause dilation. Arterioles located within skeletal muscle are compressed during muscular contraction, which would be expected to reduce the transmural pressure in the vessel leading to decreased vascular distension, vasodilation, and increased blood flow. Studies utilizing increases in extravas-cular pressures to decrease vascular transmural pressure have yielded mixed results [1, 8], and the role of myogenic control in exercise hyperemia is uncertain.
A second category of mechanical factors has to do with the distortion of arterioles that occurs during muscle contraction. This distortion as the muscle shortens can elicit both passive and active vasomotor responses in the vascula-ture [5, 8]. Passive changes during muscle shortening occur as arterioles are twisted, kinked, and compressed, and as interbranch vessel lengths and bifurcation angles at branch points are altered by the changing geometry of the arteriolar network. The net effect of these passive changes on vascular resistance and blood flow is uncertain. Active changes in vasomotor tone also occur, as shortening of muscle causes vasodilation and lengthening causes vasoconstriction. These active changes are apparently caused by sympathetic nerves that are sensitive to changing muscle length and respond to increasing length by releasing norepinephrine, a well-documented vasoconstrictor . Both passive and active muscle length-dependent changes in vascular resistance may occur rapidly and are independent of muscle metabolism, and could thus be involved in hyperemic responses both at the onset of muscular contraction and during sustained exercise.
As noted earlier, the duty cycle of contracting skeletal muscle causes a cyclical compression of blood vessels within the muscle that leads to alternating periods of arterial inflow and venous outflow during exercise. The cyclical compression of blood vessels also increases the overall rate of blood flow through contracting muscle, a phenomenon known as the "muscle pump" [1, 3]. The compression of veins during muscle contraction expels blood from veins toward the heart, thus emptying veins of their blood volume. The small veins within skeletal muscle are tethered by connective tissue to the surrounding muscle and are pulled open as the muscle relaxes again. This creates a negative pressure within the veins and effectively increases the arterial-venous pressure gradient for blood flow through the muscle. This cycle is repeated with each contraction-relaxation cycle of muscle and acts as a pump that helps drive blood flow through contracting muscle. It has been estimated that the muscle pump can account for 30 to 60 percent of the increase in blood flow during moderate intensity muscle contraction [3, 8]. The cyclical compression also appears to have important effects on fluid clearance from the interstitial spaces via pumping action on the lymphatic vessels.
There are a number of important factors to consider regarding the muscle pump. First, the pump is dependent on the contraction-relaxation cycle. Therefore, it is active only during rhythmic muscle contractions, not during isometric contractions. Second, increases in blood flow due to the muscle pump do not result from vasodilation, that is, a change in vascular conductance. Rather the increased blood flow results from decreased pressures in the small veins and increased kinetic energy imparted to the blood [1, 3]. Thus this has sometimes been called an increase in "apparent vascular conductance." Third, the efficacy of the pump mechanism is dependent on the order of activation of different muscles, a factor that separates voluntary locomotory exercise from in situ and in vitro experimental models of muscle contraction. Fourth, the effectiveness of the muscle pump appears to be greater in deeper regions of muscle than in more superficial muscle regions. Because more oxidative muscle fibers tend to be located deeper and more glycolytic fibers are located superficially, the muscle pump appears to be more effective in regions composed primarily of oxida-tive muscle fibers than in regions composed primarily of more glycolytic fibers .
The huge importance of the endothelium in the control of blood flow has come to light in the past two decades. The endothelium plays an important role in the control of vascular tone and in the adaptation of the vasculature to chronic stimuli . The endothelium produces and releases a number of vasoactive substances that exert their effects by altering vascular smooth muscle tone. Nitric oxide has been the most studied of these substances and is very important in the regulation of basal vascular tone under resting circumstances in skeletal muscle. Whether NO or other endothelium-dependent dilators contribute to the functional hyperemia of exercise is less clear. Inhibition of nitric oxide synthesis has been shown in some preparations to reduce the hyperemic response to exercise, but other studies have not shown any effect. Additionally, in some cases when NO synthesis inhibition during exercise reduces the hyperemic response, the magnitude of the reduction in blood flow is similar to the reduction seen under resting conditions. These data suggest that it is basal synthesis of NO that is being blocked in these cases rather than exercise-specific production of NO . Interpretation of these data is complicated by the redundancy of control mechanisms in the arterial vascu-lature, that is, production of other vasodilator substances may compensate for inhibition of NO synthesis. A second complication is that although NO may not increase the magnitude of the hyperemic response to whole exercising limbs, it appears to be involved in the muscle fiber-type specific distribution of blood flow within the limb as blocking NO synthesis decreases blood flow to a greater degree in highly oxidative regions of muscle than in more glycolytic regions . A third complication in interpreting data in this area is that NO may exert a greater effect on small arteries and large arterioles than on smaller arterioles . Thus the current data regarding the role of the endothelium in contributing to exercise hyperemia are not definitive.
Traditional thinking about control of blood flow has usually located the origin of that control in the vascular wall or in the surrounding parenchymal tissue, but evidence collected in the past decade indicates that red blood cells (RBCs) play a role in determining their own destination [2, 10]. The oxygen saturation of hemoglobin is dependent on the surrounding Po2, and the level of oxygen-hemoglobin saturation appears to act as a built-in sensor of oxygen levels in the surrounding environment. Low concentrations of oxygenated hemoglobin stimulate the production and release of dilator substances by RBCs. There appear to be at least two dilator substances utilized in this process. First, low levels of oxygenated hemoglobin stimulate the production of ATP by RBCs, and this ATP may act as a vasodilator at the vascular wall, either directly or through some secondary process . Second, under hypoxic conditions RBCs also appear to produce and release NO . NO stimulates vascular smooth muscle guanylate cyclase production of cGMP and consequent vascular smooth muscle relaxation. Thus hypoxic conditions in contracting skeletal muscle are sensed by RBCs, which produce vasodilators that increase vascular conductance specifically in the hypoxic region. Finally, another function of hemoglobin is that it normally acts as a nitric oxide scavenger . Hypoxia is associated with inadequate blood flow and hemoglobin levels, and when hemoglobin concentrations are low the scavenging action of hemoglobin is also reduced. The levels of NO should, therefore, remain higher under these conditions, and the associated vasodilator stimulus should remain elevated. Thus both vasodilator production by RBCs and reduced NO scavenging by RBCs in hypoxic regions help to direct blood flow specifically to those areas that are most in need.
Although metabolically mediated vasodilation of small arterioles within the exercising muscle is an important step in increasing blood flow, the magnitude of the increase in blood flow requires that larger arterioles and feeding arteries located outside the muscle also dilate. It has been estimated that 40 to 50 percent of vascular resistance in skeletal muscle is located in the feed arteries outside of the muscle proper . Dilation of arterioles without concurrent dilation of upstream feed arteries would not allow the magnitude of increase in blood flow that occurs during exercise , but a coordinated dilation at all levels from small arterioles to feed arteries enables large increases in blood flow to occur. The mechanism for feed artery dilation cannot be metabolic because these feed arteries are located outside the muscle and are not directly exposed to the metabolic environment within the muscle. Three mechanisms have been proposed to mediate feed artery dilation: flow-induced dilation, retrograde propagation, and arterial-venous coupling.
Flow-induced dilation occurs when the flow velocity in a blood vessel increases, thereby increasing the shear stress of the blood against the endothelial cell wall. Theoretically, dilation of arterioles within the muscle during exercise would cause reduced resistance to flow within the muscle and increase the rate of flow through upstream vessels. However, most studies of flow-induced dilation have been done in cultured cell or in vitro experimental preparations, and it is not clear whether flow-induced dilation contributes to the hyperemia associated with exercise in vivo. First, it is not clear that wall shear stress increases during exercise, as a dilation that matches the increase in blood flow could maintain shear stress at a constant level. Second, flow-induced dilation of rat feed arteries in vitro occurs at very low levels of shear stress, levels that are lower than the calculated shear stress present in feed arteries under normal nonexercising conditions. If flow-induced dilation in vivo also occurs at shear stress levels this low, then flow-induced dilation probably helps to determine vascular tone at rest, but is most likely not involved in exercise-induced dilation of feed arteries.
Retrograde propagation of vascular signals involves the movement of electrical signals through gap junctions between cells [5, 7]. Thus a local depolarization of vascular smooth muscle or endothelial cells within the contracting muscle caused by muscle metabolites would be propagated along the arterioles out to the feed arteries. This mechanism, too, clearly occurs in cultured cell or in vitro experimental preparations and in response to electrically induced contractions in situ, although it is unclear whether the electrical signal is propagated via smooth muscle cells, endothelial cells, or both. The propagation is very rapid, but propagated vasodilation appears to travel only limited distances, and technical problems limit the study of propagated signals in vivo and under exercising conditions. Thus the contribution of a propagated vasodilation to feed artery dilation during voluntary exercise in conscious animals has not been definitively determined.
Arterial-venous coupling is a third mechanism that has been proposed to cause dilation of feeding arterioles during exercise . Anatomically, skeletal muscle feeding arteries lie in close proximity to one or more veins draining the same muscle. Thus a metabolite or a group of metabolites produced in the muscle during exercise may exit the muscle via venous blood flow and activate the venular endothelium. The venular endothelium then produces a signaling molecule, most likely prostacyclin , which diffuses to the paired artery and causes it to dilate. Alternatively, red blood cells (RBCs) in the veins may activate the venular endothe-lium. As noted above, RBCs are known to release ATP and NO under hypoxic conditions, conditions that are likely to exist in the veins during exercise, and ATP or NO from the RBCs may be the signal that activates venular endothelium during exercise.
Thus the mechanisms causing feed artery dilation have not been clearly determined. It is probable that these three
RBC release of ATP or NO Inhibition of SNA
RBC release of ATP or NO Inhibition of SNA
Flow-induced dilation Conducted dilation Venous-arteriolar communication
Flow-induced dilation Conducted dilation Venous-arteriolar communication
Altered vessel geometry & diameter
Increased blood flow
Figure 1 Schematic of potential mechanisms involved in skeletal muscle hyperemia at the onset of exercise and during sustained exercise. Exercise onset: As muscle shortens during contraction, vessels within the muscle are compressed and distorted. These physical forces may increase blood flow by increasing the kinetic energy of the blood (muscle pump), by causing passive changes in vascular geometry, or by causing active changes in vascular tone. Sustained exercise: Small arterioles are dilated by the products of muscle metabolism and by ATP or NO released from red blood cells (RBCs). The effects of sympathetic nerve activity (SNA) are reduced by metabolites from contracting muscle. Vasodilation spreads to larger arterioles and feed arteries by flow-induced dilation, upstream signal conduction, or venous-arteriolar communication. Vasodilation of all branches of the arterial vasculature combines to cause increased blood flow and oxygen delivery to contracting muscle.
factors, possibly in concert with other as yet undetermined factors, act in combination to elicit dilation. It may also be that the exact mechanism varies between different muscles or in regions of different muscle fiber type.
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