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00005768-199907000-0001500005768_1999_31_1019_shoemaker_adaptation_7report< 146_0_7_3 >Medicine & Science in Sports & Exercise© 1999 Lippincott Williams & Wilkins, Inc.Volume 31(7)July 1999pp 1019-1026Adaptation of blood flow during the rest to work transition in humans[Basic Sciences: Symposium: Muscle Blood Flow During Exercise: The Limits Of Reductionism]SHOEMAKER, J. KEVIN; HUGHSON, RICHARD L.Section Editor(s): Hughson, Richard L.chairSchool of Kinesiology, University of Western Ontario, London, Ontario, CANADA, N6A SC1; and Department of Kinesiology, University of Waterloo, Waterloo, Ontario, CANADA N2 L 3G1Submitted for publication June 1998.Accepted for publication October 1998.This work was supported by the Natural Sciences and Research Council of Canada. Kevin Shoemaker was a recipient of NSERC graduate and postdoctoral fellowships.The authors are grateful to Mike Tschakovsky and Maureen MacDonald for many stimulating discussions about the concepts of blood flow control.Address for correspondence: Kevin Shoemaker, Ph.D., School of Kinesiology, Room 3110 Thames Hall, University of Western Ontario, London, Ontario, Canada N6A SC1ABSTRACTAdaptation of blood flow during the rest to work transition in humans. Med. Sci. Sports Exerc., Vol. 31, No. 7, pp. 1019-1026, 1999. Beat-by-beat measurements show that limb blood flow rises rapidly and in a biphasic manner at the onset of rhythmic exercise in humans. In this review the time course of change in limb flow with the onset of exercise is described and the mechanisms that may or may not contribute to its regulation are discussed. The pumping action of contracting skeletal muscle appears to form an important regulator of increasing flow with the first contraction. However, evidence from human studies suggests that vasodilation begins with the first contraction. Whether this early dilation is regulated by neural recruitment of motor fibers and/or muscle contraction per se is discussed, but the mechanism(s) remains unclear. Finally, the contribution of endothelial-derived relaxation factors to the exponential increase in flow at the exercise onset is examined. Based on studies in humans with intra-arterial infusion of blocking drugs, neither acetylcholine, nitric oxide, nor prostaglandins appear to be essential for a normal dynamic flow response on going from rest to exercise. Overall, evidence from human studies supports the hypothesis that the rate of increase in blood flow during rhythmic voluntary exercise is closely coupled to motor unit recruitment with dilation beginning at the first contraction.Muscular contractions can evoke large increases in limb blood flow that are closely related to the oxygen uptake of the active tissue (1,59). Thus local feedback regulation of vascular tone appears to be an important factor in establishing the magnitude and distribution of oxygen transport within a muscle.Much of what we know about blood flow regulatory mechanisms has been derived from measurements made at rest, during steady-state exercise, or during the recovery phase from ischemia or static exercise. However, conditions in the muscle during steady-state exercise appear to be established early in the transition between rest and exercise (48) and are affected by the rate at which blood flow to the working muscle is increased (30). Therefore, it is during the adaptation phase between rest and steady-state exercise where the control of blood flow is likely to be most critical. Since humans are seldom at steady state, understanding the mechanisms that regulate adaptation of oxygen transport to changing energy demands will facilitate comprehension of conditions where adaptation to work is slowed, such as cardiovascular disease, prolonged bed rest, and aging.Investigation into non-steady-state conditions of flow in humans requires methods that have high temporal resolution, are not dependent upon limb position, and do not interfere with the flow response. Thermodilution methodology has recently been modified to obtain transient changes in leg venous outflow dynamics during cycling exercise (21). Recent advances in Doppler ultrasound techniques for measures of blood velocity and vessel diameter have allowed noninvasive yet accurate quantitative analysis of the arterial inflow kinetics during the transition between rest and exercise in legs and arms (17,46,68,80). Blood flow is then calculated as the product of blood velocity and vessel cross-sectional area. Such measurements, in combination with experimental methods that alter either the rate of increase in limb blood flow (i.e., blood flow kinetics) and/or factors that are believed to contribute to the modulation of vascular tone, have advanced exploration of the mechanisms that regulate blood flow adaptation in humans.Walløe et al. (17,80) were the first to demonstrate the use of Doppler ultrasound for measures of femoral artery blood flow velocity during mild knee extension contractions. These early studies demonstrated a rapid increase in both cardiac output and femoral artery blood velocity. More recently, beat-by-beat measures of mean blood velocity and frequent measures of vessel cross-sectional area by pulsed and echo Doppler ultrasound, respectively, have been made during dynamic hand grip (68,69), plantar flexion (46), and knee extension exercise (49,67,70). From these combined studies it became clear that the increase in limb blood flow with repeated contractions is very rapid and is biphasic in nature. In young, healthy humans forearm blood flow increases very rapidly during rhythmic contractions and reaches an initial plateau at about 5-7 s of exercise (Phase 1). At ∼15-20 s following the onset of contractions, a second but slower increase in mean blood velocity is observed which progresses toward a new steady-state level (Phase 2; Fig. 1).Figure 1-Limb blood flow increases rapidly at the onset of exercise in a biphasic manner. An initial plateau following 5-7 s of exercise (Phase 1) gives way to a more slowly increasing segment following ∼20 s (Phase 2) toward a new steady-state level.The potential factors that might influence blood flow at the onset of exercise are numerous and must act to alter either vascular tone (vascular conductance) and/or the pressure gradient across the capillary bed (Fig. 2). Current understanding of how these factors apply to steady-state contractions has been reviewed in detail (44,45). This review focuses on recent investigations into the possible factors that could influence the time course of increase in limb blood flow during the transition from rest to exercise in humans. The rapidity of the increase during the first 5-7 s of exercise might suggest that this component does not include vasodilation but rather is controlled by local mechanical factors; however, evidence is provided that suggests that complex vascular regulation begins with the first contraction. Phase 2 (i.e., following 20 s in Fig. 1) of the on-transient flow response appears to be under much tighter feedback regulation, possibly suggesting the additional contributions of metabolic and endothelial-derived regulatory factors.Figure 2-Limb blood flow (q) is determined by the interplay between several mechanical (top row) or nonmechanical (bottom row) factors that act directly on vascular smooth muscle to reduce (−) or increase (+) limb vascular conductance (VC). Limb flow will also increase if the pressure gradient (ΔP) across the capillary bed following contraction is enhanced by activation of the muscle pump (MP) or by an increase in perfusion pressure (PP). Further, VC can be altered by the sympathetic nervous system (SNS) following integration of opposing reflex signals arising from the baroreflex (BR) and chemoreflex (CR) and from higher brain centers; the role of central command in blood flow control is not clearly defined. In turn, some factors may act indirectly by augmenting (▪) or attenuating (○) the effect of other regulatory agents (dotted lines). The combination of these factors results in a net change in limb blood flow. CNS, central nervous system; PG, prostaglandins; NO, nitric oxide; βAR, beta-adrenergic receptor; αAR, alpha-adrenergic receptor; Pi, inorganic phosphate; La−, lactate; K+, potassium ion; ACh, acetylcholine.PHASE 1Tests of mechanical influences on the early and rapid increase in limb blood flow. The very rapid increase in limb blood flow during the first 5-7 s of exercise has led to the hypothesis that a mechanical influence of the muscle pump is instrumental in elevating flow at the initiation of contractions because venous pressure is reduced with the first contraction (56) and the hyperemia occurs before any known metabolic factor could influence the flow response. The muscle pump relies on the ability of muscular contractions to empty the veins so that venous pressure is reduced during the subsequent relaxation. Thus, the pressure gradient between the arterial and venous vessels is increased. This larger pressure gradient will facilitate an increase in blood flow independent of changes in vascular tone. For example, Patterson and Shepherd (55) showed that blood flow in a maximally dilated forearm could be doubled if rhythmic contractions were also performed. It follows that a larger venous pressure before a contraction will lead to a larger change in pressure gradient and flow following the contraction. Folkow et al. (18) showed that calf muscle blood flow during heavy plantar flexion contractions increased by ∼60% when the individual was tilted upright versus the supine position. Thus, it is apparent that a positive hydrostatic pressure and the pumping action of skeletal muscle can effectively raise muscle flow.Sheriff et al. (65) tested the hypothesis that the muscle pump is responsible for the early adaptation of blood flow. In instrumented dogs, these investigators were able to alter cardiac output, mean arterial pressure, and workload as the animals exercised on a treadmill. They (65) observed that, in the absence of changes in cardiac output or mean arterial pressure, contraction rate and not workload per se appeared to influence the early phase of blood flow adaptation. Thus, they concluded that the mechanical effect of muscle pumping action, as determined by the contraction rate, was responsible for this early phase of blood flow adaptation with metabolic influences associated with workload and work rate becoming evident following ∼10 s of exercise.In humans, Leyk et al. (46) measured femoral artery blood flow responses with Doppler ultrasound during calf contractions and showed that the initial hyperemic response was greater when the subject was seated upright than for the same exercise performed with the legs positioned above the head. These data support the idea that the muscle pump is responsible for the early flow adaptation with rhythmic contractions. However, the magnitude of change in limb blood flow during the early moments of exercise between the two body positions could not be explained solely on the basis of the altered hydrostatic pressure. These authors (46) suggested that some vasodilation had also occurred within the first few seconds of exercise.Changes in body posture will alter the hydrostatic component of blood pressure in the limbs but will also affect central hemodynamics that, in turn, may have influenced the results of Leyk et al. (46). To diminish contributions of central hemodynamics during investigations of vasodilation versus muscle pump contributions to the early phase of exercise hyperemia, we have used a supine handgrip exercise model with the arm positioned above or below the heart. This model results in minimal changes in cardiac output and arterial pressure during handgrip contractions. Importantly, venous volume is reduced with the arm positioned above the heart compared with that when the arm is positioned below the heart. Thus, it was expected that the muscle pump contribution to the rapid hyperemia with the exercise onset would be diminished in the position above the heart compared with the position below the heart. Also, the issue of contraction rate versus total work rate could be investigated systematically.The increase in forearm blood flow at 5 s following the onset of rhythmic contractions was greater with the arm positioned below the heart compared with above (71). In agreement with Leyk et al. (46), however, the ∼40% increase in hydrostatic pressure with the arm positioned below versus above the heart could not explain the 50-100% difference in the flow increase between the two positions. A critical observation of this study was that the time course of change in limb blood flow was identical for different combinations of workload and contraction rate that resulted in the same absolute work rate. It appeared, therefore, that the arterial inflow response to forearm contractions was coupled to the recruitment order and/or metabolic needs of the active tissue at all times during the exercise. These data suggest that local feedback regulation of vascular tone may begin as early as the first few seconds of contractions. Without local and rapid regulation of vascular tone, the muscle pump would be the primary mechanism to elevate blood flow by increasing the perfusion gradient across the capillary bed. In this case blood flow distribution at the exercise onset would not be related to muscle recruitment or the metabolic need of individual muscle fibers. Although the majority of vasodilation is likely to occur later in the exercise, any reduction in vascular tone with the first contraction would improve flow distribution to the active tissue and perhaps enhance the coupling of oxygen transport kinetics to the rate of increase in muscle oxygen uptake (30). An intriguing question is how such a rapid vasodilation might alter the action of the muscle pump.The idea of a rapid vasodilation is not new. As early as 1935, Anrep and von Saalfeld (3) observed that the increase in dog hindlimb blood flow following a single isometric contraction was rapid and graded with the duration of the contraction. They hypothesized that a factor released from the active muscle in proportion to the contraction duration was instrumental in establishing the early flow response. Also, direct observations of rodent microvessels revealed the early dilation became more rapid as the contraction intensity was increased (20,51). In humans Corcondillas et al. (12) assessed strain gauge measures of forearm blood flow following a single isometric contraction and noted that the hyperemia following the contraction was prolonged beyond the time expected to fill the emptied veins.To further address the issue of muscle pump versus vasodilatory contributions to the early increase in flow, Tschakovsky et al. (76) used Doppler ultrasound to compare the beat-by-beat hyperemic response with a single dynamic contraction of 1-s duration with a condition in which the veins were mechanically emptied by a pneumatic cuff placed about the forearm that was rapidly inflated for 1-s and then deflated (76). These tests were performed with the arm positioned either above or below the heart, as described above, to alter venous volume. It was observed that blood flow increased following the cuff inflation/deflation with the arm positioned below the heart but not above the heart, an observation that supports the muscle pump hypothesis. However, with the voluntary contraction, blood flow increased in both positions. In addition, the flow response to a voluntary contraction with the arm held below the heart was greater than to the cuff action alone. These data confirm that the muscle pump may exert a large influence on the rapid hyperemia at the onset of exercise and also argue that a very rapid vascular dilation contributes to the initial increase in exercise hyperemia.Mechanisms of early dilation. Early speculation about the cause(s) of the rapid dilation following the onset of exercise suggested that the compression of arterioles during a brief tetanic contraction of skeletal muscle resulted in a myogenic dilation (53). Subsequent investigations using in vitro canine gracilis muscle preparations discounted this hypothesis (6). Studies in humans also suggest that myogenic dilation cannot account for the rapid changes in flow at the onset of contractions. When the forearm was elevated above the heart to empty the veins and a cuff was inflated then deflated repeatedly over 1 min, there was no hyperemia (76). Thus vessel dilation in response to mechanical compression of these vessels could not have occurred.If the purpose of the rapid dilation is to enhance the coupling of muscle perfusion with muscle contraction, this (these) rapid vasodilator(s) would need to be related to recruitment of motor fibers, or muscle contraction. Early studies have shown that both the production and liberation of the vasodilator substance(s) must take place during the contraction to facilitate reduction in vasomotor tone and the subsequent hyperemia upon relaxation (3). Intravital microscopy measures of hamster cremaster muscle preparations have extended these conclusions with evidence that the recruitment of capillary networks was regulated by local muscle contraction (7). Further observations from hamster striated muscle (81) suggest that acetylcholine (ACh) released at neuromuscular junctions with neuromotor recruitment can diffuse to nearby arterioles and initiate a rapidly conducted vasodilatory signal. These findings provide a mechanism for earlier observations that exercise flow responses to partially curarized rat muscles, without simultaneous atropine treatment, were maintained at the same level as the control muscles (5). However, studies in dogs (54), rats (4), and humans (66), where intra-arterial infusions of atropine were used to diminish muscarinic receptor-mediated dilation, do not support the idea that ACh is an important contributor to exercise hyperemia dynamics. Nonetheless, evidence for the existence of both luminal and abluminal muscarinic receptors (58) suggests that ACh might play a role in vasoregulation. Thus, it must be considered that incomplete blockade of these muscarinic receptors by atropine might account for the negative results in these studies. Regardless, neuromuscular blockade has eliminated the hyperemic response to stimulated contractions in dogs (3) and to attempted voluntary contractions in humans (14), further discounting a role for ACh in the regulation of vascular tone in these species.In addition to the possibility that muscle activation may be coupled with a rapid local dilation, the potential for products of muscle contraction to alter the tone of nearby vascular tissue must also be considered. Many metabolites released from skeletal muscle during contraction are vasoactive. These have been reviewed (15,25,44,74). Metabolic regulation of muscle perfusion appears to involve either direct effects on vascular smooth muscle tone or by interference with adrenergic constrictor influences (44,64). However, it is generally believed that metabolic regulation of blood flow does not occur during the Phase 1 response but rather develops over time to assist in the maintenance of steady-state flow conditions (5,25,29).Of the many vasoactive products released from muscle during contractions, the one that could possibly evoke dilation following a single contraction is potassium released with skeletal muscle depolarization (27). Interstitial (73) and arterial accumulation of K+ (36,83) are linked with acute increases in blood flow. Ion-selective electrodes placed within the interstitium of skeletal muscle (28) or in the femoral vein (24) have shown that potassium release and accumulation occurs rapidly at the initiation of exercise in an intensity-dependent manner. Also, venous effluent blood concentrations of potassium correlate well with the blood flow response following ischemic exercise (34,75). Thus, it has been hypothesized that this cation may regulate vascular tone early in exercise (25). In support of this hypothesis Chen et al. (11) measured dog hindlimb arterial perfusion pressure during muscle contractions as an index of vascular tone before and after ouabain treatment to block potassium-induced alterations in vascular membrane potential. Ouabain had little effect on the magnitude of fall in resistance with contractions. However, ouabain treatment did delay the onset of the vascular response to electrical stimulation and the time required for perfusion pressure to reach a steady-state value during stimulation. Nonetheless, the contribution of potassium to exercise hyperemia dynamics remains unclear. Microelectrode measures of periarteriolar potassium concentrations from the cat gastrocnemius following both twitch and tetanic stimulation indicate that very small changes in interstitial levels of potassium develop during the first 10-20 s of exercise although there was substantial hyperemia (28). In addition, Wilson et al. (85) observed very small increases in venous potassium concentrations in spite of substantial hyperemia during mild forearm contractions.Neural regulation has also been speculated to facilitate an early exercise hyperemia. Honig and Frierson (29) observed that the dilation following a single contraction of isolated dog gracilis muscle occurred without detectable changes in muscle metabolites and was reduced with anesthestics. They (29) thereby proposed that this early dilation was neurogenically mediated. Human skeletal muscle is under tonic sympathetic tone and removal of this constrictor influence can double flow at rest (63). Therefore, sympathetic withdrawal at the onset of contractions (9) would enhance the flow response. However, brachial artery flow in the inactive arm was not changed during the transition from rest to exercise performed by the contralateral arm (68); systemic mean arterial blood pressure was not altered by this exercise protocol. Also, the early forearm blood flow response in both supine and upright postures was similar despite anticipated differences in sympathetic tone (33). Overall, evidence indicates that the increase in muscle blood flow during exercise is the result of local control rather than alterations in systemic sympathetic activity (45).In the absence of systemic changes in sympathetic outflow with the exercise onset, perhaps local inhibition of norepinephrine release with muscle activation could effectively disconnect vascular tissue from sympathetic constrictor tone following a single contraction. Potassium ion and adenine nucleotides (79) and acetylcholine (77,78) inhibit adrenergic neurotransmission at concentrations that are lower than those required to directly affect vascular smooth muscle tone. In addition, nitric oxide (86) and adenosine (64) appear to diminish the effects of sympathetic activation on vascular tone. Thus, it may be that the reduction in vascular tone within the first seconds of exercise is caused by a localized sympathoinhibition rather than a direct action of dilator influences on vascular tissue.To summarize, evidence suggests that in humans the muscle pump and an early vasodilation combine to establish the blood flow response within the first seconds of exercise. The rate of flow adaptation with the exercise onset in humans appears to be tightly coupled to the pattern of muscle activation, but the mechanism remains to be established. It is unlikely that this early dilatory response is related to the metabolism of the recruited fibers because short-term endurance training results in both a faster femoral artery blood velocity response (70) and also tighter metabolic coupling (22,23) at the onset of leg exercise. It is expected that training-induced alterations in muscle metabolism would reduce muscle metabolite production at the onset of contractions. Furthermore, reports of excess oxygen delivery at the onset of leg exercise (21) question the coupling of metabolism and early dilation and also highlight the continued uncertainty regarding regulation of vascular tone and blood flow distribution early in exercise.While the dilatory response during Phase 1 of the hyperemic adaptation to exercise is rapid, it is not adequate to achieve the steady-state blood flow required during exercise. This further dilatory response occurs in a delayed Phase 2 response.PHASE 2The exponential increase in flow that follows 15-20 s after the onset of exercise suggests that this second phase, more than Phase 1, is under feedback regulation. In addition to metabolic factors discussed above, local regulation of flow during this time might involve endothelial factors believed to be released following an increase in blood velocity and shear stress (60). Therefore, it is expected that the increased blood velocity during the first seconds of exercise may evoke production and release of endothelial-derived dilating factors that would contribute to the flow adaptation between rest and steady-state exercise. To date, the major dilatory endothelial-derived factors are believed to be prostaglandins (38) and nitric oxide (60).In a series of papers, Koller et al. (40-42) demonstrated that, in isolated rat arteriole preparations, endothelial-derived prostaglandins were important vasodilators. The early release of PG following an increase in blood velocity (38), and evidence that prostaglandins may exert control over reactive hyperemia responses (10,13,35) prompted our investigation of the hypothesis that prostaglandin release may enhance the rate of adaptation for blood flow to exercise in humans, particularly following ∼15 s of exercise. In a placebo controlled study, subjects consumed 1200 mg·d−1 of ibuprofen for 2 d to diminish prostaglandin synthesis and then performed handgrip contractions while the flow response was monitored by Doppler ultrasound (69). Although prostaglandin synthesis was reduced, as indicated by slowed platelet aggregation times, the overall flow response was not altered at any time during the exercise. Thus, it appeared that in humans prostaglandins were not essential in establishing the time course or magnitude of change in forearm blood flow on going from rest to exercise. These data were in contrast to earlier observations that the inhibition of prostaglandin synthesis in humans resulted in small alterations to limb flow under steady-state conditions (83).In humans, nitric oxide (NO) has been shown to affect limb blood flow at rest (57,84) and during steady-state exercise (15). Thus, NO may also modulate the time course of change in blood flow with the onset of exercise. NO is released in human vessels following passive increases in flow (32) by a shear stress mechanism. Also, neurally released ACh has been shown to stimulate muscarinic receptors on the vascular endothelium of coronary vessels leading to the release of NO (8). In addition, local release of ACh from neighboring endothelial cells may also stimulate NO production and release (52).To investigate the interaction of ACh and NO in human blood flow regulation, we studied the adaptation of exercise hyperemia to rhythmic hand grip exercise before and after combined intra-arterial infusions of atropine and of atropine + NG-monomethyl-L-arginine (L-NMMA) (66). At rest, FBF was reduced by atropine and was further reduced by atropine + L-NMMA. During exercise, FBF was reduced by atropine treatment with no further effect of atropine + L-NMMA. However, intra-arterial infusion of atropine alone or of atropine plus L-NMMA did not alter the rate or magnitude of the increase in FBF above rest. It was concluded that while both ACh and NO mechanisms contribute to FBF levels at rest and that a cholinergic mechanism contributes to exercise FBF, neither Ach nor NO are essential for the maintenance of a normal time course of exercise hyperemia with the onset of rhythmic contractions.The reason for the discrepancy regarding the role of NO in regulating exercise hyperemia may result, in part, from the methods employed to measure blood flow. Strain gauge plethysmography requires cessation of exercise so that the measured flow probably reflects postexercise reactive hyperemia rather than exercise flow during rhythmic contractions. Importantly, repeated experiments support the role of NO during reactive hyperemia (16,31) and following exercise (66). However, the periodic interruption of flow by the muscular contraction during rhythmic exercise may reduce the shear stress-induced release of NO.Vascular dilation appears to be initiated in the smallest microvessels (51,61) with the dilatory signal progressing upstream to include feed arteries (43,82). In this manner the distribution of flow is regulated by the microvessels, whereas the magnitude of flow and vascular resistance is adjusted by feed artery dilation (43,62). To examine the role of conduit vessel responses to flow dynamics, we have used combined echo and pulsed Doppler techniques to follow changes in brachial artery diameter and blood flow velocity, respectively, during the transition from rest to dynamic handgrip exercise. When 2.16 W, but not 1.62 W rhythmic work was performed, a progressive vasodilation of the brachial artery was observed for exercise beyond 60 s (68). This dilation was independent of arm position (perfusion pressure) and could not be related to the time course of change in blood flow. Therefore, flow-induced dilation could not have been responsible for this delayed conduit vessel dilation, in contrast to observations made during passive increases in flow (2,47,72). These observations are consistent with those of Hilton et al., (26) who concluded that femoral artery dilation during cat hindlimb contractions was a result of a conducted vasodilatory signal originating from microvessels embedded within the active skeletal muscle. Data such as these support the hypothesis that tissue metabolic requirements form a critical factor in regulating vascular tone as exercise continues, even at the conduit vessel level. This is in contrast to the early dilation that appears to associated with the pattern of motor unit recruitment.SUMMARYOn going from rest to exercise there is a rapid increase in limb blood flow. It appears that even during the adaptation stage on going from rest to exercise blood flow is regulated by multiple and redundant mechanisms. These potential regulators of the time course for exercise hyperemia in humans are shown in Figure 3. With sufficient venous blood pressure and volume, the muscle pump makes a considerable contribution to the magnitude of increase in flow following the first contraction. However, evidence is accumulating to support the hypothesis of a rapid vasodilation that occurs within 2 s of the first contraction. The mediator(s) of this dilation has yet to be determined but must be related to muscle recruitment and/or contraction. Neither ACh, NO, nor prostaglandins appear to be essential to achieve the normal time course of exercise hyperemia on going from rest to exercise in humans. However, these substances may have a role in establishing baseline vascular tone which, in turn, will likely regulate the effectiveness of the muscle pump. In addition, altered baseline vascular tone may modify the magnitude of vasodilation achieved for a given level of dilatory stimuli and influence the steady-state blood flow response at rest and during exercise (37).Figure 3-Working hypothesis for the control of limb blood flow adaptation following the onset of contractions in humans. Limb blood flow (q) is the product of vascular conductance (VC) and the pressure gradient across the capillary bed (ΔP). In Phase 1 the flow response in the first 5-7 s of exercise is determined primarily by a change in ΔP by the muscle pump in combination with a smaller change in vascular conductance resulting from vasodilation. The mechanism of the early dilation is unknown but may involve either potassium ion (K+) or acetylcholine (ACh). Greater feedback regulation of the flow response is likely to begin in Phase 2 where adenosine, endothelial-derived dilators, and metabolic factors may exert greater changes in vascular conductance. PG, prostaglandins; NO, nitric oxide.FUTURE DIRECTIONSQuestions remain regarding flow regulation during the transition phase between rest and exercise in humans.1. Experiments in animals (19,39) and in patients who exhibit endothelial dysfunction (87) provide evidence that a functional endothelial layer is critical for the normal flow responses, at least following ischemia or following infusion of vasoactive drugs. Thus, an important step will be to examine whether the endothelial lining as a whole is important for a normal blood flow response during rhythmic contractions rather than any of the individual compounds released by this layer. It may be that individually endothelial-derived vasodilators exert immeasurable effects on exercise hyperemia but that together their contribution is substantial.2. The effect that locally released ACh and/or potassium ion have on local norepinephrine release and vascular tone in humans remains to be clarified. 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KEVIN; HUGHSON, RICHARD L.Basic Sciences: Symposium: Muscle Blood Flow During Exercise: The Limits Of Reductionism731InternalMedicine & Science in Sports & Exercise200133181-91JAN 2001Vascular smooth muscle: integrator of vasoactive signals during exercise hyperemiaHAROLD LAUGHLIN, M; KORZICK, DH & Science in Sports & Exercise10.1249/MSS.0b013e31815ef29b2008403462-474MAR 2008Control of Oxygen Uptake during ExercisePOOLE, DC; BARSTOW, TJ; MCDONOUGH, P; JONES, AM & Science in Sports & Exercise20043681357-1363AUG 2004Effect of Exercise Intensity on Relationship between V̇O2max and Cardiac OutputLEPRETRE, P; KORALSZTEIN, J; BILLAT, VL & Science in Sports & Exercise10.1249/01.mss.0000177471.65789.ce20053791559-1566SEP 2005Dynamics of Muscle Microcirculatory Oxygen ExchangePOOLE, DC; BEHNKE, BJ; PADILLA, DJ & Science in Sports & Exercise10.1249/01.mss.0000230341.86870.4f200638101811-1818OCT 2006Muscle Blood-Flow Dynamics at Exercise Onset: Do The Limbs Differ?TSCHAKOVSKY, ME; SAUNDERS, NR; WEBB, KA; O'DONNELL, DE