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doi: 10.1152/japplphysiol.00895.2011111:1527-1538, 2011. First published 1 September 2011;J Appl Physiol

Darren P. Casey and Michael J. Joynerexercise: influence of available oxygenLocal control of skeletal muscle blood flow during

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Local control of skeletal muscle blood flow during exercise: influenceof available oxygen

Darren P. Casey1,2 and Michael J. Joyner1

Departments of 1Anesthesiology and 2Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota

Submitted 18 July 2011; accepted in final form 31 August 2011

Casey DP, Joyner MJ. Local control of skeletal muscle blood flow duringexercise: influence of available oxygen. J Appl Physiol 111: 1527–1538, 2011. Firstpublished September 1, 2011; doi:10.1152/japplphysiol.00895.2011.—Reductionsin oxygen availability (O2) by either reduced arterial O2 content or reducedperfusion pressure can have profound influences on the circulation, includingvasodilation in skeletal muscle vascular beds. The purpose of this review is to putinto context the present evidence regarding mechanisms responsible for the localcontrol of blood flow during acute systemic hypoxia and/or local hypoperfusion incontracting muscle. The combination of submaximal exercise and hypoxia pro-duces a “compensatory” vasodilation and augmented blood flow in contractingmuscles relative to the same level of exercise under normoxic conditions. A similarcompensatory vasodilation is observed in response to local reductions in oxygenavailability (i.e., hypoperfusion) during normoxic exercise. Available evidence sug-gests that nitric oxide (NO) contributes to the compensatory dilator response undereach of these conditions, whereas adenosine appears to only play a role duringhypoperfusion. During systemic hypoxia the NO-mediated component of thecompensatory vasodilation is regulated through a �-adrenergic receptor mechanismat low-intensity exercise, while an additional (not yet identified) source of NO islikely to be engaged as exercise intensity increases during hypoxia. Potentialcandidates for stimulating and/or interacting with NO at higher exercise intensitiesinclude prostaglandins and/or ATP. Conversely, prostaglandins do not appear toplay a role in the compensatory vasodilation during exercise with hypoperfusion.Taken together, the data for both hypoxia and hypoperfusion suggest NO isimportant in the compensatory vasodilation seen when oxygen availability islimited. This is important from a basic biological perspective and also haspathophysiological implications for diseases associated with either hypoxia orhypoperfusion.

hypoxia; hypoperfusion; vasodilation

DURING DYNAMIC MUSCLE CONTRACTIONS there is an increasedmetabolic demand that is matched closely by increases inskeletal muscle blood flow (exercise hyperemia) and oxygendelivery. Blood flow increases rapidly at the onset of contrac-tions and can increase up to 100-fold over resting values duringintense exercise (2). The mechanisms responsible for increas-ing blood flow at the onset of exercise as well as maintainingit over time involve a complex interaction between mechanicalfactors and various local metabolic and endothelial derivedsubstances that influence vascular tone (132). Over the lastseveral decades exercise hyperemia in general and the potentialmechanisms responsible for the regulation of flow to contract-ing skeletal muscles have been reviewed extensively (13, 33,35, 68, 75, 80, 81, 131, 152). These reviews have focusedprimarily on blood flow responses during exercise under nor-moxic conditions. However, reductions in oxygen (O2) avail-ability (i.e., hypoxia) bring about several cardiovascular ad-

justments and can have profound influences on the circulation.Along these lines, the mechanisms responsible for the localregulation of skeletal muscle blood flow during exercise arelikely enhanced and possibly different than those during nor-moxic exercise.

Therefore, the purpose of this review is to discuss how O2

availability can impact blood flow and vasodilation in con-tracting skeletal muscles. Although cardiac pumping capac-ity (especially during large muscle mass and/or high inten-sity exercise) can be important in the hyperemic response toexercise, the emphasis in this review is on the local mech-anisms regulating active muscle blood flow under conditionsof reduced O2 availability during submaximal exercise.Specifically, this review will focus on 1) how acute hypoxiaand hypoperfusion interact with exercise to govern thehyperemic responses in contracting muscles of humans and2) the local vasodilator signals involved in the regulation ofmuscle blood flow during acute systemic (hypoxia) andlocal (hypoperfusion) reductions in O2 availability. We willalso discuss the potential role of any systemic pressorresponse under these conditions.

Address for reprint requests and other correspondence: D. P. Casey, Dept. ofAnesthesiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail:[email protected]).

J Appl Physiol 111: 1527–1538, 2011.First published September 1, 2011; doi:10.1152/japplphysiol.00895.2011. Review

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SYSTEMIC HYPOXIA

Effect on Blood Flow to Resting Muscle

At rest acute exposure to moderate hypoxia elicits vasodi-lation and an augmented blood flow in skeletal muscle vascularbeds of young apparently healthy humans (9–11, 25, 26, 37,84, 124, 158, 160, 161). This vasodilation occurs despite theresting muscle being relatively overperfused, as evidenced bylimited O2 extraction (25, 26, 59). The augmented skeletalmuscle vasodilation in response to hypoxia also occurs despitean enhanced sympathetic vasoconstrictor activity (52, 83, 130,143). Evidence suggests that a reduced �-adrenergic respon-siveness associated with hypoxia is not responsible for thisdilation (37, 161). Local blockade of �-adrenergic receptors inthe forearm reveals a substantially greater vasodilator responseduring systemic hypoxia (158, 160). Thus activation of sym-pathetic vasoconstrictor nerves during hypoxia likely masksthe degree of vasodilation. It should be noted that other studieshave reported that hypoxia-mediated forearm vascular conduc-tance was unaffected by local blockade of sympathetic nerves(9) and �-adrenergic blockade (118). Taken together, vasodi-lation prevails over the vasoconstrictor response in determiningvasomotor tone during acute hypoxia in resting skeletal mus-cle.

A number of vasodilator substances or systems, includingbut not limited to �-adrenergic receptor activation, nitricoxide (NO), prostaglandins, and adenosine, have been im-plicated to be involved in hypoxic vasodilation at rest andhave been previously reviewed in detail (51). Briefly, weand others (10, 158, 160) have demonstrated that �-adren-ergic receptor activation is responsible for a substantialportion of the hypoxic vasodilation at rest. Moreover, alarge portion of the �-adrenergic receptor-mediated hypoxicvasodilation at rest occurs through a NO pathway (158).This is consistent with the NO-dependent nature of at leastsome of the vasodilator responses to �2-mediated vasodila-tion (31, 45). Along these lines, NO synthase (NOS) inhi-bition attenuates the hypoxic vasodilator response in thehuman forearm in some studies (11, 25) but not others (90).In the latter study, the investigators locally blocked �-ad-renergic receptors via intra-arterial infusions of propranololprior to the experimental trials with NOS inhibition andtherefore potentially masked the NO-mediated vasodilatorresponse that is observed in other studies without concurrent�-adrenergic blockade. Under similar conditions, singleinhibition of prostaglandin synthesis also did not attenuatethe vasodilator response to systemic hypoxia (90). However,the combined inhibition of NO and prostaglandins abolished thevasodilator response to hypoxia at rest, thus indicating asynergistic role between these two pathways in regulatingperipheral vascular tone and ultimately blood flow (90). Recentevidence suggests both interstitial and plasma adenosine stim-ulates NO and prostacyclin formation in the human leg undernormoxic conditions (103). Moreover, there is strong evidencein animals that adenosine plays a major role in hypoxia-induced skeletal muscle vasodilation (15, 100, 114, 115, 141).However, available data related to the contribution of adeno-sine in the hypoxic vasodilator response in human studies areconflicting (25, 26, 84).

Hypoxic Exercise

The combination of submaximal dynamic exercise and hyp-oxia produces a “compensatory” vasodilation and augmentedblood flow in contracting muscles (both quadriceps and fore-arm) relative to the same level of exercise under normoxicconditions (16, 26, 32, 122, 126, 160, 161). This augmentedvasodilation exceeds that predicted by a simple sum of theindividual dilator responses to hypoxia alone and normoxicexercise. Additionally, this enhanced hypoxic exercise hyper-emia is proportional to the hypoxia-induced fall in arterial O2

content, thus preserving muscle O2 delivery and ensuring it ismatched to demand (32, 49, 122, 126). Compensatory vaso-dilation is also observed when O2 availability is reduced bycarbon monoxide administration and/or experimentally in-duced anemia (48, 49, 121, 122). In this context, O2 deliv-ery, rather than blood flow, appears to be the regulatedvariable producing the augmented hyperemia during hy-poxic exercise (47).

Potential Causes of Compensatory Vasodilation

Acute exposure to systemic hypoxia results in substantialreductions in arterial O2 content (CaO2

) as well as arterial O2

tension (PaO2). Theoretically, reductions in each of these vari-

ables could serve as a signal for the compensatory vasodilationobserved during hypoxic exercise (77, 78, 122). Roach andcolleagues (122) reported that blood flow and O2 delivery tothe lower limbs during rhythmic two-legged knee extensionexercise with normoxia, anemia, hypoxia, and anemia � hyp-oxia were dependent on CaO2

not PaO2. Evidence that a low

PaO2alone does not cause vasodilation was based on the

observation of similar limb blood flows in the two conditions(hypoxia and anemia) with nearly identical CaO2

but widelydifferent PaO2

(�40 vs. �105 mmHg). In a subsequent study,leg blood flow and vascular conductance were shown to betightly coupled to the level of arterial oxyhemoglobin, regard-less of a normal or an 11-fold difference in PaO2

(47–538mmHg) (49). Taken together, these results strongly suggestthat factors sensitive to CaO2

serve as the signal for thecompensatory increases in skeletal muscle blood flow andvasodilation during hypoxic exercise.

Regulation of the Vascular Tone During Hypoxic Exercise

Vasodilator line-up: usual suspects? Several vasodilatorpathways have been proposed and examined as likely regula-tors of skeletal muscle blood flow in response to changes inCaO2

. Increases in arterial epinephrine are evident with acuteexposure to systemic hypoxia and are increased further duringsubmaximal cycling exercise (92). Additionally, an intensity-dependent rise in arterial epinephrine occurs during incremen-tal forearm exercise, suggesting that �-adrenergic receptor-mediated vasodilation might contribute to the augmented hy-poxic exercise hyperemia (161). Wolfel and colleagues (163)originally demonstrated that �-adrenergic blockade reduced O2

delivery to the contracting muscles during submaximal exer-cise at altitude, but was compensated for by an enhanced tissueO2 extraction. However, the use of systemic �-blockade re-duced cardiac output and likely engaged vasoconstricting car-diovascular reflexes, therefore making it difficult to determinewhether alterations in �-adrenergic receptor-mediated vasodi-

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lation within skeletal muscle vasculature contributed to thereduced O2 delivery. Along these lines, local inhibition of�-adrenergic receptors (via intra-arterial infusion of proprano-lol) has demonstrated that in the absence of overlying sympa-thetic vasoconstriction, �-adrenergic receptor activation con-tributes to the hypoxic compensatory vasodilation during mild(10% maximum voluntary contraction; MVC) forearm exercise(160). However, the �-adrenergic component decreases withincreased exercise intensity (20% MVC). Taken together, thissuggests that other local vasodilating factors are likely respon-sible for the compensatory vasodilation during hypoxic exer-cise, especially at higher exercise intensities.

NO release from an endothelial source and/or desaturation ofhemoglobin in erythrocytes (85, 109, 140, 147) has beenproposed during hypoxia. Along these lines, there is a signif-icant blunting of the compensatory vasodilation in the forearmduring mild to moderate (10–20% MVC) hypoxic exerciseafter NOS inhibition (25). Although NO-mediated mechanismscontribute to the compensatory vasodilation during hypoxicexercise, it appears that it is regulated through different path-ways with increasing exercise intensity. At lower-intensityforearm exercise (10% MVC) NO contributes to the compen-satory vasodilation via �-adrenergic receptor activation. Athigher intensity exercise the contribution of NO becomesindependent of the �-adrenergic receptors (19). Therefore, analternative and currently unknown stimulus for NO-mediatedvasodilation occurs during higher intensity hypoxic exercise.

Increases in plasma but not skeletal muscle interstitial NOduring hypoxia in humans suggest an endovascular or endo-thelial NO source (85). Therefore, it is possible that theaugmented vasodilation during hypoxic exercise is a result ofthe direct release of NO from endothelial cells and/or erythro-cytes. In this context, luminal hypoxia can elicit the directrelease of NO from the endothelium (109) and from erythro-cytes in the form S-nitrosohemoglobin (147). However, basedon the location for intraluminal NG-monomethyl-L-arginine(NOS inhibitor) administration and the fact that NOS inhibitionis effective in reducing forearm blood flow during hypoxicexercise (25), it is reasonable to suspect that the NO respon-sible for the compensatory vasodilatation is from endothelialsources vs. an erythrocyte source. Furthermore, the effective-ness of NOS inhibition in reducing the compensatory vasodi-latation during hypoxic exercise also argues against the ideathat nitrite and/or formation of erythrocyte nitroso species is akey vasodilator in this response (39, 46). Along these lines, ifnitrite were responsible, either directly or indirectly (via reduc-tion to NO), the compensatory vasodilation would have beenmaintained despite NOS inhibition.

In animals adenosine is thought to be a key mediator ofskeletal muscle blood flow during normoxic exercise (95, 107,110, 111). However, adenosine receptor blockade appears toonly modestly attenuate the exercise-induced skeletal musclevasodilation in human limbs, but these findings are not con-sistent (26, 91, 98, 112). The classic adenosine hypothesisproposes that adenosine mediates vasodilation and helps toensure adequate blood flow to metabolically active tissueduring periods of reduced O2 availability (i.e., hypoxia and/orischemia) (7). This concept would therefore suggest that aden-osine may contribute to the compensatory vasodilation duringhypoxic exercise. However, our group demonstrated that aden-osine is not obligatory for the compensatory vasodilation

during hypoxic exercise in humans (26). This was observedwith and without overlying sympathetic �-adrenergic vasocon-striction, suggesting that the enhanced sympathetic outflowassociated with systemic hypoxia did not mask any underlyingadenosine-mediated vasodilation. Moreover, adenosine doesnot contribute to the compensatory vasodilation after NOSinhibition, thus indicating that adenosine does not act throughan NO-independent pathway in this response (25). Usingpositron emission tomography (PET) imaging, Heinonen andcolleagues (59) recently demonstrated that adenosine receptorantagonism (via aminophylline) did not affect blood flow inexercising human quadriceps femoris muscle, suggesting nocontribution of adenosine to capillary blood flow during hy-poxic exercise. Additionally, adenosine receptor blockade didnot change blood flow heterogeneity within the active andinactive muscles during hypoxic exercise.

Deoxygenation (i.e., hypoxia) and mechanical deformation(i.e., exercise) of red blood cells can lead to ATP release fromerythrocytes (6, 64, 144, 145). Moreover, venous plasma levelsof ATP are elevated during hypoxia at rest and during exercisecompared with normoxic conditions (48, 99). Both in vitro andin vivo studies suggest that ATP-induced vasodilation is me-diated through a NO pathway (28, 94, 96), thus an ATP/NO-mediated component to the compensatory vasodilation duringhypoxic exercise is an attractive hypothesis. It is believed thatthe vasodilator actions of ATP are mediated through thepurinergic P2y receptors located on vascular endothelial cells(113). Unfortunately, specific pharmacological antagonists forP2 receptors to address the role of ATP in the hypoxia-inducedcompensatory vasodilation are currently unavailable for humanuse. However, it is important to note that experimentallyincreasing limb vasodilation during hypoxic exercise (via intra-arterial ATP infusion) does not improve leg and systemic O2

consumption due to a reduction in O2 extraction across theexercising leg (17). Another potential candidate for stimulatingand/or interacting with NO in the compensatory vasodilatorresponse might be prostaglandins. There is strong evidence thatsuggests an interaction between prostaglandins and NO in theregulation of skeletal muscle blood flow at rest and duringnormoxic exercise (97, 101, 133, 134). As indicated earlier,there is also evidence to suggest a synergistic role betweenthese two pathways in the compensatory vasodilation duringhypoxia at rest (90). Recent evidence suggests that combinedNO/PG inhibition substantially reduces forearm blood flow andvasodilation during hypoxic exercise in young healthy adults(29). It is important to note that the aforementioned study didnot include single inhibition trials of each vasodilator pathwayof interest (NO and prostaglandins). Therefore, it is difficult todiscern the relative contribution of PGs and its interaction withNO in the compensatory vasodilation during hypoxic exercise.

Sympathetic Restraint of Hypoxia-InducedCompensatory Vasodilation

In young healthy humans the sympathetic response to exer-cise is greater in hypoxia than it is in normoxia (54, 69, 136).The increased sympathetic vasoconstrictor activity has beenpostulated to be needed to match O2 delivery with O2 demand(88) and maintain arterial blood pressure during the hypoxicstress and in turn limit the degree of compensatory vasodilation(148). Along these lines, �-adrenergic receptor blockade in the

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human forearm (160) and in the hindlimbs of dogs (148)reveals a greater vasodilation during hypoxic exercise com-pared with control hypoxic exercise conditions (i.e., duringsaline infusion). Despite the augmented sympathetic vasoconstric-tor activity a substantial compensatory vasodilation persistsduring hypoxic exercise. It is well documented that sympa-thetic vasoconstrictor responses are blunted in the vascularbeds of contracting skeletal muscle of animals (150, 151) andhumans (36, 56, 57, 117, 153), a phenomenon referred to as“functional sympatholysis.” Moreover, there is evidence tosuggest that hypoxia can attenuate vasoconstrictor responses tosympathetic nerve activation and exogenous norepinephrine inresting skeletal muscle of animals and humans (12, 60, 61).Therefore, it is possible that an augmented functional sympa-tholysis might partially explain the compensatory vasodilationduring hypoxic exercise. In this context, Hansen et al. (55)demonstrated a reduced forearm vasoconstrictor responsive-ness to lower body negative pressure during moderate hypoxicexercise compared with normoxic exercise. However, our lab-oratory (161) has demonstrated that the greater vasodilationobserved during hypoxic forearm exercise was not due to areduced postjunctional vasoconstrictor responsiveness (aug-mented functional sympatholysis) to endogenous norepineph-rine (via intra-arterial infusion of tyramine).

Compensatory Vasodilation: Is it Always Present?

It is clear that compensatory vasodilation occurs in responseto acute hypoxia during submaximal forearm (19, 25, 26, 29,160, 161) and single and/or two-legged knee extension (16, 32,77, 122, 126) exercise. That is, during submaximal exercise,alterations in O2 availability are compensated for by an aug-mented muscle blood flow to help maintain O2 delivery to theactive muscles. However, this compensatory vasodilation ap-pears to be absent during maximal exercise, especially whenperformed with a large muscle mass (74, 77, 78, 120). Themuscle blood flow and vasodilator response to maximal exer-cise during moderate and severe hypoxia are likely limited toa certain degree by a reduction in maximal cardiac output (16)and not fully capable of compensating when the maximalpumping capacity of the heart is taxed. Under these circum-stances it seems likely baroreflex-mediated vasoconstrictorresponses are engaged. However, it is important to note thateven in well trained cyclists who have a high cardiovascularreserve, leg blood flow and leg O2 consumption is reduced atpeak exercise using the one-legged knee extension model(119). The lack of a compensatory vasodilation is also ob-served during submaximal exercise after acclimatization (long-term exposure to hypoxia), which may be due to an increasein CaO2

.In summary, the studies discussed here clearly demonstrate

that reductions in available O2 via systemic hypoxia promotecompensatory vasodilation and an augmented blood flow inskeletal muscle vascular beds at rest and during submaximalexercise. The compensatory vasodilation during hypoxic exer-cise is essential to ensure the maintenance of oxygen deliveryto the active muscles. It appears that factors sensitive to CaO2

serve as the signal for the compensatory increases in skeletalmuscle blood flow and vasodilation during hypoxic exercise. Inhumans, NO-mediated vasodilation plays an obligatory role inthe augmented blood flow during incremental hypoxic exer-

cise. However, the NO-mediated component of the compensa-tory vasodilation during hypoxic exercise is regulated throughdifferent pathways with increasing exercise intensity. That is, a�-adrenergic receptor-stimulated NO component exists duringlow-intensity hypoxic exercise, whereas the source of NOcontributing to compensatory dilation is less dependent on�-adrenergic mechanisms as exercise intensity increases. It iscurrently unclear what the stimulus of NO release is withincreasing intensity of muscle contraction but does not appearto be adenosine. ATP released from erythrocytes and/or endo-thelial-derived prostaglandins remain attractive candidates forstimulating NO during higher intensity hypoxic exercise.

The vasodilator response to acute hypoxia detailed above inyoung healthy humans has been demonstrated to be attenuatedin older adults at rest and during exercise (27, 79). Addition-ally, limited reports suggest that compensatory vasodilation isimpaired in some populations with cardiovascular risk factors(5), whereas it is preserved in others (86, 157). From a clinicalperspective, if an attenuated vasodilator response occurs inother vascular beds (i.e., coronary circulation) with aging andcardiovascular risk factors, certain individuals may be at risk ofreduced perfusion of the myocardium and consequently myo-cardial injury during exercise with hypoxia.

HYPEROXIA: THE OPPOSITE SIDE OF THE COIN

It is apparent that compromises in O2 availability (i.e.,hypoxia) elicit a compensatory vasodilator response in skeletalmuscle vascular beds to ensure adequate O2 delivery. Con-versely, increased O2 availability (i.e., hyperoxia) reducesresting muscle blood flow in humans (8, 58, 116, 165). Addi-tionally, muscle blood flow is reduced during and after hyper-oxic exercise compared with normoxic conditions (24, 48, 116,159). The challenge of increasing O2 availability by increasingthe fraction of inspired O2 (i.e., FIO2

� 100% O2) undernormobaric environments is that CaO2

can only be elevated5–10%. Additional approaches using hyperoxia (FIO2

� 100%O2) superimposed onto experimentally induced polycythemiahave also been employed to study the effects of increased O2

availability on muscle blood flow during knee-extensor exer-cise (47). However, this approach only resulted in an �11%increase in CaO2

. These relatively small increases in CaO2are

near the signal-to-noise ratio for muscle blood flow measure-ments. To address this potential limitation, studies on the bloodflow response in the exercising forearm to larger increases inestimated CaO2

via hyperbaric hyperoxia have recently beenperformed (24). Large increases in estimated O2 content (�25–30%) resulted in a substantial reduction in exercising forearmblood flow despite significantly higher perfusion pressures,thus indicating a greater increase in vascular resistance com-pared with normoxic conditions (24). The blunted forearmvascular conductance during hyperoxic exercise (�25% lower)mirrored the estimated increase in arterial O2 content (�25–30%). These findings during hyperbaric hyperoxic exerciseparallel previous findings in which hypoxic-mediated increasesin forearm vascular conductance during exercise mirrors thefall in O2 content (25, 26).

The mechanisms responsible for the increased vascular re-sistance and reduced blood flow during hyperoxic exercise arecurrently unclear. In general, the potential mechanisms includebut are not limited to 1) greater sympathetic restraint and/or

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2) decreased release of or responsiveness to local vasodilatorswithin the contracting muscle. Although hyperoxia reducesmuscle sympathetic nerve activity at rest (62, 135, 165), itis unclear whether this holds true during exercise and contrib-utes to the reduced muscle blood flow and vasodilation. Lim-ited evidence suggests that hyperoxia does not appear toenhance the magnitude of change in sympathetic nerve activityto non-active skeletal muscle during dynamic exercise (135).Additionally, it is possible that increased oxygen levels mayattenuate functional sympatholysis and therefore enhance va-soconstriction in the contracting muscles (55). Finally, someevidence suggests that the vascular response (i.e., constriction)to hyperoxia in the hindlimbs of dogs is not mediated by theautonomic nervous system but is rather attributed to a directaction of high arterial O2 tension (4). Therefore, it is possiblethat the increase in vascular resistance under hyperoxic exer-cise conditions may be a direct vasoconstrictor action of O2 onthe arterial and arteriolar wall. As discussed earlier, erythro-cytes have the ability to sense changes in O2 during hypoxicconditions and modulate vascular tone via release of ATP, thusleading to appropriate changes in blood flow and matching O2

delivery with metabolic need (42). Therefore, large increases inO2 availability during hyperbaric hyperoxic exercise couldtheoretically attenuate the release of ATP from erythrocytes(Fig. 1) (48).

A shift in the vasodilator/vasoconstrictor balance due to anattenuated release of or responsiveness to local vasodilatorswithin the contracting muscle could also promote the reducedblood flow during hyperoxic exercise. In this context, prosta-glandin-mediated vasodilation following isometric exercise isreduced during hyperoxia (162). Additionally, vasoconstrictionvia a reduction in basal NO production has been observed in

porcine coronary arteries exposed to elevated levels of O2

(106). Along the same lines, an increase in free radical pro-duction (i.e., superoxide anions) during hyperbaric oxygen-ation causes vasoconstriction in the cerebral circulation of ratsvia inactivation of NO (167). However, recent evidence sug-gests that NO metabolites are unaffected in humans duringnormobaric hyperoxic exercise (39). Therefore it is unclearwhether alterations in the local vasodilator milieu are respon-sible for the blunted blood flow response to hyperoxic exercise.

LOCAL REDUCTIONS IN OXYGEN (VIA HYPOPERFUSION)

Over the past several years our laboratory has been inter-ested in addressing whether the compensatory vasodilator sig-nals that maintain oxygen delivery to active muscles duringexercise with systemic hypoxia are the same or different thanthose that cause compensatory vasodilation during normoxicexercise with hypoperfusion. During conditions of insufficientoxygen delivery to the active muscle (e.g., hypoperfusion orischemia), metabolites can accumulate that either stimulateblood pressure, raising sensory nerves within the muscle, orevoke vasodilation (1, 30, 67, 70, 137, 155, 156). Either ofthese mechanisms might act to restore blood flow to thecontracting muscle and relieve the flow/metabolism mismatch.

Reflex Pressor Response

Activation of chemosensitive afferent nerves in the activemuscle evokes reflex increases in sympathetic outflow andarterial pressure, termed the muscle chemoreflex or metabore-flex (1, 30, 67, 70, 155, 156). The increased pressure is thoughtto augment blood flow to the contracting muscle and partiallyrestore the flow/metabolism matching. Evidence for restorationof blood flow to active muscle via a reflex pressor responsecomes primarily from studies in conscious animals. In dogs,the hemodynamic consequences of muscle chemoreflex acti-vation, via graded reductions in flow and perfusion pressure,have been studied extensively using the “Seattle model” (53,104, 105, 138, 139, 164). In this model, a terminal aorticoccluder in combination with a flow probe in close proximityis used to suddenly reduce blood flow to the hindlimb musclesof dogs running on a treadmill. Using this model, imposedreductions in blood flow and oxygen delivery to activehindlimb muscles during dynamic exercise can evoke a pow-erful pressor response that restores �50% of the flow deficit(105). The reflex pressor response to acute hypoperfusionduring exercise in dogs is dependent on the intensity of theexercise (123) and apparently generated when O2 delivery fallsbelow some critical level causing accumulation of a pressorsubstance (Fig. 2) (139). The reflex pressor response in normaldogs is generated primarily by a rise in cardiac output (3, 53,72, 104, 164), whereas in dogs with congestive heart failure thesystemic pressor response is caused primarily by peripheralvasoconstriction (53). Taken together, the Seattle model clearlydemonstrates that the reflex pressor response contributes to therestoration of blood flow in the hindlimbs of dogs duringexercise. However, it should be noted that Britton et al. (14)demonstrated that autoregulation in the hindlimbs of dogs alsocontributes significantly to the regulation of blood flow inresponse to acute hypoperfusion during exercise.

Fig. 1. Thigh plasma venous ATP responses at rest and during incrementalknee-extensor exercise with exposure to normoxia, hypoxia, hyperoxia, andcarbon monoxide (CO) � normoxia. *Significantly different from restingvalues (P � 0.05). [Adapted with permission from Ref. 48].

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Is the Pressor Response Apparent in Humans?

In humans, large increases in blood pressure during ischemicexercise were first described by Alam and Smirk (1). Theseinvestigators observed that the activity of even a small group ofmuscles may give rise to a substantial increase in systolic bloodpressure (up to 70 mmHg) provided that the circulation of theblood through the exercising muscles was arrested completely.Lorentsen (87) later demonstrated that the blood pressureresponse to plantar flexion in patients with unilateral intermit-tent claudication due to atherosclerosis obliterans was signifi-cantly greater during exercise with the diseased limbs com-pared with exercise with nondiseased limbs. Taken together,these studies suggest that the reflex pressor response in humansis engaged during exercise with ischemia and/or hypoperfu-sion. However, stimulation of the muscle chemoreflex evokesa large increase in vasoconstricting sympathetic nerve trafficdirected toward the skeletal muscle (30, 89, 154). While thereflex increase in arterial pressure has the potential to restoreblood flow and O2 delivery to the active muscles, the reflexincrease in vasoconstricting sympathetic outflow might alsorestrain blood flow to some degree. Whether the pressorresponse improves blood flow to the hypoperfused activehuman skeletal muscle has not been extensively studied (rela-tive to that in animals) and is not well understood.

To evaluate the blood flow response to hypoperfusion incontracting muscles the majority of studies in humans haverelied on the use of external pressure to reduce limb blood flowduring exercise, which have produced conflicting results (30,66, 127, 149). Using O2 saturation of venous blood (%SvO2

) asan indirect method of measuring blood flow, studies in theforearm reported that the reflex pressor response did not appearto restore blood flow to rhythmically contracting muscles (66).In contrast, Rowell et al. (127) concluded that the reflex pressorresponse partially restored the decrease in leg blood flow(%SvO2

) induced by external positive pressure. Using a more

direct measurement of flow (brachial artery mean blood veloc-ity), Daley et al. (30) demonstrated that flow is not restored bya reflex pressor response at higher levels of external pressure(�50 mmHg) due to sympathetic vasoconstriction limiting theability of the pressor response to restore the flow. Potentialproblems of these earlier studies mainly revolve around theindirect measures of blood flow (66, 127) and the method usedto reduce limb blood flow (positive pressure) during exercise(30, 66, 127, 149). While external positive pressure clearlyreduces perfusion pressure to the contracting muscles, it differsfundamentally with the Seattle model because it affects allelements of the vascular tree, including the microcirculationand veins, and might either limit expression of local vasodila-tation or limit the ability of changes in arterial pressure toimprove blood flow.

To address the limitations of external pressure, our labora-tory recently developed an experimental model in humans todirectly measure the blood flow response in hypoperfusedskeletal muscle produced by forearm exercise in the presenceof a brachial artery occlusion. For this purpose a small ballooncatheter is inserted into the brachial artery and inflated toreduce forearm blood flow and vascular conductance duringhandgrip exercise (Fig. 3) (23). With this experimental modelthere is a substantial restoration of flow to hypoperfusedexercising human muscle. Interestingly, the restoration of flowoccurs in the absence of a significant pressor response, thussuggesting local vasodilator and/or myogenic mechanisms arelikely responsible. The absence of a significant pressor re-sponse (above exercise alone) during hypoperfusion suggeststhat a reflex increase in pressure is not necessary to restoreblood flow to hypoperfused contracting human muscle. Thelack of a pressor response in our model may be explained bythe small muscle mass (forearm), moderate exercise intensity(20% MVC), magnitude of the reduction in forearm blood flow(�50%) induced by balloon inflation, or a combination ofthese being not sufficient enough to augment the pressorresponse beyond that of exercise alone. However, recent evi-dence suggests that using an upper arm cuff to reduce flow by�40% during forearm exercise at 15% MVC was sufficient toevoke a reflex pressor response (63). It should be noted that theuse of an upper arm cuff likely blocked venous outflow,leading to increased intramuscular pressure, which could acti-vate sympathoexcitatory mechanosensitive afferents (93, 125).Therefore, the reflex pressor response observed might havebeen due to an enhanced mechanoreflex, which is not likelyengaged using an intra-arterial balloon catheter to inducehypoperfusion.

Local Vasodilation

During systemic hypoxia there is a compensatory vasodila-tion that mirrors the decrease in O2 content (25, 26, 47, 160,161). However, during local reductions in O2 availability (viahypoperfusion) the compensatory response appears to be lessthan perfect in humans (20–23). That is, flow does not returncompletely (100% recovery) to preinflation levels. One poten-tial explanation for the incomplete compensatory vasodilationduring acute hypoperfusion may be related to an initial rise invascular resistance at the onset of balloon inflation. The initialrise in vascular resistance in these studies is in contrast to theclassic view of autoregulation (a decrease in perfusion pressure

Fig. 2. Effects of CO on the rise of systemic arterial pressure to gradedreductions in hindlimb perfusion during exercise (2 mph, 0% grade). Squaresand solid lines are control (no CO) exercise data, and circles and dashed linesare exercise with CO data. Filled symbols represent free-flow data; opensymbols represent data collected during reduced hindlimb perfusion. Thesedata demonstrate that when terminal aortic flow is decreased during mildexercise the reflex rise in systemic arterial pressure occurs at higher flows afterarterial oxygen content is reduced with CO. [Adapted with permission fromRef. 139].

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is followed by a reduction in resistance to blood flow throughthe muscle) (14, 50, 108, 146). However, the initial increase invascular resistance is not unprecedented in that an immediateincrease in vascular resistance has also been reported to occurin isolated perfused skeletal muscle of dogs (65). The reasonfor the acute increase in vascular resistance at the onset ofballoon inflation in our model of hypoperfusion is not com-pletely clear but may be related to dampening of pulsatile flowby balloon inflation. One possibility is that pulsatile flow is acritical component for the release of endothelium-derived va-sodilators (128). Another possibility is that a sudden drop inperfusion pressure causes the resistance vessels to recoil beforeautoregulatory vasodilation, a response that was also noted byKoch et al. (76) during mild exercise in dogs. Alterations invascular bed compliance at the onset of balloon inflation mayalso contribute to the acute increase in vascular resistanceobserved in our model of hypoperfusion (166). Since no majorpressor response is observed at the onset of balloon inflation(20–23) it is unlikely that a marked rise in sympathetic outflowexplains the acute increase in vascular resistance.

The increase in vascular resistance at the onset of ballooninflation is followed by gradual autoregulatory compensationsuch that the vascular resistance decreases over time towardand, in some cases, below preinflation values. In this contextthe magnitude of blood flow restoration following acute hypo-perfusion in contracting human skeletal muscle is predicted bythe reduction in downstream forearm vascular resistance(Fig. 4). Additionally, the recovery of flow is not associatedwith changes in balloon resistance and systemic arterial pres-sure (i.e., pressor response). Therefore, local vasodilator mech-anisms must be responsible for the reduction in vascularresistance and restoration of flow to hypoperfused contractingforearm muscles.

VASODILATOR MECHANISMS: USUAL SUSPECTS REVISITED?

The vasodilator mechanisms in the microcirculation thatcontribute to the regulation of flow distal to the occlusion likelyinclude a myogenic response of the microcirculation and all themechanisms that are involved in vasodilation in response toincreased metabolic needs, including endothelial factors andmetabolic messengers released from the muscle. As previouslymentioned, NO appears to contribute to the regulation ofskeletal muscle blood flow during systemic hypoxia (11, 19,

25, 29, 158). Similarly NOS inhibition during moderate inten-sity handgrip exercise blunts the magnitude of restoration offorearm blood flow and vascular conductance in hypoperfusedcontracting muscles (21). Moreover, the compensatory vaso-dilation to hypoperfusion in the contracting human forearmwas slowed with NOS inhibition. To our knowledge this is theonly study to examine the contribution of NO to the restorationof blood flow in hypoperfused contracting skeletal muscle.However, parallel findings have been reported in the coronarycirculation (40, 142). Duncker and Bache (40) assessed thecontribution of NO to the vasodilation of coronary resistancearteries during exercise in the presence of a flow-limitingcoronary stenosis. Inhibition of NO production during partialinflation of a hydraulic coronary occluder in dogs performingmoderate treadmill exercise resulted in a decreased meanmyocardial blood flow in the region perfused by the stenoticartery, but not in the normally perfused control region.

A substantial recovery of forearm blood flow still remainsafter NOS inhibition, thus suggesting that additional vasodila-

Fig. 3. Schematic of intra-arterial balloon catheter system.Forearm blood flow is reduced by partially occluding thebrachial artery via inflation of a Fogarty balloon catheterwith saline using a calibrated microsyringe for tight controlof balloon volume. Brachial artery blood velocity is mea-sured (via Doppler ultrasound) proximal to the balloon. Theconfiguration of the balloon upstream from the lumen of theintroducer allows measurement of the brachial arterial pres-sure (BAP) distal to the balloon that is perfusing thecontracting forearm muscles. Rhythmic forearm exercise isperformed with a hand grip device by lifting a weight 4–5cm over a pulley system at a duty cycle of 1 s contraction/and 2-s relaxation (20 contractions/min).

Fig. 4. Linear regression analysis of the relationship between % recovery offorearm blood flow (FBF) and reduction in vascular resistance (%) duringballoon inflation (n � 151) from all trials performed in references (20–23).The correlation demonstrates that the magnitude of flow restoration is pre-dicted by the reduction in vascular resistance during forearm exercise withhypoperfusion.

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tor mechanisms are involved in the compensatory response.Previous evidence in the Seattle model suggests that adenosinereceptor antagonism blunts the recovery of hindlimb bloodflow in dogs during high-intensity exercise in response topartial vascular occlusion (76). Additionally, active hyperemiain dog skeletal muscle is potentiated during experimentallyrestricted flow in the presence of dipyridamole, thus suggestinga role of adenosine in the regulation of blood flow underconditions of arterial occlusion (73). Furthermore, adenosineproduction is positively correlated to the degree of hypoperfu-sion in the coronary circulation of dogs (34) and appears tocontribute to vasodilation of the coronary resistance vesselsduring exercise in the presence of a flow-limiting stenosis (82).In agreement with the aforementioned studies in dogs, data inthe human forearm suggest 1) adenosine contributes to theoverall magnitude of compensatory vasodilation during exer-cise with acute hypoperfusion in a manner that can be inde-pendent of NO-mediated mechanisms and 2) combined inhi-bition of adenosine receptors and NO formation results inadditive reduction in the compensatory vasodilation (20).

Lastly, prostaglandins have been reported to be involved inthe regulation of skeletal muscle blood flow following periodsof ischemia (18, 43, 71, 102) and during systemic hypoxia (29,90, 114). However, non-selective cyclooxygenase (COX) in-hibition with Ketorolac to block the production of prostaglan-dins failed to reduce the recovery of forearm blood flow andvascular conductance during exercise with acute hypoperfusion(22). These findings are in agreement with available data in thecoronary circulation of pigs where COX inhibition with indo-methacin did not alter coronary blood flow in response to anexperimentally induced flow-limiting stenosis (129). However,COX inhibition in patients with coronary artery disease causescoronary vasoconstriction (38, 44), thus suggesting that vaso-dilator prostaglandins may play greater role in the regulation ofcoronary vasomotor control in chronic vs. acute ischemia andin blood vessels subjected to atherosclerotic disease processes.Taken together, the mechanisms involved in the compensatoryvasodilator response to acute hypoperfusion in contractinghuman muscle suggests that adenosine and NO contribute,whereas prostaglandins are not obligatory (Fig. 5).

SUMMARY AND PERSPECTIVES

This review highlights the key vasodilator signals and/orpathways that contribute to the local control of skeletal muscleblood flow during exercise under conditions with reducedoxygen availability (Table 1). Both acute systemic (hypoxia)and local (hypoperfusion) mediated reductions in O2 availabil-ity elicit a compensatory vasodilator response. Although NOappears to be a common link between the hypoxia and hy-poperfusion-induced vasodilation (Table 1), its stimulus and/orinteractions with other vasodilator systems varies between thetwo conditions. Both NO and adenosine contribute to thecompensatory vasodilator responses to hypoperfusion (20, 21).By contrast, adenosine does not seem to play a major role inthe compensatory vasodilator responses to hypoxia (25, 26,59). Thus the story with adenosine is mixed; during hypoper-fusion it appears to contribute in a synergistic manner withnitric oxide to compensatory vasodilation. By contrast, duringhypoxia it does not contribute. Although combined NOS/COXinhibition has been demonstrated to reduce the compensatoryvasodilator response during hypoxic forearm exercise (29), it isunclear what the independent role of prostaglandins are in thisresponse. Available evidence suggests prostaglandins are notobligatory to the compensatory dilation observed during fore-arm exercise with hypoperfusion (22).

Despite the majority of the data presented in this reviewbeing from studies in young apparently healthy adults, it has

Fig. 5. Reduction in compensatory vasodilation [i.e., % recovery of forearmvascular conductance (FVC) compared with respective control (no drug) trial]during various pharmacological trials. Single inhibition of NOS with NG-monomethyl-L-arginine (white bar) and adenosine receptor blockade withaminophylline (black bar) substantially attenuates the compensatory vasodila-tion during exercise with acute hypoperfusion. Combined NOS/ADO inhibi-tion (dark gray bar) reveals an even greater reduction in %FVC compared withblockade of each factor alone. Single inhibition of COX with Ketorolac hasminimal effect on the compensatory vasodilation (light gray bar). CombinedNOS/COX inhibition (hatched bar) has minimal effect on the compensatoryvasodilation compared with NOS inhibition alone (white bar). Data werederived from Refs. 20–22. ADO, adenosine; COX, cyclooxygenase; NOS,nitric oxide synthase; PG, prostaglandin.

Table 1. Systemic vs. local reductions in oxygen availability: contribution of local vasodilators in the control of humanskeletal muscle blood flow during exercise

Systemic Hypoxia Local Hypoperfusion

(Low O2) (Low O2 � 2 perfusion)Perfect (proportional to the fall in arterial O2 content) Compensation Imperfect (�100% recovery)�� -adrenergic receptor activation* ?�� Nitric oxide �� Adenosine ��? Prostaglandins �

*Is exercise intensity dependent; contribution decreases with increased exercise intensity. ��Contributes to the compensatory vasodilation; � is notobligatory in the compensatory; vasodilation; ?lack of evidence for or against a role in the compensatory vasodilation.

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important implications for understanding conditions associatedwith impaired endothelial function or reduced NO bioavailabil-ity. In this context, data from aging humans clearly demon-strate an attenuated compensatory vasodilation during hypoxicexercise, which appears to be from reduced NO signaling (27).Additionally, the observation that NO contributes to the com-pensatory flow response in the microcirculation during an acuteproximal occlusion (21) raises concerns that the ability torestore flow might be impaired in conditions with endothelialdysfunction and/or reduced NO bioavailability (i.e., vasculardisease). Therefore, patients with impaired endothelium-de-pendent dilation are likely to be more susceptible to hypoper-fusion and/or ischemia during exercise, especially in vascularregions distal to a stenosis. Finally, there appears to be a greatdeal of similarity between the regulation of resistance vesseltone in human skeletal muscle (20–22) with those observed inthe coronary circulation of dogs and pigs during exercise withacute hypoperfusion (34, 40, 41, 82, 129). Thus an impairedcompensatory vasodilator response in the forearm might reflectimpairments in other vascular beds.

In conclusion, the available literature reviewed here showsthat under most circumstances skeletal muscle vasodilation istightly coupled to changes in available O2. Indeed, the com-pensatory vasodilation observed during hypoxic exercise gen-erally mirrors the fall in CaO2

. Conversely, under conditions ofincreased O2 availability (i.e., hyperoxia), vascular conduc-tance is reduced and mirrors the increase in CaO2

. Takentogether, these findings suggest that skeletal muscle blood flowis perfectly matched to changes in systemic O2 availability. Incontrast, the compensatory vasodilation in response to localreductions in O2 availability via hypoperfusion appears to beless than perfect in human skeletal muscle.

GRANTS

This work was supported by the National Institutes of Health researchGrants HL-46493 (to M. J. Joyner) and AR-55819 (to D.P. Casey) and byCTSA RR-024150. The Caywood Professorship via the Mayo Foundation alsosupported this research.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

Author contributions: D.P.C. prepared figures; D.P.C. and M.J.J. draftedmanuscript; D.P.C. and M.J.J. edited and revised manuscript; D.P.C. andM.J.J. approved final version of manuscript.

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