Carotid Chemo Receptor Modulation of Blood Flow

8/3/2019 Carotid Chemo Receptor Modulation of Blood Flow

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J Physiol589.24 (2011) pp 62196230 6219

The

JournalofPhysiolo

gy

Carotid chemoreceptor modulation of blood flow duringexercise in healthy humans

Michael K. Stickland1,2, Desi P. Fuhr1, Mark J. Haykowsky3, Kelvin E. Jones4, D. Ian Paterson5,

Justin A. Ezekowitz5 and M. Sean McMurtry51Division of Pulmonary Medicine and5Division of Cardiology, Department of Medicine, 3Faculty of Rehabilitation Medicine and4Faculty of Physical

Education and Recreation, University of Alberta, Edmonton, Alberta, Canada2Centre for Lung HealthCovenant Health, Edmonton, Alberta, Canada

Non-technical summary Exercise causes an increase in sympathetic activity which helps toredistribute blood flow while maintaining blood pressure. The exact mechanisms that regulate

sympatheticactivity and bloodflowduring exercise are not completely understood.By modulatingthe activity of a specific chemical receptor (the carotid chemoreceptor), we showed that thisreceptor contributes to the regulation of blood flow during exercise in healthy subjects. These

findings demonstrate the importance of the carotid chemoreceptor in the regulation of bloodflow during exercise in health.

Abstract Carotid chemoreceptor (CC) inhibition reduces sympathetic nervous outflow in

exercising dogs and humans. We sought to determine if CC suppression increases muscle bloodflow in humans during exercise and hypoxia. Healthy subjects (N= 13) were evaluated at rest

and during constant-work leg extension exercise while exposed to either normoxia or hypoxia(inspired O2 tension, FIO2 , 0.12, target arterial O2 saturation= 85%). Subjects breathed hyper-oxic gas (FIO2 1.0) and/or received intravenous dopamine to inhibit the CC while femoral

arterial blood flow data were obtained continuously with pulsed Doppler ultrasound. Exerciseincreasedheart rate, mean arterial pressure, femoral blood flow andconductancecompared to rest.Transient hyperoxia had no significant effect on blood flow at rest, but increased femoral blood

flow and conductance transiently during exercise without changing blood pressure. Similarly,dopamine had no effect on steady-state blood flow at rest, but increased femoral blood flowand conductance during exercise. The transient vasodilatory response observed by CC inhibition

with hyperoxia during exercise could be blocked with simultaneous CC inhibition with dopamine.Despite evidence of dopamine reducing ventilation during hypoxia, no effect on femoral bloodflow, conductance or mean arterial pressure was observed either at rest or during exercise with

CC inhibition with dopamine while breathing hypoxia. These findings indicate that the carotidchemoreceptor contributes to skeletal muscle blood flow regulation during normoxic exercise inhealthy humans, but that the influence of the CC on blood flow regulation in hypoxia is limited.

(Received 17 August 2011; accepted after revision 23 October 2011; first published online 24 October 2011)

Corresponding author M. Stickland: Division of Pulmonary Medicine, Department of Medicine, 8334B Aberhart

Centre, University of Alberta, Edmonton, Alberta, Canada, T6G 2B7. Email: [email protected].

Abbreviations CC, carotid chemoreceptor; FIO2 , inspired O2 tension; I.V., intravenous; MSNA, muscle sympathetic

nerve activity; PET,CO2 , end-tidal CO2; PET,O2 , end-tidal O2; SpO2 , arterial oxygen saturation.

Introduction

Exercise increases sympathetic neural vasoconstrictoroutflow, which acts to redistribute blood flow away from

non-contracting muscle and other inactive vascular bedsand to redirect cardiac output to contracting muscle(Buckwalter & Clifford, 2001). The increased sympathetic

C2011 The Authors. Journal compilation

C2011 The Physiological Society DOI: 10.1113/jphysiol.2011.218099


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6220 M. K. Stickland and others J Physiol589.24

neural vasoconstrictor activity also partially constrainsblood flow to exercising muscle (Joyner et al. 1992;Buckwalter & Clifford, 1999) in order to maintain bloodpressure (Rowell & OLeary, 1990). It is generally assumedthat the increased sympathetic nervous activity duringexercise results from feedforward mechanisms, includingcentral command, as well as feedback from muscle

metaboreceptors, muscle mechanoreceptors and/or aresetting of systemic baroreceptors (Rowell & OLeary,1990).

The carotid chemoreceptors (CCs) are generallyconsidered the major oxygen sensor in the body. CCstimulation causes an increase in ventilation (Olsonet al. 1988; Curran et al. 2000), and elicits increases insympathetic neural vasoconstrictor outflow to the skeletalmuscle, renal and mesenteric vascular beds (Rutherford& Vatner, 1978; Balkowiec et al. 1993; Sun & Reis, 1994;Guyenet, 2000). CC sensitivity is significantly enhancedwith exercise. Specifically, the ventilatory response to the

CC stimulant doxapram is greater with exercise (Forsteret al. 1974), and exercise has been shown to greatlypotentiate the ventilatory (Weil et al. 1972) and musclesympathetic nerve activity (MSNA) (Seals et al. 1991b)response to hypoxia. Passive exercise in anaesthetizedanimals has been shown to increase CC activity via feed-back from the exercised limb in one (Biscoe & Purves,1967), butnot all, studies (Davies & Lahiri, 1973; Aggarwalet al. 1976).

Recently, we have shown in dogs that specific, trans-ient inhibition of the CC with either dopamine orhyperoxic Ringer solution during exercise caused peri-pheral vasodilatation, measured by increases in hind-limb flow and conductance (Stickland et al. 2007).The vasodilatory response was not observed at rest,and the vasodilatory response following CC inhibitionduring exercise was abolished with-adrenergic blockade,indicating that vasodilatation was due to a reduction insympathetic outflow. We subsequently found that trans-ient CC inhibition with hyperoxia in humans reducedMSNA during handgrip exercise, but not at rest (Sticklandetal. 2008).ItisunknownwhetherthisreductioninMSNAfrom CC inhibition observed in humans translates into anincrease in muscle blood flow in the exercising limb.

As mentioned above, hypoxia is associated with an

increase in sympathetic vasoconstrictor output secondaryto CC stimulation, and hypoxia potentiates the MSNAresponse to exercise (Seals et al. 1991b). -Adrenergicblockade has demonstrated that there is considerablehypoxia-induced sympathetic restraint of muscle bloodflow during exercise (Stickland et al. 2009). While nota consistent finding (Dinenno et al. 2003; Wilkins et al.2006), some previous work has shown that the vascularresponse to sympathetic stimulation may be blunted withhypoxia both at rest (Heistad & Wheeler, 1970; Hansenet al. 2000) and during exercise (Hansen et al. 2000),

suggesting hypoxia-induced functional sympatholysis, i.e.a reduced vasoconstriction in response to sympatheticstimulation (Remensnyder et al. 1962). It remains to bedetermined if the CC contributes to muscle blood flowregulation during hypoxia in humans.

The purpose of the presentinvestigation was to examinethe effect of CC inhibition on muscle blood flow at rest

and during exercise, in normoxia and hypoxia, in humans.We hypothesized that the CC would be activated duringexercise, as well as during hypoxia, and consequently, CCinhibition would cause peripheral vasodilatation duringexercise and/or hypoxia.

Methods

Ethical approval

Thirteen healthy participants (9 men, 4 women)aged 33 4 years (range, 2835 years), of normal

weight (82 16 kg), height (175 5 cm) and VO2max(51 13mlkg1 min1) participated in the study afterproviding written, informed consent. All of the subjectswere physically active, with three subjects being end-urance trained athletes who had VO2max values above60mlkg1 min1. All subjects were free from apparentcardiovascular disease as judged by normal resting EKGand a normal EKG/blood pressure response to exercise.No subject had evidence of baseline airflow obstruction orexercise-induced bronchoconstriction. No subjects weretaking vasoactivemedications. All four womenwere takingoral contraception; however, no apparent differences wereobserved with chemoreceptor inhibition between the menand women, and therefore all were combined into onegroup. The studywas approvedby theUniversityof AlbertaHealth Research Ethics Board (Biomedical Panel). Thestudy conformed to the standards set by the latest revisionof the Declaration of Helsinki.

Sessions and exercise acclimatization

Three experimental sessions were completed over a3 week period in the following order: a graded cardio-pulmonary exercise test to rule out exercise-inducedECG abnormalities and characterize V

O2max, a practice

session where subjects familiarized themselves with theknee-extension exercise set-up and performed a gradedknee-extension exercise test to exhaustion, and theexperimental day.

Cardiorespiratory measures

For the experimental session, all data were recordedand integrated with a data acquisition system (Powerlab16/30; ADInstruments, New South Wales, Australia) and


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J Physiol589.24 Carotid chemoreceptor modulation of blood flow during exercise 6221

analysed offline using associated software (LabChart7.0 Pro; ADInstruments). Subjects breathed through amouthpiece with the nose occluded. Inspired gas washumidified (HC 150; Fisher and Paykel Healthcare,Auckland, New Zealand) and delivered continuously usinga flow-through system to prevent rebreathing of expiredgas. Ventilation was measured by a pneumotachometer

(3700 series; Hans Rudolph, Kansas City, MO, USA) justdistal to the mouthpiece. Expired CO2 and O2 (mmHg)were measured (CD-3A and S-3A; AEI Technologies,Naperville, IL, USA) continuously from a small sampleport off the mouthpiece to obtain end-tidal CO2 (PET,CO2 )and end-tidal O2 (PET,O2 ). Arterial oxygen saturation(SpO2 ) was estimated with pulse oximetry (N-595; NellcorOximax,Boulder,CO,USA)usingaforeheadsensor.Heartrate was recorded with a single-lead ECG (lead II, DualBio Amp;ADInstruments). Bloodpressure was monitoredusing finger photoplethysmography which was calibratedto brachial blood at regular intervals (Finometer model 2;

Finapres, Amsterdam, the Netherlands).

Doppler blood flow

Similar to previous work (DeLoreyet al. 2004; MacPheeet al. 2005), femoral arterial mean blood velocity wasobtained from the right leg by using pulsed-wave Dopplerultrasound (GE Vivid-7, 45 MHz,


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Table 1. Mean ( SEM) cardiorespiratory data at baseline and during transient hyperoxia at rest (N= 13)

Baseline Hyperoxia

060 s 6175 s 7690 s 91105 s 106120 s 121135 s 163150 s 151165 s 166180 s

Heart rate 67 68 67 64 64 63 62 62 61

(beats min1) 2 2 2 2 2 2 2 3 3

Blood pressure 88 87 86 87 87 86 86 86 86(mmHg) 2 2 2 2 2 2 2 2 2

Tidal volume 833 853 770 746 786 773 955 946 910

(ml) 65 79 83 99 113 81 184 132 116

Breathing frequency 14 13 13 14 14 14 13 13 13

(breaths min1) 0.9 1.2 1.5 0.9 1.4 1.1 0.8 1.1 1.1

Minute ventilation 11.2 10.4 9.4 9.9 10.4 10.2 11.7 12.4 11.1

(l min1) 0.5 0.7 0.9 0.9 1.2 1.0 1.9 1.7 1.0

End-tidal PO2 111 253 361 439 504 562 585 604 617

(mmHg) 3 36 26 15 13 15 12 8 7

End-tidal PCO2 (mmHg) 39 39 38 39 40 39 38 38 37

1 2 3 2 1 1 2 2 2

SpO2 (%) 98 98 99 100 100 100 100 100 100

0 0 0 0 0 0 0 0 0

P< 0.05 vs. baseline.

to avoid any possible hypoxia-induced sensitization of theCC which could potentially confound the normoxic trials.The steady-state rest and exercise hypoxic interventionsperformed in random order were: (1) I.V. saline and (2)I.V. dopamine. All trials were separated by 10 min to allowrecovery and clearance of dopamine (Gilman et al. 1985).

Data analysis

For all inferential analyses, the probability of type Ierror was set at 0.05. Group data for each variable areexpressed as means SEM. Trials were only analysed ifgood consistent Doppler data were obtained throughoutthe trial. As we have previously shown the response tohyperoxia to be rapid (Stickland et al. 2008), the mean15 s changes from baseline with inhaled hyperoxia werecompared at rest and exercise using a repeated-measuresANOVA. Where main effects were found, Fisher leastsignificant difference post hoc tests were used. The peak15 s value for blood flow and conductance within eachhyperoxic intervention was also determined, and the peakresponse at rest was compared to the peak response during

exercise using a paired ttest. For all dopamine and hypo-xia trials 1 min average steady-state data were obtainedand comparisons were conducted with repeated-measuresANOVA.

Results

Hyperoxia at rest (N= 13)

See Table 1 for groupedcardiorespiratory data. Within 15 sof breathing hyperoxia PET,O2 was increased above base-

line. Likewise, SpO2 was increased above baseline within30 s of breathing hyperoxia. As compared to normoxia,breathing hyperoxia at rest did not change heart rate,mean arterial pressure, femoral blood flow or femoralconductance (Fig. 1).

Hyperoxia during exercise (N= 13)

See Table 2 for grouped cardiorespiratory data. Exercise

itself significantly increased heart rate, mean arterialpressure, tidal volume, breathing frequency, minuteventilation, femoral blood flow and femoral conductancecompared to resting values. Similar to the responseat rest, within 15 s of breathing hyperoxia, PET,O2 wasincreased above baseline, while SpO2 was increased abovebaseline within 30 s of breathing hyperoxia. Heart ratewas increased over the first 30 s of breathing hyperoxia.Femoral blood flow and conductance was increased trans-iently above baseline within 30 s of breathing hyperoxia,and remained elevated for 30 s before returning to base-line values (see Fig. 2). The peak 15 s change in femoral

conductance at rest or during exercisewithinthe initial60 sof breathing hyperoxia was also determined for each trialand reported in Fig. 3. Hyperoxia given during exerciseresulted in a greater change in peak conductance ascompared to rest.

Dopamine at rest (N= 9)

See Table 3 for grouped cardiorespiratory data. Whilebreathing room air, dopamine resulted in a small increasein PET,CO2 compared to saline control; however, minute




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ventilation was not significantly different (P= 0.10). Ascompared to I.V. saline, dopamine at rest did not changeheart rate, mean arterial pressure, femoral blood flow orfemoral conductance (Fig. 4).

Dopamine during exercise (N= 9)

See Table 4 for grouped cardiorespiratory data. Duringexercise, dopamine caused a reduction in ventilationand a corresponding increase in PET,CO2 in all subjects,indicating that all subjects had chemoreceptor inhibitionwith dopamine. Heart rate, femoral blood flow andfemoral conductance were increased with dopamine in allsubjects, while blood pressure was reduced as comparedto control I.V. saline (Fig. 5). No other cardiorespiratorydifferences were observed between dopamine and I.V.saline during exercise.

Dopamine and hyperoxia during exercise (N= 8)

The femoral blood flow and conductance response totransient hyperoxia during exercise while simultaneouslyreceiving I.V. dopamine are detailed in Fig. 6. Unlike whatis observed when hyperoxia was given while receivingI.V. saline, there was no transient effect of hyperoxia

on femoral blood flow, conductance, heart rate ormean arterial pressure when simultaneously receiving I.V.dopamine.

Hypoxia and dopamine at rest (N= 9)

See Table 3 for grouped cardiorespiratory data. Ascompared to normoxia, hypoxia resulted in a reductionin PET,O2 and SpO2 . Hypoxia increased heart rate andminute ventilation, while PET,CO2 was correspondinglydecreased. Femoral blood flow and conductance wereincreased with hypoxia (see Fig. 4). Compared to I.V.saline, dopamine administered while breathing hypoxiareduced tidal volume, minute ventilation and increasePET,CO2 in all subjects. Femoral blood flow, conductanceand mean arterial pressure were unchanged withdopamine.

Hypoxia and dopamine during exercise (N= 9)

See Table 4 for grouped cardiorespiratory data. Ascompared to normoxic exercise, hypoxic exercise resultedin a lower SpO2 and PET,O2 . Minute ventilation wasincreased, and correspondingly, PET,CO2 was reducedwith hypoxia, while heart rate, femoral blood flow

Figure 1. Blood flow response to transient hyperoxia at restP< 0.05 vs. mean 1 min baseline data.




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Table 2. Mean ( SEM) cardiorespiratory data at baseline and during transient hyperoxia during exercise (N= 13)

Baseline Hyperoxia

060 s 6175 s 7690 s 91105 s 106120 s 121135 s 163150 s 151165 s 166180 s

Heart rate 94 100 99 97 96 95 95 95 94

(beats min1) 5 6 6 6 6 6 6 6 7

Blood pressure 98 95 96 96 95 97 97 95 96(mmHg) 5 3 3 3 3 1 2 3 2

Tidal volume 1349 1514 1497 1415 1486 1520 1786 1475 1462

(ml) 177 831 852 705 750 822 1089 830 750

Breathing frequency 23 22 22 23 22 22 21 21 22

(breaths min1) 1.0 1.6 1.6 1.3 1.0 1.1 1.5 1.1 1.5

Minute ventilation 29.5 31.9 31.4 30.7 31.3 31.1 33.5 30.5 31.6

(l min1) 2.9 4.7 4.1 4.0 4.1 4.2 5.2 4.9 5.3

End-tidal PO2 104 279 472 522 537 583 591 586 583

(mmHg) 1 23 17 20 25 32 32 32 33

End-tidal PCO2 39 39 39 39 39 39 39 39 39

(mmHg) 1 2 2 2 2 2 2 2 2

SpO2 98 98 99 100 100 100 100 100 100

(%) 0 0 0 0 0 0 0 0 0

P< 0.05 vs. baseline during exercise.

and femoral conductance were increased (see Fig. 5)as compared to normoxic exercise. As comparedto saline control infusions, I.V. dopamine causeda reduction in minute ventilation and an increase

in PET,CO2 during hypoxic exercise in all subjects.No other cardiorespiratory differences were observedbetween saline and dopamine infusions during hypoxicexercise.

Figure 2. Blood flow response to transient hyperoxia during constant-work exerciseP< 0.05 vs. mean 1 min baseline data.




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Discussion

Inhibition of the carotid chemoreceptor using eitherpharmacological (I.V. dopamine) or physiological (inhaledhyperoxia) interventions resulted in an increase in femoralmuscle blood flow and conductance during exercise inhealthy humans. Carotid chemoreceptor inhibition at

rest did not result in a similar increase in peripheralblood flow. When the CCs were inhibited by a constantinfusion of I.V. dopamine, additional inhibition withhyperoxia did not produce any additional increase inmuscle blood flow or conductance. Despite ventilatoryevidence that dopamine reduced CC activity during hypo-xia, CC inhibition with I.V. dopamine did not affect muscleblood flow or conductance at rest, nor did it affect muscleblood flow during exercise in hypoxia. Combined, theseresults indicate that the CC contributes to the sympatheticcontrol of skeletal muscle blood flow during normoxicexercise.

Our main finding, that the CC contributes to thesympathetic control of skeletal muscle blood flow duringexercise, extends the findings of our earlier work(Stickland et al. 2007, 2008). Previously, we showed thatdirect CC inhibition with either dopamine or hyperoxicRinger solution via an indwelling close-carotid catheterresulted in increased peripheral muscle blood flow andconductance in exercising canines, and this responsecould be abolished with carotid body denervation or-adrenergic blockade (Stickland et al. 2007). Similarly,we saw a reduction in MSNA in humans duringhandgrip exercise when the CC was inhibited by hyperoxia(Stickland et al. 2008). The current study demonstrates

the physiological significance of the previous MSNAwork in humans, by showing that tonic CC activityrestrains exercising muscle blood flow during normoxicwhole-body exercise. It is noteworthy that despite adifferent exercise model (handgrip vs. leg extension) there

PeakChangein

Conductance(%)

0

10

20

30

40

Rest Exercise Exercisew/ dopamine

*

Figure 3. Peak 15 s change in femoral conductance to

transient hyperoxiaP< 0.05 vs. rest.

Table 3. Mean ( SEM) cardiorespiratory data at rest in normoxia

and hypoxia with either I.V. saline or dopamine (N= 9)

Normoxia Normoxia Hypoxia Hypoxia

saline dopamine saline dopamine

Heart rate 70 71 83 79

(beats min1) 2 2 3 2

Blood pressure 89 89 86 87(mmHg) 8 6 1 2

Tidal volume 863 767 1239 841

(ml) 163 105 166 75

Breathing frequency 13 13 14 13

(breaths min1) 1.0 1.0 1.4 0.7

Minute ventilation 10.0 9.6 16.4 11.3

(l min1) 0.9 0.8 1.6 0.9

End-tidal PO2 101 99 54 54

(mmHg) 3 2 3 5

End-tidal PCO2 42 43 35 39

(mmHg) 1 1 1 1

SpO2 98 96 85 85

(%) 0 0 1 1

P< 0.05 vs. normoxic saline, P< 0.05 vs. hypoxic saline.

Figure 4. Steady-state femoral blood flow and conductance

response to I.V. dopamine at rest in normoxia and hypoxiaP< 0.05 vs. normoxia.




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Table 4. Mean ( SEM) cardiorespiratory data during exercise in

normoxia and hypoxia with either I.V. saline or dopamine (N= 9)

Normoxia Normoxia Hypoxia Hypoxia

saline dopamine saline dopamine

Heart rate 104 110 120 121

(beats min1) 4 6 5 5

Blood pressure 101 97 99 101(mmHg) 4 4 5 5

Tidal volume 1591 1540 1800 1701

(ml) 144 151 154 114

Breathing frequency 23 22 25 24

(breaths min1) 1.1 1.1 1.7 1.2

Minute ventilation 36.0 33.1 42.6 39.7

(l min1) 2.6 3.0 2.0 1.5

End-tidal PO2 105 103 57 59

(mmHg) 2 2 3 4

End-tidal PCO2 40 41 36 38

(mmHg) 2 2 2 2

SpO2 97 97 86 85

(%) 0 0 1 1

P< 0.05 vs. normoxic saline, P< 0.05 vs. hypoxic saline.

was a similar time-course of response in both MSNAand blood flow/conductance following CC inhibition withhyperoxia.

In the current study, despite having the subjectsbreathe hyperoxic gas for 2 min, the vasodilatory responsereturned towards baseline values after60 s of hyperoxia.The mechanism(s) for this are unclear, but are probablyrelated to the increased oxygen delivery from systemichyperoxia and the corresponding reduction in blood flowrequirement to the exercising muscle and/or the auto-nomic response to prolonged hyperoxia. Previous studieshave shown that when subjects breathe hyperoxic gas forat least 5 min, there is a reduction in steady-state bloodflow at rest and during exercise compared to normoxia(Reich et al. 1970; Hansen & Madsen, 1973; Welch et al.1977; Gonzalez-Alonso et al. 2002; Casey et al. 2011b).These results indicate that steady-state skeletal muscleblood flow is regulated by the amount of oxygen available,and that with sustained increases in arterial O2 contentthere is a corresponding reduction in blood flow. Ofnote, our study was purposely designed to examine the

response to CC inhibition, which we have previouslyshown responds quickly to hyperoxia (Stickland et al.2007, 2008), and therefore we were primarily interested inthe immediate, transient blood flow response with hyper-oxia. Further, examining the transient response minimizesthe influence of secondary time-dependent influences,such as changes in O2 delivery, on the steady-statecardiovascular response (Britton & Metting, 1999). Inaddition, previous work has shown that prolonged hyper-oxia can increase central neural stimulation probably fromincreased oxidative stress(Dean etal. 2004). While we have

previously shown a reduction in MSNA during exercisewith 1 min of hyperoxia (Stickland etal. 2008),others haveshown that breathing hyperoxia for 34 min results in nochange in MSNA during steady-state exercise (Seals et al.1991a), while breathing hyperoxic gas for 15 min resultsin an increased MSNA response to exercise (Houssiereet al. 2006). Further, both Reich et al. (1970) and Welch

et al. (1977) found a reduction in blood flow duringsteady exercise with sustained (>10 min) hyperoxia, whileblood pressure was unchanged, prompting the authorsto conclude that prolonged hyperoxia increases vascularresistance. Thus, it seems likely that with sustainedexposure to hyperoxia muscle blood flow probably returnsto baseline or may even be further reduced because of theincreased arterial content with hyperoxia and/or the auto-nomic effect of prolonged hyperoxia.

Importantly, we were able to sustain the increase infemoral blood flow and conductance during exercise withconstant CC inhibition with I.V. dopamine. As a per cent

change from baseline, CC inhibition with I.V. dopamineresulted in a steady-state increase in femoral conductanceof 25%, which is below the peak change of 33% observedwith breathing hyperoxic gas. The lower response with

Cond

uctance

(mlmin-1(100mmHg)-1)

0

500

1000

1500

2000

2500

3000

Normoxia Hypoxia

*

NormoxiaDopamine

HypoxiaDopamine

**

BloodFlow(mlmin-1)

0

500

1000

1500

2000

2500

3000

Normoxia Hypoxia

*

NormoxiaDopamine

HypoxiaDopamine

*

*

Figure 5. Steady-state femoral blood flow and conductance

response to I.V. dopamine during exercise in normoxia and

hypoxiaP< 0.05 vs. normoxia.




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dopamine is probably explained by the use of 1 minaveraging as opposed to a peak 15 s response with hyper-oxia. In addition, the longer steady-state response withdopamine would result in recruitment of the myogenicmechanism, resulting in a lowered mean response withdopamine. Of note, the steady-state response to dopaminewas examined as opposed to a time-course response as it

was not possible to determine the precise onset of actionfor I.V. dopamine.

Consistent with previous human work (Heistad &Wheeler, 1970; Rowell et al. 1986; Koskolou et al. 1997;Weisbrod et al. 2001; Gonzalez-Alonso et al. 2002;Calbet et al. 2003; Dinenno et al. 2003; Wilkins et al.2006), hypoxia caused vasodilatation at rest and duringexercise as evidenced by increases in femoral conductance.These findings indicate that the local vasodilatory factorsproduced with hypoxia over-ride the increase in MSNAwith hypoxic exercise (Seals et al. 1991b). As mentionedpreviously, hypoxia potentiates the ventilatory (Weil

et al. 1972) and MSNA (Seals et al. 1991b) responseto exercise. In the current study, dopamine appeared toinhibit the CC while breathing hypoxia, as demonstratedby an increase in end-tidal CO2. Surprisingly, despiteevidence that the CCs were indeed inhibited, no significantcardiovascular response was observed. While sympatheticblockade experiments have shown that there is significantsympathetic restraint of muscle blood flow during hypoxic

whole-body exercise (Stickland et al. 2009), sympatheticoutflow may also be affected in hypoxia by feedbackfrom muscle metaboreceptors, muscle mechanoreceptors(Rowell & OLeary, 1990) and/or arterial baroreceptors(Halliwill et al. 2003). While sympathoexcitation iswell documented with hypoxia, Hanada et al. (2003)demonstrated that a reduction in arterial PO2 , and thus

chemoreception stimulation, may not be the key signalto evoke the elevation in MSNA with reduced bloodoxygenation. Hanada et al. (2003) found that whenO2 content is reduced via inhalation of CO to levelscomparable to breathing hypoxia, MSNA was increased atrest and during exercise similarly to what was observedwith hypoxia, while heart rate and ventilation werenot increased. While breathing CO, the carotid chemo-receptors were then inhibited with hyperoxia; however, noeffect on MSNA or blood flow was observed. These resultswould indicate that a second mechanism, independent ofthe CC, contributes to the MSNA response to hypoxia, and

these previous findings would explain our lack of bloodflow response to CC inhibition during hypoxia despiteventilatory evidence that the CCs were indeed inhibited.

Finally, alterations in peripheral vascular adrenergicsensitivity with hypoxia may explain the lack of cardio-vascular response with CC inhibition. There is evidenceof functional sympatholysis with hypoxia both at rest(Heistad & Wheeler, 1970; Hansen et al. 2000) and during

Figure 6. Blood flow response to transient hyperoxia during constant-work exercise while

simultaneously receiving 2 g kg1 I.V. dopamineP< 0.05 vs. mean 1 min baseline data.




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exercise (Hansen et al. 2000) as compared to normoxia.Therefore, while dopamine may have inhibited the CC,reducing sympathetic vasoconstrictor outflow, the neteffect on muscle blood flow may be minimal. Studiesusing direct measurement of MSNA would further theunderstanding of the CC contribution to sympathetic andmuscle blood flow control in hypoxia.

Previously, we have argued that the transient reductionin MSNA with hyperoxia during handgrip exercise wasthe direct result of CC inhibition (Stickland et al. 2008).The rationale for the reduction in MSNA being from theCC and not other systemic effects can be summarized asfollows: (1) the time-course of the response is consistentwith the circulatory time from lung to the CC estimated inthe healthy human (Sebert et al. 1990; Solin et al. 2000; Xieet al. 2006), (2) the timing of the sympathetic response toCC stimulation from hypoxia during exercise was virtuallyidentical to the previously documented hyperoxic MSNAresponse (Stickland et al. 2008), suggesting that both

MSNAresponsesweretheresultofCCmodulation,(3)theaortic chemoreceptors are much less sensitive to changesin PO2 as compared to the CC (Lahiri et al. 1981), (4)the central chemoreceptors are normally only sensitive toextremely low PO2 (Sun & Reis, 1994), and (5) centralhyperoxia appears to be excitatory to the central chemo-receptors,not inhibitory (Deanetal. 2004).Forthereasonslisted above, we would argue that the immediate femoralblood flow/conductance response observed in the pre-sent study were similarly the result of CC inhibition fromhyperoxia. Finally, the experiments wherebyI.V. dopaminewas infused during normoxic exercise and hyperoxia sub-sequently breathed, further support that the vasodilatoryresponse observed with transient hyperoxia was the resultof direct CC inhibition. In these experiments, the CCs weretonically inhibited with I.V. dopamine prior to receivinghyperoxia, and thus no further vasodilatation would beexpected. If the vasodilatory response from hyperoxia wasinstead the result of a systemic effect, we would haveexpected the response to be intact even while the CCs werebeing inhibited with dopamine. In summary, the previousstudies documenting a rapid CC response to a change inPO2 , the similar blood flow time-course of response to ourpreviousMSNA response to hyperoxia/hypoxia,combinedwith the abolishment of the vasodilatory response to

hyperoxia with simultaneous CC inhibition with I.V.dopamine support the interpretation that the increase inblood flow/conductance during exercise with hyperoxia ismost probably secondary to CC inhibition.

Unlike the canine model, we were not able to deliverclose-carotid injections of dopamine or hyperoxic Ringersolution to rapidly inhibit the CC. As a result, theremay have been systemic effects from I.V. dopamineadministration. As an example, in addition to inhibitingthe CC (Lahiri et al. 1980; Goldberg, 1989), low-dosedopamine can stimulate peripheral vascular dopamine

receptors, resulting in vasodilatation (Clark & Menninger,1980). However, if stimulation of the peripheral vasculardopamine receptors were the explanation for the vaso-dilatation observed during exercise, then we wouldhave expected vasodilatation to have occurred with I.V.dopamine at rest as well as during hypoxia. Being that weonly saw vasodilatation during normoxic exercise, which

is consistent with our hyperoxia response, we rationalizethat this was indeed secondary to CC inhibition.

Previous work of others (Biscoe & Purves, 1967; Weilet al. 1972; Forster et al. 1974; Seals et al. 1991b), as well asour more recent work (Stickland et al. 2007, 2008) wouldsuggest that exercise increases either basal CC activityand/or that chemoreceptor sensitivity is enhanced withexercise. We found evidence of increased chemoreceptoractivity despite no change in obvious circulating chemo-receptor stimuli (PO2 , PCO2 , [H

+], pH, lactate, potassium,etc.) (Stickland et al. 2007, 2008), suggesting a changein sensitization is more likely, rather than increased CC

stimulation with exercise. Importantly, the current studywasnot designed toexamine theunderlyingmechanism(s)for CC activation with exercise. The exact mechanismsfor CC sensitization with exercise are unclear, but mayoccur at the level of the chemoreflex and/or at the levelof central integration, and may involve feedback fromsomatic inputsfrom exercising muscle and/or feedforwardfrom central command. Future work is needed, probablyusing animal models, to examine exercise-inducedchemo-sensitivity and the resulting cardiovascular response.

Conclusion

Carotid chemoreceptor inhibition using eitherpharmacological (I.V. dopamine) or physiological(inhaled hyperoxia) interventions is associated with anincrease in femoral muscle blood flow and conductanceduring exercise. Surprisingly, CC inhibition did notaffect cardiovascular function in hypoxia either at restor during exercise. Our findings extend previous workin the canine, as well as work using isometric handgripexercise in humans, and demonstrate that the CC playsan important role in cardiovascular regulation duringnormoxic exercise.

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Author contributions

All authors contributed to the conception and design of

the experiments, as well as the drafting and revising of the

manuscript.M.K.S., D.P.F. and M.S.M. led on the data collection,analysis andinterpretation of data. Allauthorsapproved thefinal

version for publication.

Acknowledgements

This research was conducted through the Clinical Physiology

Laboratory, Alberta Cardiovascular and Stroke Research Centre(ABACUS), Mazankowski Alberta Heart Institute. The authors

gratefullyacknowledgethecontributionsofTraceyClare,andthe

volunteers who participated as subjects in this study. Funding

for this study was provided by the Heart and Stroke Foundation

of Canada. M.K.S. was supported by a Canadian Institutes ofHealth Research New Investigator Award and Heart and Stroke

Foundation of Canada New Investigator Award.



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Carotid Chemo Receptor Modulation of Blood Flow

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