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• W2104433225 abstract "Non-technical summary Exercise causes an increase in sympathetic activity which helps to redistribute blood flow while maintaining blood pressure. The exact mechanisms that regulate sympathetic activity and blood flow during exercise are not completely understood. By modulating the activity of a specific chemical receptor (the carotid chemoreceptor), we showed that this receptor 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 blood flow 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 blood flow 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, , ≈ 0.12, target arterial O2 saturation = 85%). Subjects breathed hyperoxic gas (≈ 1.0) and/or received intravenous dopamine to inhibit the CC while femoral arterial blood flow data were obtained continuously with pulsed Doppler ultrasound. Exercise increased heart rate, mean arterial pressure, femoral blood flow and conductance compared 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 flow and 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 blood flow, 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 carotid chemoreceptor contributes to skeletal muscle blood flow regulation during normoxic exercise in healthy humans, but that the influence of the CC on blood flow regulation in hypoxia is limited. Exercise increases sympathetic neural vasoconstrictor outflow, which acts to redistribute blood flow away from non-contracting muscle and other inactive vascular beds and to redirect cardiac output to contracting muscle (Buckwalter & Clifford, 2001). The increased sympathetic neural vasoconstrictor activity also partially constrains blood flow to exercising muscle (Joyner et al. 1992; Buckwalter & Clifford, 1999) in order to maintain blood pressure (Rowell & O’Leary, 1990). It is generally assumed that the increased sympathetic nervous activity during exercise results from feedforward mechanisms, including central command, as well as feedback from muscle metaboreceptors, muscle mechanoreceptors and/or a resetting of systemic baroreceptors (Rowell & O’Leary, 1990). The carotid chemoreceptors (CCs) are generally considered the major oxygen sensor in the body. CC stimulation causes an increase in ventilation (Olson et al. 1988; Curran et al. 2000), and elicits increases in sympathetic neural vasoconstrictor outflow to the skeletal muscle, renal and mesenteric vascular beds (Rutherford & Vatner, 1978; Balkowiec et al. 1993; Sun & Reis, 1994; Guyenet, 2000). CC sensitivity is significantly enhanced with exercise. Specifically, the ventilatory response to the CC stimulant doxapram is greater with exercise (Forster et al. 1974), and exercise has been shown to greatly potentiate the ventilatory (Weil et al. 1972) and muscle sympathetic nerve activity (MSNA) (Seals et al. 1991b) response to hypoxia. Passive exercise in anaesthetized animals has been shown to increase CC activity via feedback from the exercised limb in one (Biscoe & Purves, 1967), but not all, studies (Davies & Lahiri, 1973; Aggarwal et al. 1976). Recently, we have shown in dogs that specific, transient inhibition of the CC with either dopamine or hyperoxic Ringer solution during exercise caused peripheral vasodilatation, measured by increases in hindlimb flow and conductance (Stickland et al. 2007). The vasodilatory response was not observed at rest, and the vasodilatory response following CC inhibition during exercise was abolished with α-adrenergic blockade, indicating that vasodilatation was due to a reduction in sympathetic outflow. We subsequently found that transient CC inhibition with hyperoxia in humans reduced MSNA during handgrip exercise, but not at rest (Stickland et al. 2008). It is unknown whether this reduction in MSNA from CC inhibition observed in humans translates into an increase in muscle blood flow in the exercising limb. As mentioned above, hypoxia is associated with an increase in sympathetic vasoconstrictor output secondary to CC stimulation, and hypoxia potentiates the MSNA response to exercise (Seals et al. 1991b). α-Adrenergic blockade has demonstrated that there is considerable hypoxia-induced sympathetic restraint of muscle blood flow during exercise (Stickland et al. 2009). While not a consistent finding (Dinenno et al. 2003; Wilkins et al. 2006), some previous work has shown that the vascular response to sympathetic stimulation may be blunted with hypoxia both at rest (Heistad & Wheeler, 1970; Hansen et al. 2000) and during exercise (Hansen et al. 2000), suggesting hypoxia-induced functional sympatholysis, i.e. a reduced vasoconstriction in response to sympathetic stimulation (Remensnyder et al. 1962). It remains to be determined if the CC contributes to muscle blood flow regulation during hypoxia in humans. The purpose of the present investigation was to examine the 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 during exercise, as well as during hypoxia, and consequently, CC inhibition would cause peripheral vasodilatation during exercise and/or hypoxia. Thirteen healthy participants (9 men, 4 women) aged 33 ± 4 years (range, 28–35 years), of normal weight (82 ± 16 kg), height (175 ± 5 cm) and (51 ± 13 ml kg−1 min−1) participated in the study after providing written, informed consent. All of the subjects were physically active, with three subjects being endurance trained athletes who had values above 60 ml kg−1 min−1. All subjects were free from apparent cardiovascular disease as judged by normal resting EKG and a normal EKG/blood pressure response to exercise. No subject had evidence of baseline airflow obstruction or exercise-induced bronchoconstriction. No subjects were taking vasoactive medications. All four women were taking oral contraception; however, no apparent differences were observed with chemoreceptor inhibition between the men and women, and therefore all were combined into one group. The study was approved by the University of Alberta Health Research Ethics Board (Biomedical Panel). The study conformed to the standards set by the latest revision of the Declaration of Helsinki. Three experimental sessions were completed over a 3 week period in the following order: a graded cardiopulmonary exercise test to rule out exercise-induced ECG abnormalities and characterize , a practice session where subjects familiarized themselves with the knee-extension exercise set-up and performed a graded knee-extension exercise test to exhaustion, and the experimental day. For the experimental session, all data were recorded and integrated with a data acquisition system (Powerlab 16/30; ADInstruments, New South Wales, Australia) and analysed offline using associated software (LabChart 7.0 Pro; ADInstruments). Subjects breathed through a mouthpiece with the nose occluded. Inspired gas was humidified (HC 150; Fisher and Paykel Healthcare, Auckland, New Zealand) and delivered continuously using a flow-through system to prevent rebreathing of expired gas. Ventilation was measured by a pneumotachometer (3700 series; Hans Rudolph, Kansas City, MO, USA) just distal to the mouthpiece. Expired CO2 and O2 (mmHg) were measured (CD-3A and S-3A; AEI Technologies, Naperville, IL, USA) continuously from a small sample port off the mouthpiece to obtain end-tidal CO2 () and end-tidal O2 (). Arterial oxygen saturation () was estimated with pulse oximetry (N-595; Nellcor Oximax, Boulder, CO, USA) using a forehead sensor. Heart rate was recorded with a single-lead ECG (lead II, Dual Bio Amp; ADInstruments). Blood pressure was monitored using finger photoplethysmography which was calibrated to brachial blood at regular intervals (Finometer model 2; Finapres, Amsterdam, the Netherlands). Similar to previous work (DeLorey et al. 2004; MacPhee et al. 2005), femoral arterial mean blood velocity was obtained from the right leg by using pulsed-wave Doppler ultrasound (GE Vivid-7, 4–5 MHz, <60 deg angle of insonation) by a cardiologist with expertise in peripheral vascular ultrasound (MSM). The ultrasound probe was positioned distal to the inguinal ligament, but proximal to the femoral artery bifurcation. The quadrature output of the ultrasound spectrum of velocities was demodulated (model 500M; Multigon, Yonkers, NY, USA) to provide a continuous analog signal of the instantaneous forward and backward blood velocity (Shoemaker et al. 2000), and the velocity data were then integrated into the Powerlab. Femoral arterial diameter was determined at baseline and immediately after exercise. No significant difference in femoral diameter was observed with exercise, which is consistent with previous work showing no difference with normoxic (Radegran, 1997; MacDonald et al. 1998; Radegran & Saltin, 1998; MacPhee et al. 2005) or hypoxic exercise (DeLorey et al. 2004), and therefore the baseline diameter was used throughout. Leg blood flow was calculated as (in millilitres per minute) the mean blood velocity (cm s−1) πr2× 60, where r is the radius of the femoral artery (DeLorey et al. 2004; MacPhee et al. 2005). Femoral vascular conductance was calculated as femoral blood flow/mean arterial pressure and expressed as millimeters per minute per 100 mmHg (Casey et al. 2011a). Prior to the experimental session, an intravenous (i.v.) catheter was inserted into an antecubital vein in the arm. Subjects received either isotonic i.v. saline or i.v. dopamine HCl (2 μg kg−1 min−1; Hospira, Lake Forest, IL, USA) via an automated constant-infusion pump (Alaris, San Diego, CA, USA). This dose was selected as it has previously been shown to inhibit the carotid chemoreceptors (Lahiri et al. 1980; Goldberg, 1989). Higher doses (i.e. 4 μg kg−1 min−1) were not given as these resulted in hypertension during pilot work. Inspired oxygen was modulated using either an air–oxygen or air–nitrogen blender system. Two-minute hyperoxia interventions (≈ 1.0) were conducted at rest and during steady-state exercise. For trials conducted during hypoxia, a of 85% was targeted by adding nitrogen to the inspired air. For the hypoxic trials, subjects breathed hypoxic gas for 10 min before data collection was initiated. Two-legged knee exercise was performed on a custom-built apparatus attached to a Monark cycle ergometer (Model 818E) similar to equipment previously described (MacPhee et al. 2005). Based on the practice session, the workload for the exercise trials was set to the highest intensity that could be sustained for the entire trial while limiting movement and obtaining good-quality continuous Doppler data. Subjects maintained a consistent leg extension frequency and power output throughout each exercise trial, and the exercise intensity was equivalent to 77 ± 4% of peak knee-extension workload. Typically, the subject exercised for 2–3 min to obtain a steady state in cardiovascular variables, then an intervention was conducted. Subjects performed a total of six exercise trials (4 normoxia, 2 hypoxia), and each trial was under 10 min in duration. Following instrumentation, subjects breathed freely on the mouthpiece for 10 min so that resting eupnoeic data could be obtained. Interventions were then conducted at rest, during steady-state exercise and then while breathing hypoxia (target 85%). At rest, interventions performed in random order were: (1) i.v. saline, (2) inhaled hyperoxia (≈ 1.0) and (3) i.v. dopamine. During steady-state exercise, interventions performed in random order were: (1) i.v. saline, (2) inhaled hyperoxia (≈ 1.0), (3) i.v. dopamine and (4) inhaled hyperoxia during steady-state i.v. dopamine. While recent evidence suggests that the blood flow response between randomized hypoxic and normoxic trials is reproducible (Casey et al. 2011a), hypoxic interventions were performed last so as to avoid any possible hypoxia-induced sensitization of the CC which could potentially confound the normoxic trials. The steady-state rest and exercise hypoxic interventions performed in random order were: (1) i.v. saline and (2) i.v. dopamine. All trials were separated by 10 min to allow recovery and clearance of dopamine (Gilman et al. 1985). For all inferential analyses, the probability of type I error was set at 0.05. Group data for each variable are expressed as means ± SEM. Trials were only analysed if good consistent Doppler data were obtained throughout the trial. As we have previously shown the response to hyperoxia to be rapid (Stickland et al. 2008), the mean 15 s changes from baseline with inhaled hyperoxia were compared at rest and exercise using a repeated-measures ANOVA. Where main effects were found, Fisher least significant difference post hoc tests were used. The peak 15 s value for blood flow and conductance within each hyperoxic intervention was also determined, and the peak response at rest was compared to the peak response during exercise using a paired t test. For all dopamine and hypoxia trials 1 min average steady-state data were obtained and comparisons were conducted with repeated-measures ANOVA. See Table 1 for grouped cardiorespiratory data. Within 15 s of breathing hyperoxia was increased above baseline. Likewise, was increased above baseline within 30 s of breathing hyperoxia. As compared to normoxia, breathing hyperoxia at rest did not change heart rate, mean arterial pressure, femoral blood flow or femoral conductance (Fig. 1). Blood flow response to transient hyperoxia at rest *P < 0.05 vs. mean 1 min baseline data. See Table 2 for grouped cardiorespiratory data. Exercise itself significantly increased heart rate, mean arterial pressure, tidal volume, breathing frequency, minute ventilation, femoral blood flow and femoral conductance compared to resting values. Similar to the response at rest, within 15 s of breathing hyperoxia, was increased above baseline, while was increased above baseline within 30 s of breathing hyperoxia. Heart rate was increased over the first 30 s of breathing hyperoxia. Femoral blood flow and conductance was increased transiently above baseline within 30 s of breathing hyperoxia, and remained elevated for 30 s before returning to baseline values (see Fig. 2). The peak 15 s change in femoral conductance at rest or during exercise within the initial 60 s of breathing hyperoxia was also determined for each trial and reported in Fig. 3. Hyperoxia given during exercise resulted in a greater change in peak conductance as compared to rest. Blood flow response to transient hyperoxia during constant-work exercise *P < 0.05 vs. mean 1 min baseline data. Peak 15 s change in femoral conductance to transient hyperoxia *P < 0.05 vs. rest. See Table 3 for grouped cardiorespiratory data. While breathing room air, dopamine resulted in a small increase in compared to saline control; however, minute ventilation was not significantly different (P= 0.10). As compared to i.v. saline, dopamine at rest did not change heart rate, mean arterial pressure, femoral blood flow or femoral conductance (Fig. 4). Steady-state femoral blood flow and conductance response to i.v. dopamine at rest in normoxia and hypoxia *P < 0.05 vs. normoxia. See Table 4 for grouped cardiorespiratory data. During exercise, dopamine caused a reduction in ventilation and a corresponding increase in in all subjects, indicating that all subjects had chemoreceptor inhibition with dopamine. Heart rate, femoral blood flow and femoral conductance were increased with dopamine in all subjects, while blood pressure was reduced as compared to control i.v. saline (Fig. 5). No other cardiorespiratory differences were observed between dopamine and i.v. saline during exercise. Steady-state femoral blood flow and conductance response to i.v. dopamine during exercise in normoxia and hypoxia *P < 0.05 vs. normoxia. The femoral blood flow and conductance response to transient hyperoxia during exercise while simultaneously receiving i.v. dopamine are detailed in Fig. 6. Unlike what is observed when hyperoxia was given while receiving i.v. saline, there was no transient effect of hyperoxia on femoral blood flow, conductance, heart rate or mean arterial pressure when simultaneously receiving i.v. dopamine. Blood flow response to transient hyperoxia during constant-work exercise while simultaneously receiving 2 μg kg−1 i.v. dopamine *P < 0.05 vs. mean 1 min baseline data. See Table 3 for grouped cardiorespiratory data. As compared to normoxia, hypoxia resulted in a reduction in and . Hypoxia increased heart rate and minute ventilation, while was correspondingly decreased. Femoral blood flow and conductance were increased with hypoxia (see Fig. 4). Compared to i.v. saline, dopamine administered while breathing hypoxia reduced tidal volume, minute ventilation and increase in all subjects. Femoral blood flow, conductance and mean arterial pressure were unchanged with dopamine. See Table 4 for grouped cardiorespiratory data. As compared to normoxic exercise, hypoxic exercise resulted in a lower and . Minute ventilation was increased, and correspondingly, was reduced with hypoxia, while heart rate, femoral blood flow and femoral conductance were increased (see Fig. 5) as compared to normoxic exercise. As compared to saline control infusions, i.v. dopamine caused a reduction in minute ventilation and an increase in during hypoxic exercise in all subjects. No other cardiorespiratory differences were observed between saline and dopamine infusions during hypoxic exercise. Inhibition of the carotid chemoreceptor using either pharmacological (i.v. dopamine) or physiological (inhaled hyperoxia) interventions resulted in an increase in femoral muscle blood flow and conductance during exercise in healthy humans. Carotid chemoreceptor inhibition at rest did not result in a similar increase in peripheral blood flow. When the CCs were inhibited by a constant infusion of i.v. dopamine, additional inhibition with hyperoxia did not produce any additional increase in muscle blood flow or conductance. Despite ventilatory evidence that dopamine reduced CC activity during hypoxia, CC inhibition with i.v. dopamine did not affect muscle blood flow or conductance at rest, nor did it affect muscle blood flow during exercise in hypoxia. Combined, these results indicate that the CC contributes to the sympathetic control of skeletal muscle blood flow during normoxic exercise. Our main finding, that the CC contributes to the sympathetic control of skeletal muscle blood flow during exercise, extends the findings of our earlier work (Stickland et al. 2007, 2008). Previously, we showed that direct CC inhibition with either dopamine or hyperoxic Ringer solution via an indwelling close-carotid catheter resulted in increased peripheral muscle blood flow and conductance in exercising canines, and this response could be abolished with carotid body denervation or α-adrenergic blockade (Stickland et al. 2007). Similarly, we saw a reduction in MSNA in humans during handgrip exercise when the CC was inhibited by hyperoxia (Stickland et al. 2008). The current study demonstrates the physiological significance of the previous MSNA work in humans, by showing that tonic CC activity restrains exercising muscle blood flow during normoxic whole-body exercise. It is noteworthy that despite a different exercise model (handgrip vs. leg extension) there was a similar time-course of response in both MSNA and blood flow/conductance following CC inhibition with hyperoxia. In the current study, despite having the subjects breathe hyperoxic gas for 2 min, the vasodilatory response returned towards baseline values after ∼60 s of hyperoxia. The mechanism(s) for this are unclear, but are probably related to the increased oxygen delivery from systemic hyperoxia and the corresponding reduction in blood flow requirement to the exercising muscle and/or the autonomic response to prolonged hyperoxia. Previous studies have shown that when subjects breathe hyperoxic gas for at least 5 min, there is a reduction in steady-state blood flow 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 muscle blood flow is regulated by the amount of oxygen available, and that with sustained increases in arterial O2 content there is a corresponding reduction in blood flow. Of note, our study was purposely designed to examine the response to CC inhibition, which we have previously shown responds quickly to hyperoxia (Stickland et al. 2007, 2008), and therefore we were primarily interested in the immediate, transient blood flow response with hyperoxia. Further, examining the transient response minimizes the influence of secondary time-dependent influences, such as changes in O2 delivery, on the steady-state cardiovascular response (Britton & Metting, 1999). In addition, previous work has shown that prolonged hyperoxia can increase central neural stimulation probably from increased oxidative stress (Dean et al. 2004). While we have previously shown a reduction in MSNA during exercise with 1 min of hyperoxia (Stickland et al. 2008), others have shown that breathing hyperoxia for 3–4 min results in no change in MSNA during steady-state exercise (Seals et al. 1991a), while breathing hyperoxic gas for 15 min results in an increased MSNA response to exercise (Houssiere et al. 2006). Further, both Reich et al. (1970) and Welch et al. (1977) found a reduction in blood flow during steady exercise with sustained (>10 min) hyperoxia, while blood pressure was unchanged, prompting the authors to conclude that prolonged hyperoxia increases vascular resistance. Thus, it seems likely that with sustained exposure to hyperoxia muscle blood flow probably returns to baseline or may even be further reduced because of the increased arterial content with hyperoxia and/or the autonomic effect of prolonged hyperoxia. Importantly, we were able to sustain the increase in femoral blood flow and conductance during exercise with constant CC inhibition with i.v. dopamine. As a per cent change from baseline, CC inhibition with i.v. dopamine resulted in a steady-state increase in femoral conductance of 25%, which is below the peak change of 33% observed with breathing hyperoxic gas. The lower response with dopamine is probably explained by the use of 1 min averaging as opposed to a peak 15 s response with hyperoxia. In addition, the longer steady-state response with dopamine would result in recruitment of the myogenic mechanism, resulting in a lowered mean response with dopamine. Of note, the steady-state response to dopamine was examined as opposed to a time-course response as it was not possible to determine the precise onset of action for 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 during exercise as evidenced by increases in femoral conductance. These findings indicate that the local vasodilatory factors produced with hypoxia over-ride the increase in MSNA with hypoxic exercise (Seals et al. 1991b). As mentioned previously, hypoxia potentiates the ventilatory (Weil et al. 1972) and MSNA (Seals et al. 1991b) response to exercise. In the current study, dopamine appeared to inhibit the CC while breathing hypoxia, as demonstrated by an increase in end-tidal CO2. Surprisingly, despite evidence that the CCs were indeed inhibited, no significant cardiovascular response was observed. While sympathetic blockade experiments have shown that there is significant sympathetic restraint of muscle blood flow during hypoxic whole-body exercise (Stickland et al. 2009), sympathetic outflow may also be affected in hypoxia by feedback from muscle metaboreceptors, muscle mechanoreceptors (Rowell & O’Leary, 1990) and/or arterial baroreceptors (Halliwill et al. 2003). While sympathoexcitation is well documented with hypoxia, Hanada et al. (2003) demonstrated that a reduction in arterial , and thus chemoreception stimulation, may not be the key signal to evoke the elevation in MSNA with reduced blood oxygenation. Hanada et al. (2003) found that when O2 content is reduced via inhalation of CO to levels comparable to breathing hypoxia, MSNA was increased at rest and during exercise similarly to what was observed with hypoxia, while heart rate and ventilation were not increased. While breathing CO, the carotid chemoreceptors were then inhibited with hyperoxia; however, no effect on MSNA or blood flow was observed. These results would indicate that a second mechanism, independent of the CC, contributes to the MSNA response to hypoxia, and these previous findings would explain our lack of blood flow response to CC inhibition during hypoxia despite ventilatory evidence that the CCs were indeed inhibited. Finally, alterations in peripheral vascular adrenergic sensitivity with hypoxia may explain the lack of cardiovascular response with CC inhibition. There is evidence of functional sympatholysis with hypoxia both at rest (Heistad & Wheeler, 1970; Hansen et al. 2000) and during exercise (Hansen et al. 2000) as compared to normoxia. Therefore, while dopamine may have inhibited the CC, reducing sympathetic vasoconstrictor outflow, the net effect on muscle blood flow may be minimal. Studies using direct measurement of MSNA would further the understanding of the CC contribution to sympathetic and muscle blood flow control in hypoxia. Previously, we have argued that the transient reduction in MSNA with hyperoxia during handgrip exercise was the direct result of CC inhibition (Stickland et al. 2008). The rationale for the reduction in MSNA being from the CC and not other systemic effects can be summarized as follows: (1) the time-course of the response is consistent with the circulatory time from lung to the CC estimated in the healthy human (Sebert et al. 1990; Solin et al. 2000; Xie et al. 2006), (2) the timing of the sympathetic response to CC stimulation from hypoxia during exercise was virtually identical to the previously documented hyperoxic MSNA response (Stickland et al. 2008), suggesting that both MSNA responses were the result of CC modulation, (3) the aortic chemoreceptors are much less sensitive to changes in as compared to the CC (Lahiri et al. 1981), (4) the central chemoreceptors are normally only sensitive to extremely low (Sun & Reis, 1994), and (5) central hyperoxia appears to be excitatory to the central chemoreceptors, not inhibitory (Dean et al. 2004). For the reasons listed above, we would argue that the immediate femoral blood flow/conductance response observed in the present study were similarly the result of CC inhibition from hyperoxia. Finally, the experiments whereby i.v. dopamine was infused during normoxic exercise and hyperoxia subsequently breathed, further support that the vasodilatory response observed with transient hyperoxia was the result of direct CC inhibition. In these experiments, the CCs were tonically inhibited with i.v. dopamine prior to receiving hyperoxia, and thus no further vasodilatation would be expected. If the vasodilatory response from hyperoxia was instead the result of a systemic effect, we would have expected the response to be intact even while the CCs were being inhibited with dopamine. In summary, the previous studies documenting a rapid CC response to a change in , the similar blood flow time-course of response to our previous MSNA response to hyperoxia/hypoxia, combined with the abolishment of the vasodilatory response to hyperoxia with simultaneous CC inhibition with i.v. dopamine support the interpretation that the increase in blood flow/conductance during exercise with hyperoxia is most probably secondary to CC inhibition. Unlike the canine model, we were not able to deliver close-carotid injections of dopamine or hyperoxic Ringer solution to rapidly inhibit the CC. As a result, there may have been systemic effects from i.v. dopamine administration. As an example, in addition to inhibiting the CC (Lahiri et al. 1980; Goldberg, 1989), low-dose dopamine can stimulate peripheral vascular dopamine receptors, resulting in vasodilatation (Clark & Menninger, 1980). However, if stimulation of the peripheral vascular dopamine receptors were the explanation for the vasodilatation observed during exercise, then we would have expected vasodilatation to have occurred with i.v. dopamine at rest as well as during hypoxia. Being that we only saw vasodilatation during normoxic exercise, which is consistent with our hyperoxia response, we rationalize that this was indeed secondary to CC inhibition. Previous work of others (Biscoe & Purves, 1967; Weil et al. 1972; Forster et al. 1974; Seals et al. 1991b), as well as our more recent work (Stickland et al. 2007, 2008) would suggest that exercise increases either basal CC activity and/or that chemoreceptor sensitivity is enhanced with exercise. We found evidence of increased chemoreceptor activity despite no change in obvious circulating chemoreceptor stimuli (, , [H+], pH, lactate, potassium, etc.) (Stickland et al. 2007, 2008), suggesting a change in sensitization is more likely, rather than increased CC stimulation with exercise. Importantly, the current study was not designed to examine the underlying mechanism(s) for CC activation with exercise. The exact mechanisms for CC sensitization with exercise are unclear, but may occur at the level of the chemoreflex and/or at the level of central integration, and may involve feedback from somatic inputs from exercising muscle and/or feedforward from central command. Future work is needed, probably using animal models, to examine exercise-induced chemosensitivity and the resulting cardiovascular response. Carotid chemoreceptor inhibition using either pharmacological (i.v. dopamine) or physiological (inhaled hyperoxia) interventions is associated with an increase in femoral muscle blood flow and conductance during exercise. Surprisingly, CC inhibition did not affect cardiovascular function in hypoxia either at rest or during exercise. Our findings extend previous work in the canine, as well as work using isometric handgrip exercise in humans, and demonstrate that the CC plays an important role in cardiovascular regulation during normoxic exercise. 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 and interpretation of data. All authors approved the final version for publication. This research was conducted through the Clinical Physiology Laboratory, Alberta Cardiovascular and Stroke Research Centre (ABACUS), Mazankowski Alberta Heart Institute. The authors gratefully acknowledge the contributions of Tracey Clare, and the 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 of Health Research New Investigator Award and Heart and Stroke Foundation of Canada New Investigator Award." @default.
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• W2104433225 date "2011-12-14" @default.
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• W2104433225 title "Carotid chemoreceptor modulation of blood flow during exercise in healthy humans" @default.
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• W2104433225 doi "https://doi.org/10.1113/jphysiol.2011.218099" @default.
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