Dopamine receptor blockade improves pulmonary gas exchange but decreases exercise performance in healthy humans

Abstract

Pulmonary gas exchange, as evaluated by the alveolar–arterial oxygen difference (A-a), is impaired during intense exercise, and has been correlated with recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) as measured by agitated saline contrast echocardiography. Previous work has shown that dopamine (DA) recruits IPAVA and increases venous admixture () at rest. As circulating DA increases during exercise, we hypothesized that A-a and IPAVA recruitment would be decreased with DA receptor blockade. Twelve healthy males (age: 25 ± 6 years, : 58.6 ± 6.5 ml kg⁻¹ min⁻¹) performed two incremental staged cycling exercise sessions after ingestion of either placebo or a DA receptor blocker (metoclopramide 20 mg). Arterial blood gas, cardiorespiratory and IPAVA recruitment (evaluated by agitated saline contrast echocardiography) data were obtained at rest and during exercise up to 85% of . On different days, participants also completed incremental exercise tests and exercise tolerance (time-to-exhaustion (TTE) at 85% of ) with or without dopamine blockade. Compared to placebo, DA blockade did not change O₂ consumption, CO₂ production, or respiratory exchange ratio at any intensity. At 85% , DA blockade decreased A-a, increased arterial O₂ saturation and minute ventilation, but did not reduce IPAVA recruitment, suggesting that positive saline contrast is unrelated to A-a. Compared to placebo, DA blockade decreased maximal cardiac output, and TTE. Despite improving pulmonary gas exchange, blocking dopamine receptors appears to be detrimental to exercise performance. These findings suggest that endogenous dopamine is important to the normal cardiopulmonary response to exercise and is necessary for optimal high-intensity exercise performance.

Key points

• At rest, dopamine induces recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) and increases venous admixture (i.e. ).

• Dopamine increases during exercise, and may be partly responsible for exercise-induced IPAVA recruitment.

• In this study, we antagonized dopamine receptors with metoclopramide, and observed improved pulmonary gas exchange but no difference in IPAVA recruitment during exercise.

• Dopamine blockade decreased cardiac output at peak exercise, resulting in decreased exercise performance.

• Increasing endogenous dopamine is important for the normal healthy response to exercise.

Introduction

Intense aerobic exercise has been shown to decrease the efficiency of gas exchange in highly trained humans, as demonstrated by an increase in the alveolar–arterial oxygen difference (A-a) (Dempsey et al. 1984; Hammond et al. 1986). Increased A-a during exercise was classically thought to be a result of diffusion O₂ limitation (Dempsey et al. 1984) or inequality (Dempsey et al. 1984; Schaffartzik et al. 1992; Hopkins et al. 1999) secondary to transient interstitial pulmonary oedema or reduced pulmonary transit time. More recent research suggests that intrapulmonary arteriovenous anastomoses (IPAVA), as detected by agitated saline contrast echocardiography, are recruited during exercise (Stickland et al. 2004; Eldridge et al. 2004), and appear related to gas exchange impairment (Stickland et al. 2004). However, this anatomical evidence of IPAVA is in contrast to the considerable inert gas data which has not shown measurable right-to-left shunt during exercise (Wagner et al. 1986; Hopkins et al. 1994; Rice et al. 1999). Thus, the mechanism of IPAVA recruitment and its association with increases in A-a during heavy exercise is the subject of an unresolved debate (Hopkins et al. 2009b,2009c; Lovering et al. 2009a).

During exercise, endogenous dopamine (DA) concentrations increase curvilinearly with intensity (Hopkins et al. 2009a). Importantly, there is evidence that dopamine causes gas exchange impairment, as dopamine infusion increases venous admixture () in resting supine humans (Bryan et al. 2012) and increases right-to-left shunt ( = 0 as detected by the multiple inert gas elimination technique; MIGET) in critically ill patients with pre-existing shunt (Rennotte et al. 1989). Dopamine also decreases pulmonary vascular resistance secondary to vasodilatation in the pulmonary vasculature in both humans (Gorman, 1988; Beaulieu & Gainetdinov, 2011; Bryan et al. 2012) and animal models (Hoshino et al. 1986; Polak et al. 1992; Polak & Drummond, 1993). Additionally, our previous investigation reported that dopamine increased IPAVA recruitment with the concurrent increase in venous admixture () (Bryan et al. 2012).

We hypothesized that exercise-associated increases in dopamine concentration (Hopkins et al. 2009a) are responsible for IPAVA recruitment (Bryan et al. 2012) and correspondingly impair gas exchange with exercise; thus, dopamine blockade during exercise would improve gas exchange and reduce IPAVA recruitment. Additionally, in contrast to their detrimental effect on gas exchange, it has been speculated that these IPAVA may be important to help improve cardiac output (Stickland et al. 2004; La Gerche et al. 2010; Lalande et al. 2012), and exercise tolerance by reducing pulmonary vascular resistance, and thereby offloading the right ventricle. Thus, we also hypothesized that despite improving gas exchange, administration of a dopamine blockade would be detrimental to exercise performance.

Methods

Ethical approval

This study was approved by the Human Research Ethics Board (Biomedical Panel) at the University of Alberta, and all procedures conformed to the Declaration of Helsinki. All participants gave written, informed consent to participate.

Study design overview

This study consisted of four phases that were separated by at least a week. Phase 1: preliminary testing including pre-screening and progressive incremental exercise test (n = 12). Phase 2: evaluation of pulmonary gas exchange and intrapulmonary arteriovenous anastomosis recruitment during exercise with or without dopamine blockade. To validate this protocol, a separate sample of participants completed an identical protocol, but with placebo at both time points (n = 15). Phase 3: time-to-exhaustion (TTE) trials at 85% of , with or without dopamine blockade (order randomized and separated by at least 48 h). Phase 4: incremental exercise test to on a cycle ergometer with or without dopamine blockade (order randomized and separated by at least 48 h) (n = 15).

Phase 1: preliminary testing

Twelve healthy, non-smoking males (mean age ± SD: 25 ± 6 years, : 4.39 ± 0.59 l min⁻¹; 56.6 ml kg⁻¹ min⁻¹) participated in phases 1–3.

Participants completed physical activity readiness questionnaires (PAR-Q), were screened for any cardiopulmonary disorders and/or medications, and were screened for presence of a patent foramen ovale (PFO) with Doppler echocardiography and agitated saline contrast (FASE et al. 2014). No PFOs were observed in any study participant. Additionally, participants were screened for risks associated with ingestion of a telemetry pill. Participants then performed an incremental cycle (Ergoselect II 1200 Ergoline, Blitz, Germany) test to volitional fatigue to determine (Encore229 Vmax, SensorMedics, Yorba Linda, CA, USA). The initial power output was set to 50 W and the power output was increased by 25 W every 2 min until ventilatory threshold was reached, as identified by a systematic increase in both the slope of the / and respiratory exchange ratio (RER)–power output curve (Wasserman, 1987). Each stage above ventilatory threshold was characterized by increments of 25 W per minute. The criterion for confirmation of required that at least three of the four following conditions were met: volitional exhaustion; a RER greater than 1.1; increases in oxygen consumption less than 100 ml min⁻¹ with further increases in power output; and reaching age-predicted maximum heart rate.

Phase 2: evaluation of gas exchange and intrapulmonary arteriovenous anastomosis recruitment

No less than 48 h after preliminary testing, participants returned to complete the gas exchange/agitated saline contrast echocardiography trial. Participants ingested a placebo pill and were then instrumented with an antecubital intravenous catheter, and a separate catheter was inserted into the radial artery for blood sampling (detailed in ‘Instrumentation and measurements’ below). Echocardiograms were performed at rest and during exercise at 30%, 50%, 70% and 85% of the power output at previously determined . Measurements were taken approximately 3 min into each 6 min stage, during steady state exercise. The relative power outputs were chosen in order to characterize the effect of the drug across varying intensities. After the first exercise period, participants ingested a dopamine blocker (metoclopramide, 20 mg orally), and recovered for 60 min before repeating an identical exercise protocol. Participants were blinded to the order of placebo and metoclopramide ingestion.

Metoclopramide

Metoclopramide is a dopamine-2 receptor antagonist; the time to peak systemic bioavailabilty of oral metoclopramide is <60 min (Taylor & Bateman, 1986; Baxter, Healthcare Corporation, 2010). Previous studies using metoclopramide have administered doses up to 40 mg (Velasco et al. 1995; Contreras et al. 2010); however, through pilot work, we determined that 20 mg was an effective dose to elicit an increase in exercise ventilation, with no apparent side-effects.

Instrumentation and measurements

A 22-gauge intravenous catheter (Insyte-W, BD, Franklin Lakes, NJ, USA) was inserted into an antecubital vein, and attached via 6-inch extension tubing to a three-way stopcock for agitation and injection of agitated saline for contrast echocardiography (Bryan et al. 2012). A 20-gauge angiocatheter (Insyte-W, BD) was inserted into the radial artery using local anaesthesia (1% lidocaine). Both catheters were kept patent using a pressurized flush system of normal saline, and samples were immediately analysed with an ABL800 FLEX blood gas analyser for , and (Radiometer Medical Aps, Brønshøj, Denmark). Core temperature was measured via telemetry capsule concurrent to arterial blood gas sampling in order to correct for increasing temperature (VitalSense, Mini Mitter Co. Inc., Bend, OR, USA). Respiratory gas-exchange data were collected using a metabolic measurement system (Encore229 Vmax, SensorMedics, Yorba Linda, CA, USA). Pulse oxygen saturation () was monitored using finger pulse oximetry (N-595; Nellcor Oximax, Boulder, CO, USA). Heart rate was measured by electrocardiography (CardioSoft, GG Medical Systems, Milwaukee, WI, USA). Cardiac output was determined beat-by-beat with impedance cardiography (PhysioFlow, Manatec, Paris, France), which has shown good agreement with the direct Fick method in previous studies (Edmunds et al. 1982; Charloux et al. 2000). All instruments were calibrated before each exercise session, and calibrations were verified at the conclusion of each session.

Contrast echocardiography

Agitated saline contrast echocardiography was used to quantify intracardiac shunt and intrapulmonary arteriovenous anastomoses, according to previously published methodologies (Stickland et al. 2004; Lovering et al. 2008a; Bryan et al. 2012). Briefly, 10 ml of saline was combined with 0.5 ml of air, and the solution was forcefully agitated through a three-way stopcock between two syringes to form fine suspended bubbles, and then injected into the antecubital i.v. catheter. A four-chamber view of the heart was recorded prior to and during contrast injection with a minimum of 20 cardiac cycles recorded. All echocardiograms were performed by one experienced sonographer (ECHOPac, Vivid Q, GE), and were later analysed by a cardiologist who was blinded to experimental conditions (exercise intensity and drug condition). Intra-cardiac shunt was graded by the appearance of contrast in the left ventricle in less than five cardiac cycles. The appearance of contrast in the left ventricle after five cardiac cycles suggests an IPAVA. No participant had evidence of an intra-cardiac shunt during the study. IPAVA was scored based on a previously described scoring system used in our laboratory (Stickland et al. 2004; Bryan et al. 2012) and others (Lovering et al. 2008b). We attempted to obtain Doppler derived pulmonary arterial systolic pressure (PASP) data at each workload; however, the lack of sufficient tricuspid regurgitant jet in most participants prevented these calculations.

Protocol validation

To address any potential order effect, a separate sample of participants (n = 15) completed an identical study protocol to the gas exchange experiment, but were given placebo pills at both Time 1 (T₁) and Time 2 (T₂). Importantly, core temperature returned to baseline resting levels before the second bout of exercise began (rest: T₁, 36.82 ± 1.24°C and T₂, 37.18 ± 0.20°C, P = 0.67). Oxygen consumption (), carbon dioxide production (), respiratory exchange ratio (RER), minute ventilation (), heart rate (HR) and were not different between T₁ and T₂ at rest or at any exercise intensity, and the change in core temperature from rest was not significantly different between T₁ and T₂ at any exercise intensity. The lack of an observed difference between the two incremental exercise sessions with placebo alone suggests no order effect from the protocol.

Phase 3: time to fatigue

Participants completed two time-to-exhaustion (TTE) trials (placebo vs. blockade, order randomized) on two separate days, at the same time of day. One hour before arrival at the laboratory, participants ingested placebo or dopamine blockade pills. Participants warmed-up at a self-selected intensity and duration, and then began a TTE trial at a power output corresponding to 85% of . Time was recorded from the onset of exercise to volitional exhaustion, defined as the inability of the participant to maintain a minimum cadence of 60 r.p.m. At least 48 h but not more than a week later, participants completed the remaining trial in the alternative condition.

Phase 4: incremental exercise testing

A separate sample of 15 healthy, non-smoking male participants (mean age ± SEM: 24 ± 1 years; height: 1.77 ± 0.02 m; mass: 80.3 ± 2.3 kg; : 4.02 ± 0.19 l min⁻¹, 52.1 ± 2.4 ml kg⁻¹ min⁻¹) participated in phase 4. This sample included five participants from phases 1–3.

Participants reported to the laboratory and ingested either a placebo pill or dopamine blocker. After 1 h, participants completed an incremental exercise test to volitional exhaustion (described above in preliminary testing). At least 48 h but not more than a week later, participants completed the remaining trial in the alternative condition.

Statistical analysis

Statistical analysis was performed using two-way repeated-measures ANOVA (SigmaPlot, v.11.1, Systat Software, Inc., San Jose, CA, USA). For the evaluation of gas exchange and IPAVA score, physiological responses (, , RER, , HR, core temperature), gas exchange variables (, , , A-a), and cardiovascular responses (, HR, SV, systolic and diastolic BP, mean arterial pressure), there were two repeated measures: exercise intensity and drug condition, with five levels of exercise intensity (rest, 30%, 50%, 70% and 85% of ) and two levels of drug condition (placebo, blockade). For the evaluation of IPAVA recruitment (IPAVA score), there were three levels of exercise intensity (rest, 70% and 85% of ) and two levels of drug condition (placebo and blockade). When main effects were found, Fisher’s least significant difference post hoc test was used. Linear regression was performed to determine relationships at peak exercise intensity between (1) change in cardiac output and A-a, (2) change in A-a and change in IPAVA score, and (3) change in IPAVA score and change in cardiac output. Note, some data were missing from two participants at peak exercise due to some technical difficulties, and therefore correlations were conducted with only 10 participants. Student’s t test for paired data was used to evaluate the effect of dopamine blockade on exercise performance: time-to-exhaustion, , RER_max, , HR_max, SV_max, peak power and . The order of these tests (placebo, blockade) was randomized. We accepted a type I error of 0.05 to determine a significant difference between variables.

Results

All participants tolerated the study phases and procedures well.

Effect of dopamine blockade on pulmonary gas exchange

Descriptive characteristics of participants in the gas exchange experiment are reported in Table1.

Table 1.

Participant characteristics (n = 12)

	Mean ± SD	Range
Age (years)	25 ± 6	20–39
Height (m)	1.78 ± 0.05	1.68–1.87
Mass (kg)	75.8 ± 7.8	63.6–91.0
(l min−1)	4.39 ± 0.59	2.96–5.33
(ml kg−1 min−1)	58.6 ± 6.5	46.6–67.3
(l min−1)	152.5 ± 32.4	98.9–217.2
Peak power output (W)	352 ± 63	250–425
HRmax (beats min−1)	184 ± 9	171–201

, maximal O₂ consumption

, maximal ventilation

HR_max, maximal heart rate.

A summary of physiological response to exercise is given in Table2. There were no significant differences in O₂ consumption or CO₂ production between the placebo and blockade conditions. In general, any differences in cardiovascular or gas exchange responses between conditions occurred at the highest stages of the protocol (70% and 85% of ).

Table 2.

Physiological responses to graded exercise with dopamine blockade (n = 12)

		Rest	30%	50%	70%	85%
PO (W)			67 ± 16	142 ± 24	234 ± 38	290 ± 47
	Placebo	0.41 ± 0.01	1.35 ± 0.06	2.22 ± 0.12	2.97 ± 0.19	3.65 ± 0.26
(l min−1)	Blockade	0.40 ± 0.02	1.43 ± 0.06	2.24 ± 0.10	3.14 ± 0.18	3.69 ± 0.26
	Placebo	0.33 ± 0.11	1.15 ± 0.05	2.17±0.07	3.34 ± 0.19	4.20 ± 0.32
(l min−1)	Blockade	0.35 ± 0.02	1.23 ± 0.07	2.19 ± 0.09	3.54± 0.16	4.25 ± 0.29
RER	Placebo	0.80 ± 0.02	0.85 ± 0.02	0.97 ± 0.02	1.02 ± 0.01	1.06 ± 0.01
	Blockade	0.84 ± 0.03	0.86 ± 0.02	0.96 ± 0.02	1.03 ± 0.02	1.05 ± 0.01
	Placebo	10.8 ± 0.5	32.1 ± 1.6	51.2 ± 2.4	95.6 ± 5.6	123.8 ± 8.7
(l min−1)	Blockade	12.5 ± 0.5	33.9 ± 1.9	55.2 ± 2.5	99.0 ± 5.1*	140.9 ± 11.0*
	Placebo	36.7 ± 0.7	37.8 ± 0.7	38.3 ± 0.9	36.2 ± 0.3	32.4 ± 0.6
(mmHg)	Blockade	35.7 ± 1.3	37.1 ± 0.7	37.7 ± 0.7	34.6 ± 0.7*	30.4 ± 0.7*
pH	Placebo	7.42 ± 0.002	7.41 ± 0.002	7.39 ± 0.002	7.33 ± 0.004	7.31 ± 0.005
	Blockade	7.41 ± 0.002	7.40 ± 0.001	7.39 ± 0.003	7.36 ± 0.004*	7.35 ± 0.004*
ΔT (°C)	Placebo		0.06 ± 0.14	0.20 ± 0.16	0.52 ± 0.16	0.67 ± 0.16
	Blockade		0.05 ± 0.02	0.21 ± 0.04	0.62 ± 0.07	0.73 ± 0.07

Values are means ± SEM. PO, power output

, partial pressure of arterial CO₂

ΔT, change in core temperature from rest. Significantly different from placebo

^*P < 0.05.

Ventilation

Minute ventilation was increased 3.5% with the blockade at 70% and 13.8% at 85% of , which was driven by significant increases in respiratory rate at 70% and at 85%, as tidal volume did not change significantly with blockade at any time point. Correspondingly, was decreased at 70% and 85% of , consistent with increased alveolar ventilation.

Cardiovascular response

A summary of cardiovascular response is given in Table3. Heart rate was significantly increased by blockade at rest, 30%, and 50% of , but not at 70% or 85%. Systolic blood pressure (SBP) was decreased at rest and 85% of . Diastolic blood pressure (DBP) was not different at any time point during exercise with blockade. Mean arterial pressure (MAP) was significantly decreased by blockade at 85% (P = 0.019). Cardiac output was significantly lower by 9.3% in the blockade condition at 85% of but not at any other workloads.

Table 3.

Cardiovascular responses to graded exercise with dopamine blockade (n = 12)

		Rest	30%	50%	70%	85%
(l min−1)	Placebo	7.4 ± 0.3	10.3 ± 0.7	14.6± 1.0	19.4 ± 1.3	22.2 ± 1.6
	Blockade	7.8 ± 0.3	11.4 ± 0.6	14.7± 0.9	19.1 ±1.0	20.0 ± 1.1*
HR (bpm)	Placebo	58 ± 3	95 ± 2	131± 3	159 ± 4	178 ± 4
	Blockade	75 ± 3	12 ± 2	139 ± 4	163 ± 4	178 ± 3
SV (ml)	Placebo	90 ± 5	103 ± 8	125 ± 7	127 ± 9	129 ± 4
	Blockade	97 ± 4	113 ± 6	128 ± 7	129 ± 7	119 ± 10
SBP (mmHg)	Placebo	111 ± 3	133 ± 4	161 ± 5	179 ± 3	195 ± 4
	Blockade	103 ± 2*	129 ± 3	153 ± 5	175 ± 7	188 ± 5*
DBP (mmHg)	Placebo	66 ± 2	59 ± 1	61 ± 1	62 ± 1	61 ± 1
	Blockade	65 ± 2	63 ± 2	62 ± 2	63 ± 2	65 ± 2
MAP (mmHg)	Placebo	81 ± 2	83 ± 2	93 ± 3	99 ± 5	105 ± 1
	Blockade	76 ± 2	83 ± 1	88 ± 1	96 ± 2	103 ± 1*

Values are means ± SEM. , cardiac output

SV, stroke volume

SBP, systolic blood pressure

DBP, diastolic blood pressure

MAP, mean arterial pressure = (1/3(SBP) + 2/3(DBP). Significantly different from placebo

^*P < 0.05.

Pulmonary gas exchange

Alveolar was not changed with dopamine blockade at any level of exercise, but arterial was significantly higher at 70% (P = 0.016) and at 85% of (P = 0.049). Accordingly, there was a significant decrease in A-a at 85% of (P = 0.038) and arterial O₂ saturation was increased at 70% (P = 0.024) and 85% of (P = 0.001) (Fig.1).

Figure 1.

Mean ± SEM pulmonary gas exchange response to dopamine blockade during exercise A-a (middle) was significantly decreased with dopamine blockade at 85% of , *P < 0.05. was significantly increased with dopamine blockade at 70% and 85% of (n = 12, n = 10 at 85% of max).

There was a significant, positive correlation between the change in cardiac output and the change in A-a with dopamine blockade at the 85% workload (r = 0.694, P = 0.021), (Fig.2A).

Figure 2.

Correlations between change in pulmonary gas exchange (A-a ), cardiac output and IPAVA score with dopamine blockadeA, relationship between individual changes in cardiac output and A-a with blockade at 85% of (R² = 0.50, P = 0.02), n = 10. B, relationship between individual changes in IPAVA score and A-a with blockade at 85% of (R² = 0.01, P = 0.58), n = 10. C, individual changes in cardiac output and IPAVA score with blockade at 85% of There was no statistically significant positive correlation (R² = 0.04, P = 0.30), n = 10.

Intrapulmonary arteriovenous anastomosis recruitment

IPAVA score increased with exercise, but no difference was observed between dopamine blockade and placebo at any intensity. Of twelve participants, five showed a mean decrease in IPAVA score of −1.4 ± 0.9 with dopamine blockade at 85% of , but there was no correlation between decreased IPAVA score and decreased A-a (Fig.2B) or change in IPAVA score and cardiac output at 85% of (Fig.2C).

Functional significance

Time to exhaustion

During the time-to-exhaustion (TTE) trials, dopamine blockade decreased exercise performance at 85% of by 38.6% (P = 0.032). At exercise termination, cardiac output was decreased in the blockade condition by 9.3% compared to placebo (P = 0.042). The decrease in cardiac output with dopamine blockade was driven primarily by the 12.4% decrease in stroke volume (P = 0.044), as no significant change in heart rate was observed (Table4). Dopamine blockade increased O₂ saturation by 0.8% at the end of the TTE (P < 0.001).

Table 4.

Exercise performance response to dopamine blockade

	Placebo	Blockade	% Change
Time-to-exhaustion 90% of (n = 12)
TTE (s)	500 ± 53	307 ± 27	−38.6*
(l min−1)	21.4 ± 1.4	19.4 ± 1.0	−9.3*
HRmax (bpm)	181 ± 2	188 ± 2	+3.9
SVmax (ml)	118 ± 9	103 ± 8	−12.6*
(%)	95.3 ± 0.2	96.1 ± 0.2	+1.0†
Graded exercise test (n = 15)
(l min−1)	4.02 ± 0.19	3.80 ± 0.17	−5.5*
RERmax	1.15 ± 0.01	1.12 ± 0.01	−3.0
HRmax (bpm)	184 ± 2	180 ± 4	−2.2*
Peak power (W)	311 ± 14	289 ± 13	−7.1*
(l min−1)	141.1 ± 8.8	127.6 ± 8.9	−9.6*

Values are means ± SEM. % Change is the percentage difference in blockade condition from placebo, at maximal exercise. , maximal cardiac output during the TTE test

SV_max, maximal stroke volume during the TTE test

TTE, time-to-exhaustion cycling at 90% of

, O₂ saturation at end of TTE.

, minute ventilation at .

^*P < 0.05

^†P < 0.01

Incremental exercise response

A summary of the effects of dopamine blockade on graded exercise performance is presented in Table4. Dopamine blockade decreased maximal exercise performance: was decreased by 5.5% (P = 0.013); peak power output was decreased by 7.1% (P < 0.001) and maximum HR decreased 2.2% (P = 0.011). Ventilation was increased at 90% of with blockade, but peak ventilation was decreased, likely to be because of a reduction in (Fig.3).

Figure 3.

Mean (±SEM) ventilatory response to graded exercise with dopamine blockade

was increased in blockade condition at 85% but decreased at 100% of , *P < 0.05. Blockade decreased , ⁺P < 0.05 (n = 15).

Discussion

This study examined the effects of a dopamine receptor blockade on pulmonary gas exchange, intrapulmonary arteriovenous anastomosis recruitment, and exercise performance. Consistent with previous studies, A-a was increased during intense aerobic exercise (Dempsey et al. 1984; Hammond et al. 1986; Hopkins et al. 1994). Dopamine blockade decreased peak exercise A-a by 22.3%, indicating an improvement in gas exchange. Within the limitations of utilizing agitated saline contrast echocardiography, dopamine receptor blockade did not appear to affect IPAVA, and the individual improvement in A-a was unrelated to the individual change in IPAVA score. Despite improving gas exchange, dopamine blockade decreased exercise performance, as measured by and time-to-exhaustion at 85% of . The results of this study suggest that endogenous dopamine is important to the normal cardiopulmonary response to exercise.

Pulmonary gas exchange during exercise

We have previously shown that exercise-induced IPAVA recruitment is related to the decreases in pulmonary gas exchange (Stickland et al. 2004). The mechanisms by which these IPAVA are recruited, and their contribution to gas exchange remain the subject of an unresolved debate (Hopkins et al. 2009c; Lovering et al. 2009b). Dopamine increases with exercise intensity (Hopkins et al. 2009a), exogenous dopamine impairs gas exchange in healthy (Bryan et al. 2012) and ill participants (Rennotte et al. 1989), and contrast echocardiography data indicate that IPAVA are recruited with exogenous dopamine (Bryan et al. 2012; Laurie et al. 2012). Therefore, we hypothesized that blocking dopamine receptors with metoclopramide would decrease IPAVA and improve pulmonary gas exchange during exercise. The results show that blocking dopamine receptors lessens the pulmonary gas exchange impairment at peak exercise, but the improvement in gas exchange appears to be unrelated to a decrease in IPAVA recruitment as evaluated by saline contrast echocardiography. Further, the individual change in A-a at peak exercise was not related to the individual change in IPAVA score following dopamine blockade (Fig.2B), suggesting that IPAVA, as evaluated by agitated saline contrast transmission, is not related to gas exchange.

While the improvement in gas exchange with dopamine blockade may be unrelated to IPAVA, there is evidence that the improvement in gas exchange was secondary to a reduction in cardiac output. In addition to the 23% improvement in A-a at the highest level of exercise, dopamine blockade resulted in a 10% reduction in cardiac output, secondary to a 7.8% reduction in stroke volume. Further, the reduction in cardiac output was correlated with the improvement in A-a (see Fig.2A). While pulmonary transit time was not determined, these findings highlight the importance of cardiac output as a determinant of gas exchange impairment and are consistent with early suggestions of a diffusion limitation secondary to reduced pulmonary transit time during heavy exercise (Dempsey et al. 1984; Hammond et al. 1986; Vidal Melo, 1998).

Dopamine infusion at rest recruited IPAVA and increased venous admixture () in a previous investigation (Bryan et al. 2012). However, there was no change in the A-a due to the concurrent increase in mixed venous oxygen content, resulting from the increased cardiac output. In the current study, oxygen consumption during the highest level of exercise was unchanged by dopamine blockade, while cardiac output was reduced. Therefore, mixed venous oxygen content would have been reduced as a result of increased peripheral O₂ extraction. Based on principles of gas exchange, a reduction in mixed venous by itself would cause an increase in A-a (Stickland et al. 2013); however, the improvement in A-a with dopamine blockade, despite a reduction in mixed venous , indicates that a component of gas exchange (likely to be ventilation–perfusion matching) was improved following dopamine blockade.

The increased ventilation with dopamine blockade caused a significant reduction in and subsequent increase in pH (Table2), which would have resulted in a leftward shift of the oxygen–haemoglobin dissociation curve (Brimioulle & Kahn, 1990). Based on previous calculations (Severinghaus, 1966), the 0.4 unit increase in pH following dopamine blockade would have increased by 0.4%. These calculations suggest that approximately half of the improvement in with dopamine blockade can be explained by a shift in the oxygen–haemoglobin dissociation curve, with the remaining improvement the result of enhanced gas exchange.

Cardiovascular effects of dopamine blockade

While dopamine blockade seems to improve pulmonary gas exchange, we observed a contrasting effect on exercise tolerance. Decreases were seen in measures of peak exercise performance ( and peak power) and time-to-exhaustion cycling at a power output corresponding to 85% of . While was not measured during the time-to-exhaustion trial, the decrease in TTE was consistent with decreased cardiac output, secondary to a reduction in stroke volume. Based on the gas exchange data, the increase in and observed with dopamine blockade would have increased arterial O₂ content by only 1%, which is in contrast to the 10% decrease in cardiac output. The resultant 9% decrease in convective O₂ delivery contributed to the diminished exercise performance with dopamine blockade despite improved pulmonary gas exchange.

While low dose dopamine acts as a pulmonary vasodilator in humans (Polak et al. 1992) and animals (Hoshino et al. 1986; Polak & Drummond, 1993), blocking dopamine receptors increases pulmonary artery pressure (PAP) via increased pulmonary vascular resistance (Polak et al. 1992). Further, dopamine blockade has been shown to decrease exercise tolerance (Balthazar et al. 2010). Acutely increasing PAP via lower body positive pressure (Stickland et al. 2006) as well as saline infusion (Robertson et al. 2004) increases the ventilatory response to exercise. While we were unsuccessful in determining PAP in the present study as none of our participants had sufficient tricuspid regurgitation to estimate pulmonary artery systolic pressure (Oh et al. 2006), we observed an increase in ventilation and a decrease in stroke volume during exercise with dopamine blockade, which could be due to J receptor stimulation in the lung secondary to a potentiated PAP response to exercise (Paintal, 1969). Although speculative, it is plausible that dopamine blockade increased PAP, limiting cardiac output, and by extension, exercise performance due to increased right ventricular afterload (Stickland et al. 2004; La Gerche et al. 2010). The results of the present study highlight the importance of endogenous dopamine in the normal cardiopulmonary response to exercise.

Previous work has demonstrated that dopamine receptor agonists inhibit carotid chemoreceptors (CCs) in humans (Stickland et al. 2011) and animals (Stickland et al. 2007; Tsuchiya et al. 2011), decreasing sympathetic vasoconstrictor outflow (Stickland et al. 2007; 2011; Edgell et al. 2015) and ventilatory drive during exercise (Whipp, 1994). Conversely, dopamine blockade may sensitize the CCs, increasing sympathetic outflow, decreasing skeletal muscle blood flow (Stickland et al. 2011) and increasing the ventilatory drive during heavy exercise (Whipp, 1994). In the current study, peak cardiac output was reduced by dopamine blockade; yet, systolic and diastolic blood pressures were not different, suggesting that sympathetic outflow may have been increased secondary to heightened CC activity. Additional work is needed to evaluate the effect of dopamine blockade on CC activity/sensitivity and the sympathetic control of cardiovascular function.

Study limitations

Agitated saline contrast echocardiography has been utilized in several studies to assess IPAVA recruitment during exercise, but the practice has been debated in a recent Point:Counterpoint discussion (Hopkins et al. 2009c; Lovering et al. 2009b). Several contributors pointed out shortcomings of this technique, primarily the qualitative nature of the interpretation of images, and the inability to determine the size of micro-bubbles in contrast solution (Hopkins et al. 2009b). Thus, in the current study it is possible that the method of detection was not sufficiently sensitive to detect such subtle changes between drug and placebo conditions. Acknowledging this limitation, the improvement in pulmonary gas exchange observed with dopamine blockade does not appear to be related to IPAVA, as assessed by agitated saline contrast.

We attempted to determine PASP via tricuspid regurgitant velocity; however, due to our young and healthy sample, we were not able to obtain a suitable signal. As a supplement to our non-invasive cardiac output estimation, we attempted to measure aortic velocity–time integral; however, due to movement artifact during exercise, we were not able to maintain an acceptable window to obtain a high quality Doppler-derived cardiac output measurement. Future experiments should employ the multiple inert gas elimination technique to confirm if dopamine blockade decreases diffusion limitation during exercise, or attenuates ventilation–perfusion inequality during exercise.

It is possible that not all dopamine-2 receptors may have been blocked in our experiment. To the best of our knowledge, there is no method to evaluate if dopamine receptors are fully blocked in humans, and we acknowledge this limitation. The 38.6% reduction in time-to-exhaustion with dopamine-2 blockade was larger than what would be expected by the 9.3% reduction in cardiac output observed during these trials. As metoclopramide was given systemically, it may have influenced central (i.e. brain) dopamine receptors. Long term and/or high dose metoclopramide use increases the risk of the development of neurological and muscle control disorders such as tardive dyskinesia (Rao & Camilleri, 2010; Lai et al. 2012), suggesting that central dopamine-2 receptors may be important for motor control and/or motor output during exercise. Thus, it is possible that the decreased exercise performance observed with dopamine blockade may be partly explained by central dopamine-2 receptor antagonism.

Finally, because dopamine blockade reduced , all workloads in the blockade condition represent a greater relative percentage of maximal effort. This presents a potential limitation in drawing comparison between the blockade and placebo condition. However, we aimed to examine the cardiopulmonary response to dopamine blockade at the same rate of oxygen demand, and therefore compared the two conditions across the same absolute workloads.

Conclusion

We examined the effect of a dopamine-2 receptor blockade on the cardiopulmonary response to exercise. We found that blocking dopamine-2 receptors with 20 mg metoclopramide improved gas exchange during near-peak exercise; however, cardiac output and exercise tolerance were decreased. IPAVA recruitment, as evaluated by saline contrast echocardiography, was unaffected with dopamine blockade, suggesting that the improvement in gas exchange was unrelated to a decrease in IPAVA. These findings suggest that endogenous dopamine contributes to exercise-induced gas exchange impairment; however, dopamine is an important mediator of the normal convective O₂ delivery during exercise by optimizing blood flow, cardiac output and exercise performance.

Glossary

A-a

alveolar–arterial oxygen difference

BP

blood pressure

DA

dopamine

IPAVA

intrapulmonary arteriovenous anastomoses

partial pressure of arterial CO₂

partial pressure of alveolar O₂

partial pressure of arterial O₂

PAP

pulmonary arterial pressure

PVR

pulmonary vascular resistance

venous admixture-fraction of shunted blood to total cardiac output

RER

respiratory exchange ratio

percentage arterial O₂ saturation

percentage arterial O₂ saturation estimated by pulse oximetry

TTE

time-to-exhaustion

ventilation–perfusion inequality

carbon dioxide production

oxygen consumption

Additional information

Competing interests

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

Author contributions

This experiment was performed in the Clinical Physiology Laboratory at the University of Alberta. Each author contributed to the following aspects of the study: conception and design of the experiments: V.T., R.C.W., S.R.P., M.K.S.; collection, analysis and interpretation of data: V.T., T.L.B., S.V.D., L.E.M., M.M.B., S.R.P., R.C.W., M.K.S.; drafting the article or revising it critically for important intellectual content: V.T., T.L.B., S.V.D., L.E.M., M.M.B., S.R.P., R.C.W., M.K.S. All authors approved the final version of the manuscript.

Funding

Funding was provided by the Natural Sciences and Engineering Research Council (M. K. Stickland). M. K. Stickland is supported by a Heart and Stroke Foundation of Canada New Investigator Salary Award.