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

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.