Carotid chemoreceptors: the link between pulmonary and cardiovascular disease?

Chemoreceptors located within the carotid bodies trigger sympathetic outflow in response to an increase in arterial carbon dioxide or reduction in arterial oxygen levels. Principally, this reflex serves to increase respiratory drive as a means to remedy blood gas imbalances, but chronic activation of the carotid chemoreflex leads to sustained elevations in sympathetic tone. Specifically, systemic hypoxaemia (low oxygen saturation) elicits sympathetic alpha-mediated vasoconstriction, thus reducing oxygen delivery to skeletal muscle and other organs, subsequently creating a physiological ‘tug-of-war’ between oxygen supply and demand (Joyner & Casey, 2014). Thus, chronic stimulation of the carotid chemoreceptors via hypoxia is an important experimental and clinical paradigm in the aetiology of cardiovascular diseases, especially in patients with chronic obstructive pulmonary disease (COPD) who demonstrate exaggerated carotid chemoreflex sensitivity. The cascade of biochemical reactions linking hypoxaemia, sympathetic nervous system activity and cardiovascular regulation has, to date, remained poorly understood in COPD. Therefore, a recent study published in this issue of The Journal of Physiology by Phillips and colleagues (2018) attempted to resolve one important piece of this puzzle. Specifically, authors used a single-blind, placebo-controlled cross-over design which investigated carotid chemoreceptor sensitivity in 13 patients with mild–moderate COPD (GOLD Stages 1 and II, not prescribed oxygen therapy). Intravenous dopamine infusion (2 μg kg−1 min−1) and acute exposure to hyperoxia (2 min of = 1.0) were employed as a means to blunt carotid chemoreceptor activity and reduce muscle sympathetic nerve activity. Central (carotid-femoral) and peripheral (carotid-radial) pulse wave velocities (m s−1; index of arterial stiffness) as well as blood velocity in the brachial artery (cm s−1; via Doppler ultrasound) were measured during rest, hyperoxia, and dopamine infusion. Blood velocity, in concert with brachial artery diameter, was used to calculate blood flow (ml min−1), then normalized for blood pressure, yielding vascular conductance (ml min−1 mmHg−1), which served as surrogates of hyperaemia and vasodilatation, respectively. Muscle sympathetic nerve activity (bursts min−1) was also measured via microneurography in a subset of seven COPD patients while breathing room air and hyperoxic gas. As expected, acute dopamine infusion and hyperoxia were successful in blunting the carotid chemoreflex which reduced central- and peripheral-artery pulse wave velocity, indicating reduced arterial stiffness. Patients in this study also demonstrated greater vascular conductance of the brachial artery during dopamine infusion, probably attributable to a reduction in mean arterial pressure (Table 3 in Phillips et al. 2018). In line with this notion, muscle sympathetic nerve activity during hyperoxia was reduced in the subset of seven patients with COPD. Collectively, these findings provide novel insight into the relationship between carotid chemoreceptor overactivity and cardiovascular regulation in patients with COPD by demonstrating that acute blunting of carotid chemoreceptor activity reduces arterial stiffness and improves vasodilatation, presumably through attenuation of sympathetic nerve activity in patients with mild-to-moderate COPD. Targeting the carotid chemoreceptors as a means to improve health-related outcomes is a new and exciting field of biomedical research which has yielded promising results. While Phillips and colleagues (2018) provide novel insight into this field, nitric oxide (NO), historically known for its robust vasodilatory effects, has also been shown to blunt carotid chemoreceptor activity in preclinical and human models. For example, chronic supplementation of inorganic nitrate in the form of beetroot juice increases circulating NO bioavailability via the nitrate-nitrite-nitric oxide pathway, and has been show to attenuate carotid chemoreflex sensitivity (Bock et al. 2018). While this study (Bock et al. 2018) was not designed to investigate vascular function (e.g. arterial stiffness, vasodilatation), it did provide compelling evidence to support the concept that carotid chemoreflex activity can be reduced in a healthy, older population by boosting NO bioavailability using a nutraceutical intervention. The carotid chemoreflex has also been attenuated with NO-boosting therapies in clinical populations. Patients with obstructive sleep apnoea (OSA), much like patients with COPD, are known to have exaggerated carotid chemoreflex sensitivity. These two populations also share elevated levels of inflammation and oxidative stress with an associated reduction in NO (Jelic et al. 2008; Maclay & MacNee, 2013). To this point, Maclay & MacNee (2013) discuss oxidative stress and inflammation being increased with an associated reduction of NO in patients with COPD. Likewise, Jelic and colleagues (2008) demonstrated that patients with OSA had greater nitrotyrosine (oxidative stress) and cyclooxygenase-two (inflammation) but less NO-synthase protein expression on venous endothelial cells. This study also demonstrated a reduction in both oxidative stress and biomarkers of inflammation with concomitant improvement in protein expression of NO-synthase and vascular function (flow-mediated dilatation) following treatment with continuous positive airway pressure (CPAP). Interestingly, and of relevance to Phillips et al. (2018), CPAP therapy attenuates the ventilatory response to hypoxia (carotid chemoreflex sensitivity), increases NO bioavailability which reduces carotid chemoreceptor activity, and ultimately lowers sympathetic nerve activity. Taken together, these studies suggest the link between lower carotid chemoreflex sensitivity and vascular health in patient populations (i.e. COPD and OSA) may be mediated by reducing oxidative stress and inflammation or attenuation in sympathetic nerve activity, although further studies are needed to fully assess this presumption. Despite the present study's innovation, there are some experimental considerations warranting attention. The cross-sectional design of this study inherently limits extrapolation to the effects of an intervention; thus longitudinal work supporting these findings is required before clinically oriented interpretations can be confidently made. Such a study design may include properly titrated supplemental oxygen therapy which may reduce oxidative stress or inflammation, much like CPAP therapy does in patients with OSA (Jelic et al. 2008), and would support the hyperoxia component of the present study. It should be noted that chronic hyperoxia can exert deleterious effects (e.g. inflammation, arterial stiffening) and thus caution should be demonstrated when administering supplemental oxygen for extended periods of time. Additionally, given the surmounting evidence that NO attenuates carotid chemoreceptor activity, and the profound vasodilatory effects of NO, future longitudinal prospective works should investigate circulating NO bioavailability (nitrate and nitrite) or endothelial protein expression of NO-synthase. In conclusion, Phillips et al. (2018) advance our understanding of the relationship between carotid chemoreceptors, muscle sympathetic nerve activity and vascular function in patients with COPD. The authors show for the first time that reducing carotid chemoreceptor activity leads to attenuation of central and peripheral artery stiffness as well as greater vasodilatation in distal conduit arteries of patients with COPD. Nevertheless, additional future studies will be needed to fully unravel the clinical significance of these findings. None declared. The author apologizes for not citing all relevant articles due to reference limitations. Gratitude is extended to Dr Nicholas T. Kruse for his insightful comments and critical evaluation of this article.