Mild central chemoreflex activation does not alter arterial baroreflex function in healthy humans.

Patients with obstructive sleep apnoea experience repeated episodes of partial or total upper airway collapse during sleep. These periods of apnoea/hypopnoea result in concomitant hypoxia and hypercapnia (i.e. asphyxia) on a systemic level (Parish & Somers, 2004). During asphyxia, hypercapnia activates both the central chemoreceptors, located near the ventral surface of the medulla (Bruce & Cherniack, 1987), and the peripheral chemoreceptors, located in the carotid and aortic bodies. Hypoxia activates primarily the peripheral chemoreceptors (Fitzgerald & Lahiri, 1986). Peripheral and central chemoreceptor stimulation during obstructive apnoea is associated with sympathetic activation and surges in blood pressure during sleep, and this repeated sympathoexcitation may contribute to daytime elevations in sympathetic nerve activity and blood pressure observed in obstructive sleep apnoea patients (Somers et al. 1995). However, the link between chronic chemoreflex activation and the development of hypertension is poorly understood. Evidence suggests that patients with obstructive sleep apnoea have altered baroreflex control of sympathetic outflow compared with healthy controls matched for age, body mass index and blood pressure (Narkiewicz et al. 1998). Thus, it is important to understand how baroreflex function is altered acutely during chemoreflex stimulation in order to better understand the root of daytime hypertension in obstructive sleep apnoea. In animals, a major central interaction between chemoreflexes and baroreflexes was demonstrated by Heistad et al. (1974, 1975) on the basis that ventilatory and haemodynamic responses to chemoreceptor stimulation were different at varying levels of baroreceptor activity. Later work confirmed the presence of interactions between peripheral chemoreflexes and baroreflexes in humans (Somers et al. 1991; Halliwill et al. 2003). Peripheral chemoreflex activation with mild isocapnic hypoxia resets the arterial baroreflex to higher heart rates, arterial pressures, and levels of sympathetic nerve activity, without changes in reflex sensitivity (Halliwill & Minson, 2002; Halliwill et al. 2003). However, the effects of central chemoreflex activation on baroreflex function remain poorly characterized. Dean et al. (1990) have demonstrated that neurons located in the nucleus tractus solitarii are stimulated by hypercapnia in vitro, providing a neuroanatomical/physiological framework for interactions between central chemoreflexes and cardiovascular function. In vivo, Bristow et al. (1971) and Henry et al. (1998) have demonstrated a downward resetting of baroreflex control of R-R interval (to higher heart rates) during activation of central chemoreceptors. More recently, Cooper et al. (2005) studied carotid baroreflex control of forearm vascular resistance during central chemoreflex activation. In that study, chemoreceptor stimulation was associated with increases in mean arterial pressure and forearm vascular resistance, raising the possibility that baroreflex control of the vasculature was altered in some way. Thus, in vitro evidence, as well as in vivo evidence from human studies, suggests that central CO2 chemoreception may affect arterial baroreflex function. Importantly, previous human studies of central chemoreflex–baroreflex interactions have either failed to control for possible influences of increased ventilation on autonomic outflow (Cooper et al. 2005), or have only assessed baroreflex control of heart rate (Bristow et al. 1971; Henry et al. 1998). Furthermore, none of these studies have assessed baroreflex control of sympathetic outflow using direct nerve recordings. One aspect common to the studies cited above is the use of relatively severe hypercapnia (end-tidal PCO2≥ 10 mmHg above eucapnia) to probe interactions between central chemoreflexes and baroreflexes. In contrast, several studies suggest a mild CO2 stimulus (+5 mmHg) can alter cardiovascular regulation (Morgan et al. 1995; Shoemaker et al. 2001). For example, Shoemaker et al. (2001) demonstrated that mild hypercapnia (end-tidal PCO2 5 mmHg above eucapnia) abolishes the increase in muscle sympathetic nerve activity during orthostasis. These data could be explained by a number of possibilities, including a peripheral vascular effect during hypercapnia (Shoemaker et al. 2002), baroreflex inhibition by hyperpnoea (Van De Borne et al. 2000), or a hypercapnia-mediated reduction in arterial baroreflex gain. Concerning the latter, arterial baroreflex function has not been tested during central chemoreceptor stimulation with mild hypercapnia. With the above information as a background, the current investigation was undertaken to assess the effect of mild central chemoreflex activation on baroreflex function while controlling for increases in ventilation. We used hyperoxia to isolate the central chemoreflex from peripheral chemoreflex responses (Lahiri & DeLaney, 1975). Baroreflex control of heart rate and sympathetic vasoconstrictor outflow was tested in healthy subjects exposed to mild hyperoxic hypercapnia and matched hyperoxic hyperpnoea. Specifically, we tested the hypothesis that hyperoxic hypercapnia, and not hyperoxic hyperpnoea, alters baroreflex function in healthy humans.