Adrenaline and the carotid body during hypoglycaemia: an amplifying mechanism?

Abstract

The moment-to-moment regulation of metabolism is essential to life. It optimises conditions to keep cells working efficiently even when faced with a variety of metabolic challenges that occur constantly in both physiological and pathological situations. To respond adequately to these challenges, a well-orchestrated adjustment at the molecular, cellular, tissue and system levels is necessary. Quite recently the carotid body has been considered as a multifunctional structure. Besides its well-established role in promoting autonomic and ventilatory adjustments to changes in O2, CO2 and/or pH in arterial blood, there is a growing body of scientific evidence revealing that the carotid body can respond to other stimuli such as glucose, hormones, K+, osmolarity, proinflammatory cytokines and temperature (Kumar & Prabhakar, 2012). Because of this unique ability to accurately monitor the chemical composition of arterial blood, the carotid body may be involved in numerous physiological and pathological processes such as hypertension and heart failure. Currently, considerable attention has been paid to elucidate the role of the carotid body in the regulation of metabolism. More specifically, some studies have shown that the carotid body is essential in maintaining body homeostasis during metabolic challenges such as hypoglycaemia. In a recent study published in The Journal of Physiology, Thompson et al. (2016) highlighted that the carotid body plays an important role in a counter-regulatory response to hypoglycaemia. The authors showed that carotid body activation is crucial to match ventilation to the hypermetabolic state induced by hypoglycaemia, avoiding an increase in PaCO2 and consequently acidosis. Using an impressive range of in vivo functional studies, the new discovery was that the carotid body-mediated ventilatory adjustments to hypoglycaemia were adrenaline dependent and mediated by β-adrenoceptors. In anaesthetised Wistar rats, they showed that insulin-induced hypoglycaemia increased ventilation and CO2 sensitivity. Both effects were abolished by either adrenalectomy or propranolol administration, strongly suggesting that these adjustments during hypoglycaemia depend on adrenaline and its β-adrenoceptors. The other arm of the study was to verify the effect of adrenaline itself on ventilation and CO2 sensitivity. Through intravenous adrenaline infusion, Thompson et al. (2016) found that adrenaline mirrored the effects caused by hypoglycaemia, increasing both ventilation and CO2 sensitivity. However, when adrenaline was infused after bilateral carotid sinus nerve section, the rise in minute ventilation was significantly attenuated and PaCO2 was found to be higher compared with control, denoting a clear ventilation–metabolism mismatch. This protocol revealed that the carotid body mediates the ventilatory changes during adrenaline infusion. It is important to note that, to exclude a possible effect of blood pressure changes on ventilation, the authors carefully chose an adrenaline dose that did not affect arterial blood pressure levels. Finally, through a Ca2+ imaging experiment, the authors demonstrated that the hypercapnia-induced increase in intracellular Ca2+ in isolated carotid body type I cells is potentiated by adrenaline, supporting the notion that this hormone is able to stimulate the carotid body directly. The data presented by Thompson et al. (2016) bring new insights into the mechanisms by which the carotid body can participate in the regulation of metabolism. It is noteworthy to highlight the evidence of the important role of adrenaline in stimulating the carotid body-mediated hyperventilation during hypoglycaemia. This finding could answer a question raised by Bin Jaliah et al. (2004); in their study, Bin Jaliah et al. (2004) concluded that the carotid body-mediated hyperventilation during hypoglycaemia depends on another stimulus rather than low glucose and insulin, suggesting that this effect could be triggered by some other factor related to hypermetabolism. On the other hand, and in disagreement with these results, Ribeiro et al. (2013) concluded that insulin is the factor activating the carotid body-mediated hyperventilation during hypoglycaemia, since insulin increased ventilation even during a euglycaemic clamp and because this ventilatory response was abolished after carotid sinus nerve bilateral resection. The latter results support the hypothesis that insulin could be the first stimulus to the carotid body during hypoglycaemia, triggering a rise in sympathetic outflow. This heightened sympathetic activity could then activate the sympathoadrenal axis, increasing adrenaline release. Adrenaline, in turn, can finally stimulate the carotid body to promote the ventilatory adjustments during hypoglycaemia and further amplify the reflex increase in sympathetic activity. Thus, it is possible that the carotid body could respond in a temporally dispersed fashion during hypoglycaemia. However, further studies are needed to test this proposal. Another notable contribution of the study of Thompson et al. (2016) is that their results point towards the existence of a bidirectional link between adrenaline and carotid body. It is well known, as eluded to above, that carotid body activation increases adrenaline release through the sympathoadrenal axis. However, the effects of adrenaline on carotid body function are mostly unexplored and warrant further investigation. It could be possible that bidirectional crosstalk between adrenaline and the carotid body is engaged in the regulation of other physiological and pathological conditions. For example, there are numerous studies demonstrating the involvement of the carotid body in sympathetically mediated conditions such as hypertension, heart failure, sleep apnoea and more recently metabolic disorders (Paton et al. 2013). In all cases, carotid body hypertonicity importantly contributes to a heightened sympathetic outflow. Because of this, there is a growing interest in both experimental and clinical scenarios to better understand the mechanisms that lead to carotid body hypertonicity and hyperreflexia in order to find ways to modulate these activities. The recent study by Thompson et al. (2016) further contributes to our understanding of the mechanisms involved in carotid body aberrant signalling since they showed that adrenaline can