Functional studies of acetylcholine, ATP and cytokine release from the human carotid body: the new frontier for oxygen chemoreception physiology

The carotid body, a multimodal chemoreceptor organ that senses the arterial PO2 , PCO2 and pH levels, plays a major role in cardiorespiratory and neurohumoral homeostasis. The primary oxygen sensors in carotid body are the glomus (type I) cells, which make synaptic contact with the nerve terminals of the chemosensory petrosal ganglion neurons. The current model of chemoreception states that hypoxia induces the inhibition of K+ channels, leading to glomus cell depolarization, entry of Ca2+ through L-type Ca2+ channels and the release of excitatory transmitters, which increase the discharge frequency of the nerve endings of chemosensory neurons. Glomus cells contain several molecules, such as ACh and ATP, that are candidates to act as excitatory transmitters between glomus cells and the nerve terminals (Iturriaga et al. 2007). New, exciting evidence indicates that the carotid body plays a crucial role in the pathogenesis of several human diseases, including obstructive sleep apnoea, congestive heart failure, hypertension and metabolic syndrome (Kumar & Prabhakar, 2012). Furthermore, ablation of the carotid bodies has been proposed as a clinical treatment for severe and resistant hypertension in humans (Paton et al. 2013). Despite the great effort undertaken to understand the mechanisms of carotid chemosensory transduction, there are still some discrepancies regarding the precise nature of the oxygen-sensing detector and the excitatory transmitters and modulators involved. In addition, new evidence suggests that reactive oxygen species and pro-inflammatory cytokines are involved in the potentiation of carotid chemosensory responsiveness to hypoxia in rodent models of obstructive sleep apnoea (Prabhakar & Semenza, 2012; Del Rio et al. 2012). Accordingly, investigation of the oxygen-sensing mechanisms, the secretion of putative transmitters and the role played by cytokines in the human carotid body is essential to understand the contribution of the carotid body to human diseases. This new basic knowledge will allow the proposal and development of new therapeutic strategies to moderate the severity of the cardiovascular alterations induced by obstructive sleep apnoea and metabolic disorders. Recently, Ortega-Sáenz et al. (2013), for the first time, have provided evidence that cellular properties of the human carotid body are similar to those found in laboratory mammals, showing that human glomus cells present voltage-dependent Na+, K+ and Ca2+ currents, which are involved in the release of catecholamines in response to hypoxia and depolarization with high [K+]. In this issue of Experimental Physiology, Kåhlin et al. (2014) studied the secretory responses to hypoxia in functional human carotid bodies. Without doubt, advances in our knowledge of the physiological mechanisms in the human carotid body have been limited by the difficulties inherent in obtaining fresh tissue samples. Accordingly, most of the available physiological and morphological information about the human carotid body has been obtained from autopsy material. In contrast, the study of Kåhlin et al. (2014) used carotid body tissue harvested from male patients who underwent neck surgery for cancer. The patients did not receive radiation therapy or chemotherapy, and the tumours did not involve the carotid body. A single carotid body was removed under general anaesthesia, placed in oxygenated saline solution and transported to the laboratory for further analyses within 15 min after surgical removal. The carotid bodies were sliced, and the experiments were performed at 37°C in sealed chambers. Carotid body slices were exposed to brief (5 min) or prolonged (1 h) hypoxia (10% O2 with 5% CO2 in 85% N2). Kåhlin et al. (2014) found that brief hypoxic challenges enhanced the release of ACh and ATP fourfold, in comparison to the hyperoxic basal conditions (95% O2 with 5% CO2). Prolonged hypoxia increased the release of interleukin (IL)-1β, IL-4, IL-6, IL-8 and IL-10, while IL-2, IL-5 and tumour necrosis factor-α were undetected. Immunohistochemical analysis revealed that glomus cells from the human carotid body express cytokine receptors IL-1R1, IL-6R and IL-10R as well as hypoxia-inducible factors HIF1α and HIF2α. However, tumour necrosis factor receptor, Toll-like receptor 4 and the p65 subunit of nuclear factor κB were not found. These novel findings demonstrate that ACh and ATP are released from the human carotid body in response to hypoxia, suggesting that these putative neurotransmitters, as in several studies performed in laboratory mammals, play an important role in hypoxic signalling in the human carotid body. In addition, Kåhlin et al. (2014) showed new evidence that the carotid body may be involved in the detection of inflammation, thus providing a possible link between the immune system and the nervous system. These results are original and interesting, because functional properties of the human carotid body are largely unknown. Therefore, the pioneering work of Kåhlin et al. (2014) offers a valuable insight into the physiology of the human carotid body. This new knowledge will enable new therapies to be proposed to moderate the severity of human cardiorespiratory pathologies.