Intermittent hypoxia: endothelin‐1 and hypoxic carotid body chemosensory potentiation

The obstructive sleep apnoea (OSA) syndrome, a growing worldwide disorder of breathing during sleep, is recognized as an independent risk factor for hypertension and other cardiovascular diseases. Among the disturbances produced by OSA, chronic intermittent hypoxia (CIH) is considered to be the main factor linked to hypertension. Although the link between OSA and systemic hypertension is well established, the pathogenic mechanisms responsible for the hypertension are not entirely understood. Sympathetic hyperactivity, oxidative stress and systemic inflammation have been proposed as potential hypertensive mechanisms. Given that OSA patients show augmented reflex sympathetic, cardiovascular and ventilatory responses to acute hypoxia, it has been proposed that an enhancement of carotid body (CB) responsiveness to hypoxia is involved in the alterations induced by OSA. This proposal has received further support from studies performed in animals, which have shown that CIH selectively enhances the CB chemosensory and ventilatory responses to acute hypoxia and elicits long-term sensory potentiation of chemosensory discharges (Peng et al. 2003; Rey et al. 2004; Pawar et al. 2009). The mechanisms that underlie the enhanced CB chemosensory reactivity to hypoxia induced by CIH are not completely known. Nevertheless, the available evidence indicates that the repeated episodes of hypoxia–reoxygenation produce local oxidative stress in the CB owing to accumulation of reactive oxygen species. Among the molecules upregulated in the CB by CIH, such as vascular endothelial growth factor, inducible nitric oxide synthase and pro-inflammatory cytokines, endothelin-1 (ET-1) has been proposed as a mediator of the CB chemosensory potentiation induced by CIH (Rey et al. 2004; Pawar et al. 2009) and the hypertension (Allahdadi et al. 2008). Endothelin-1 is expressed in the endothelium, blood vessels and glomus cells of the CB (Rey et al. 2006) and induces CB chemosensory excitation in both in situ and in vitro perfused CB, but not in the superfused CB preparation showing a predominant vascular effect. Rey et al. (2006) found that the immunohistochemical expression of ET-1 increased locally by ∼10-fold in CBs from cats exposed to 4 days of CIH, while plasma levels of ET-1 remained unchanged. In the cat perfused CB preparation, CIH increased basal discharges and hypoxic chemosensory responses, which were reduced by the nonspecific ET receptor blocker bosentan in the CBs from CIH-treated cats, but not in the control CBs (Rey et al. 2006). These results indicate that a local increase of ET-1 in the CB contributes to the enhanced hypoxic chemosensory responses induced by CIH predominantly through a vasomotor mechanism. More recently, Pawar et al. (2009) tested the hypothesis that ET-1 induced by reactive oxygen species (ROS) plays an essential role in the CIH-evoked changes in the rat neonatal CB. They found an enhanced basal release of ET-1 and upregulation of the ETA receptor in response to CIH. Systemic administration of the superoxide dismutase mimetic manganese (III) tetrakis (1methyl-4-pyridyl) porphyrin pentachloride prevented the elevation of ROS, the increase in the basal release of ET-1, the upregulation of the ET-A mRNA, and the enhancement of the CB chemosensory response. These results support the idea that an ROSinduced increase of ET-1 release and upregulation of the ET-A receptor are involved in the potentiation of the CB chemosensory response elicited by CIH. Increased plasma levels of ROS and ET-1 have been implicated in the hypertension induced by CIH. Indeed, Allahdadi et al. (2008) showed that in rats exposed to CIH for 14 days, concurrent treatment with the ET-A receptor inhibitor BQ-123 prevented the development of hypertension. Thus, ET1 seems to be involved in enhancement of hypoxic CB chemosensory responses and progression of hypertension; nevertheless, the mechanisms underlying the CIHinduced upregulation of ET-1 in the CB have remained elusive. In this issue of Experimental Physiology, Peng et al. (2013) studied the mechanisms that mediate CIH-induced upregulation of ET-1 in the CB. The major finding of their study was that CIH-induced upregulation of ET-1 involves ROS-dependent activation of endothelin-converting enzyme. They found that ET-1, via the ET-A receptor, mediates the enhanced hypoxic CB chemosensory responses, but not the sensory long-term potentiation. The increased endothelinconverting enzyme activity paralleled the elevation of ET-1 levels in CBs from rats exposed to CIH, whereas manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride prevented these effects. In addition, hypoxia facilitated ET-1 release from CIH-treated CBs, but not from control CBs. In CIH-exposed CBs, mRNAs encoding the ET-A receptor were upregulated, and an ET-A receptor-specific antagonist abolished the CIH-induced enhancement of the CB chemosensory response, whereas it had no effect on the sensory long-term facilitation. These results indicate that an oxidative stressdependent increase in the production of ET1 coupled with hypoxia-evoked ET-1 release and ensuing ET-A receptor activation mediate the CIH-induced CB potentiation, but the ET-A receptor signalling pathway is not associated with sensory long-term facilitation elicited by CIH. The work of Peng et al. (2013) therefore provides a valuable insight into the pathophysiology of OSA. Understanding how oxidative stress and endothelinconverting enzyme interact to elevate ET-1 levels in the CB will provide new insights into the generation of the cardiorespiratory complications of OSA. This new knowledge will enable new therapies to be developed to moderate the severity of the cardiorespiratory alterations induced by OSA in humans. Taken together, the results suggest that it is plausible to ameliorate the hypertension induced by OSA using antioxidant agents, which will reduce the systemic oxidative stress and ET1 upregulation, as well as the CB potentiated chemosensitivity to hypoxia.