Chronic intermittent hypoxia orchestrates cardiorespiratory cacophony – adapting melody to malady

Hypertension is a major risk factor for cardiovascular morbidity and mortality. Remarkably, female animals are protected, compared with male counterparts, from genetic and experimental challenges that give rise to high blood pressure. There are exceptions, of course, but a blunted hypertensive phenotype presents in female salt-sensitive rats, spontaneously hypertensive rats and drug-induced murine models of hypertension compared with the perniciously potent effects observed in male rodents. Men too appear more susceptible to the development of high blood pressure compared with premenopausal women. The pivotal role of sex hormones is well appreciated. Alas, the decline in ovarian function at menopause, in concert with senescence, annuls the gender division. Ergo, cardiac disease is the leading cause of death in the Western world, callously claiming the hearts of men and women alike. Sacrecoeur! Hypertension is common in patients with obstructive sleep apnoea syndrome (OSAS), a debilitating sleep-related breathing disorder that, if untreated, leads to premature death. Discordant breathing in OSAS results in exposure to chronic intermittent hypoxia (CIH), which proves injurious to many body systems. Chronic intermittent hypoxia is now considered a driving force in the development and/or elaboration of several prominent co-morbidities in OSAS. For certain, CIH engenders hypertension in male rodents. In this issue of Experimental Physiology, Souza et al. (2015) set out to establish whether female rats are protected from CIH-induced hypertension. Using an established experimental model, Souza et al. (2015) revealed that exposure to CIH raises blood pressure in adult female rats; an effect equivalent to that previously reported in males. Of note, there was no difference in the pattern of the oestrous cycle in control and CIH-exposed rats, which was important to establish given that blood pressure varies during the normal cycle. Arterial blood pressure was directly measured concomitant with the respiratory pattern in conscious animals during quiet rest. Measurements were made in a pair-design approach to control for environmental and circadian influences on cardiorespiratory parameters. Elevated blood pressure and tachycardia coincident with increased variability in the respiratory pattern were evident in CIH-exposed rats; both the frequency and the duration of apnoeic episodes following augmented breaths (sighs) were significantly increased. Also, the reflex depressor response to augmented breaths was elevated in CIH-exposed animals. The observations extend previous suggestions by this group (Zoccal et al. 2009; Moraes et al. 2014) that the antecedent of hypertension in the CIH model relates to respiratory network remodelling. Now, that’s breath-taking! Autonomic dysregulation is considered to be the key contributory factor in the development of hypertension. There is considerable interest in aberrant central respiratory–sympathetic coupling following exposure to CIH (Zoccal et al. 2009; Moraes et al. 2014). Sympathetic nervous hyperactivity has long been considered causal in the manifestation of the hypertensive phenotype in OSAS, although a recent study largely refutes the respiratory hypothesis in hypertensive OSAS patients (Fatouleh et al. 2014). Neurones of the solitary tract nucleus [the dorsal medullary node that receives cardiorespiratory (and other) afferent inputs] have a potentially critical role in co-ordinating autonomic and respiratory reflex responses (Zoccal et al. 2014). Plasticity in this key region and in chemoreceptor and baroreceptor control of autonomic outflow is strongly implicated in distorted respiratory–sympathetic coupling following exposure to CIH. Intriguingly, the increased prevalence of postsigh apnoeas described by Souza et al. (2015) raises the possibility that vagally mediated pulmonary reflexes may also be altered by exposure to CIH. Of note, others have reported that the frequency of sighs and postsigh apnoeas is higher following exposure to CIH in male rats too.Given that it is established that exposure to CIH causes pulmonary hypertension in rats, it is plausible to consider that CIH triggers pulmonary reflexes affecting lung inflation to prevent atelectasis but with resultant respiratory dysrhythmia. Perhaps ‘sighs matters’ after all! Carotid body plasticity following CIH is convincingly postulated to provide the substrate for enhanced sympathetic outflow and resultant hypertension. Respiratory instability and deranged respiratory–sympathetic coupling following exposure to CIH could also be an entirely central phenomenon arising from remodelling at one or more brainstem sites. The cacophony of these ailing interplays disturbs autonomic outflow with calamitous consequence for cardiovascular control. Moreover, CIH-induced respiratory instability might well establish an inescapable cycle serving to perpetuate the morbidity. The pressure is on to find the mechanism underpinning CIH-induced hypertension, but in the search we should not lose heart. A recent study has shown that the hypertensive phenotype in CIH-exposed male rats relates to an increase in cardiac output (Lucking et al. 2014). Chronic intermittent hypoxia-induced tachycardia in male (Lucking et al. 2014) and female rats (Souza et al. 2015) implies altered autonomic control of the heart. There are likely to be direct actions of CIH on the myocardium too. More work may yet explain CIH-induced hypertension!