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• W3004697029 abstract "Patients with obstructive sleep apnoea (OSA) are at an increased risk of hypertension and related cardiovascular disease. OSA is characterized by exposure to repeated, intermittent bouts of low oxygen [intermittent hypoxia (IH)] during sleep, resulting in an increase in activity of the sympathetic nervous system. Notably, the rise in muscle sympathetic nerve activity (MSNA) seen in OSA patients during sleep persists upon return to wakefulness. This persistent increase in MSNA is considered to be partly responsible for the subsequent development of hypertension following exposure to IH. An increase in MSNA elicits neurotransmitter release (i.e. norepinephrine) from sympathetic nerve terminals, which, when bound to α-adrenergic receptors on the smooth muscle, elicit peripheral vasoconstriction, an increase in total peripheral resistance and, ultimately, a rise in blood pressure (termed ‘neurovascular transduction’). Interestingly, not all individuals with OSA develop hypertension, suggesting an uncoupling of the IH-mediated increases in MSNA and its downstream effects on the peripheral vasculature. However, the effect of IH on neurovascular transduction was previously unknown. A recent article by Stuckless et al. (2019) published in The Journal of Physiology filled this gap in knowledge by testing the effect of acute IH on the transduction of MSNA into peripheral vasoconstriction and increases in systemic blood pressure. Neurovascular transduction can be described as the translation of increases in post-ganglionic MSNA to vascular tone. However, this could be considered a simplistic way to describe a quite nuanced and complex measurement. The sympathetic nervous system is classically assumed to be most important in the acute, beat-to-beat regulation of blood pressure, primarily via a rapid-response by the baroreceptors. As such, neurovascular transduction can be quantified as the acute, beat-to-beat response of the vasculature to a single ‘burst’ of sympathetic activity (Briant et al. 2016). That being said, individual ‘bursts’ of sympathetic activity differ by both frequency and amplitude, and can appear as a single ‘burst’ or a group of ‘bursts’ occurring in succession (e.g. doublet, triplet). Such differences in axonal discharge patterns are probably important contributors to the end effect of neurovascular transduction. We now know the autonomic nervous system is also important in regulating blood pressure in the long-term, especially in pathological conditions such as hypertension. With this information in mind, rather than assessing neurovascular transduction beat-to-beat, Stuckless et al. (2019) reported data as minute averages in response to acute increases in MSNA induced by lower body negative pressure (LBNP). Although this form of analysis may mask more nuanced differences in the effect of a given ‘burst’ of sympathetic activity on blood pressure, the results may be more translational to what is observed chronically in individuals with OSA. The main findings reported by Stuckless et al. (2019) show an increase in neurovascular transduction systemically following acute IH. In other words, a given rise in MSNA resulted in a greater increase in diastolic blood pressure following IH exposure. However, any effect of the 40 min protocol on forearm sympathetic neurovascular transduction did not differ between IH and control individuals. The vascular response to a given ‘burst’ of sympathetic activation exhibits striking regional differences between skeletal muscle vascular beds (e.g. upper and lower limbs). Specifically, data obtained by Fairfax et al. (2013) show the forearms to exhibit lesser degrees of vasoconstriction during spontaneous sympathetic activation compared to the legs. In the context of data reported by Stuckless et al. (2019), we speculate that IH-mediated sympathetic vasoconstriction may occur to a greater extent in the lower vs. the upper limbs. These limb differences in neurovascular transduction may be a result of regional differences in either α-adrenergic receptor sensitivity, number or both. Unfortunately, Stuckless et al. (2019) were unable to examine lower limb blood flow and transduction as a result of the use of LBNP. For future studies, neck pressure could be considered as an alternative modality for eliciting acute increases in MSNA and would allow multisite blood flow measurements. Increases in sympathetic activity modulate perfusion to a number of vascular beds that influence systemic blood pressure. In agreement with the current literature, Stuckless et al. (2019) note that angiotensin-II is an important contributor to increased sympathetic outflow and blood pressure following IH. Briefly, renal afferent chemosensory fibres detect IH-mediated changes in perfusion and oxygenation within the kidney that elicit reflex increases in sympathetic activity and activation of the renin–angiotensin system (AlMarabeh et al. 2019). If the renal arterioles are subject to increased transduction following a rise in sympathetic activity, this may create a positive feedback loop that potentiates systemic increases in blood pressure. As such, we speculate that a portion of the increase in systemic neurovascular transduction following IH observed by Stuckless et al. (2019) could have occurred in the renal arteries, causing a reduction in renal blood flow and activation of the renin–angiotensin system. Use of renal blood flow measurements in future studies could help confirm or refute this ‘nephrogenic model’ of IH-mediated increases in blood pressure. In addition to a direct effect of MSNA on the peripheral vasculature, an increase in sympathetic outflow also results in heightened systemic inflammation (Waldburger & Firestein, 2010). The subsequent increase in inflammatory cytokines results in an increase in the production of reactive oxidative species (ROS) and scavenging of nitric oxide (NO) within the peripheral vasculature. NO is produced in response to increased shear rates to dilate the blood vessels and reduce the shear stress on the vessel wall. As such, Stuckless et al. (2019) observed a significant reduction in shear rate and resting brachial artery flow following acute IH. These data suggest impairments in vasodilation following IH, which may be a result of inflammatory and ROS-mediated reductions in NO bioavailability. Because vascular dysfunction and NO bioavailability are hallmarks of early hypertension, it is important to further explore vascular function and NO bioavailability as a potential mechanism contributing to OSA-related hypertension. Future studies examining the effect of acute IH on flow-mediated vasodilatation, arterial stiffness and/or the impact of NO-mediated therapies (i.e. tetrahydrobiopterin, nitrates, phosphodiesterase-5, anti-inflammatory/anti-ROS) on neurovascular transduction are warranted. Stuckless et al. (2019) included three important experimental controls that strengthen their data and advance understanding. First, they clamped end-tidal gases to prevent hypocapnia commonly seen with LBNP-induced hyperventilation. Such approaches prevented the potential confounding effects of altered chemoreceptor activation, as well as the unknown effects of changes in CO2 on peripheral vascular function during measures of transduction. During the IH protocol, Stuckless et al. (2019) intentionally included hypercapnia to mimic the apnea-induced rise in CO2 in patients with OSA. This important variable is often overlooked in experimental IH. Second, Stuckless et al. (2019) made careful note of changes in ventilation that occurred following IH. As observed in their illustrated representative data (i.e. their figure 2) (Stuckless et al. 2019), both IH and LBNP have clear effects on respiratory modulation of sympathetic activity, which are probably important in the timing of sympathetic ‘bursts’, neurotransmitter release and, ultimately, transduction. Notably, there appeared to be less variation in oscillations in mean arterial pressure during the final stages of LBNP following IH. Clinically, this would suggest aberrant or decreased respiratory modulation of MSNA in individuals with OSA. Third, Stuckless et al. (2019) presented individual data for the majority of main outcome variables. Given that some individuals exposed to IH develop hypertension whereas others do not, it is important to clearly see the spread of data and trend of responses. As such, Stuckless et al. (2019) also included a control group that was not exposed to IH. This is important because with these types of human studies there is the likelihood of time-dependent changes as a result of individuals lying supine and inactive for long periods of time. However, because of the potential variability in responses, it was interesting that Stuckless et al. (2019) chose to study two separate groups of individuals (i.e. a lack of a cross-over design). There were notable differences in brachial artery flow, shear rate and vascular conductance between the IH and control group at baseline, suggesting group differences in resting vascular function. Because of the inter-individual variation in pathophysiology of OSA and hypertension, a randomized cross-over design would have permitted improved interpretation of the experimental findings. The pathophysiology of hypertension is multifactorial in that it is both caused by and perpetuates many effectors. Stuckless et al. (2019) aimed to explore the effect of IH on neurovascular transduction to evaluate the connection between OSA and hypertension. Reduced NO bioavailability is associated with vascular dysfunction and can result in increased vascular stiffness and lower vascular responsiveness to vasodilatory stimuli. As such, OSA-related IH may augment transduction, resulting in greater translation of neural output to changes in blood flow and blood pressure. Overall, the study by Stuckless et al. (2019) highlights the importance of IH as an experimental modality for better understanding the underlying mechanisms concerning the relationship between OSA and hypertension, thus providing direction for future follow-up studies. No competing interests declared. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. No funding was received." @default.
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• W3004697029 title "Intermittent hypoxia and sympathetic activation: To constrict or not to constrict, that is the question" @default.
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