Autonomic Mechanisms Of Blood Pressure Alterations During Sleep In Orexin/Hypocretin-Deficient Narcoleptic Mice

Study Objectives increases in arterial pressure (AP) during sleep and smaller differences in AP between sleep and wakefulness have been reported in orexin (hypocretin)-deficient mouse models of narcolepsy type 1 (NT1) and confirmed in NT1 patients. We tested whether these alterations are mediated by parasympathetic or sympathetic control of the heart and/or resistance vessels in an orexin-deficient mouse model of NT1. Methods 13 orexin knock-out (ORX-KO) mice were compared with 12 congenic wild-type (WT) mice. The electroencephalogram, electromyogram, and AP of the mice were recorded in the light (rest) period during intraperitoneal infusion of atropine methyl nitrate, atenolol, or prazosin to block muscarinic cholinergic, β1-adrenergic, or α1-adrenergic receptors, respectively, while saline was infused as control. Results AP significantly depended on a 3-way interaction among the mouse group (ORX-KO vs WT), the wake-sleep state, and the drug or vehicle infused. During the control vehicle infusion, ORX-KO had significantly higher AP values during REM sleep, smaller decreases in AP from wakefulness to either non-rapid-eye-movement (non-REM) sleep or REM sleep, and greater increases in AP from non-REM sleep to REM sleep compared to WT. These differences remained significant with atropine methyl nitrate, whereas they were abolished by prazosin and, except for the smaller AP decrease from wakefulness to REM sleep in ORX-KO, also by atenolol. Conclusions sleep-related alterations of AP due to orexin deficiency significantly depend on alterations in cardiovascular sympathetic control in a mouse model of NT1.

Sex differences in integrated neurocardiovascular control of blood pressure following acute intermittent hypercapnic hypoxia

Repetitive hypoxic apneas, similar to those observed in sleep apnea, result in resetting of the sympathetic baroreflex to higher blood pressures (BP). This baroreflex resetting is associated with hypertension in preclinical models of sleep apnea (intermittent hypoxia, IH); however, the majority of understanding comes from males. There are data to suggest that female rats exposed to IH do not develop high BP. Clinical data further support sex differences in the development of hypertension in sleep apnea, but mechanistic data are lacking. Here we examined sex-related differences in the effect of IH on sympathetic control of BP in humans. We hypothesized that after acute IH we would observe a rise in muscle sympathetic nerve activity (MSNA) and arterial BP in young men ( n = 30) that would be absent in young women ( n = 19). BP and MSNA were measured during normoxic rest before and after 30 min of IH. Baroreflex sensitivity (modified Oxford) was evaluated before and after IH. A rise in mean BP following IH was observed in men (+2.0 ± 0.7 mmHg, P = 0.03), whereas no change was observed in women (−2.7 ± 1.2 mmHg, P = 0.11). The elevation in MSNA following IH was not different between groups (4.7 ± 1.1 vs. 3.8 ± 1.2 bursts/min, P = 0.65). Sympathetic baroreflex sensitivity did not change after IH in either group ( P > 0.05). Our results support sex-related differences in the effect of IH on neurovascular control of BP and show that any BP-raising effects of IH are absent in young women. These data enhance our understanding of sex-specific mechanisms that may contribute to BP changes in sleep apnea.

Astrocytes monitor cerebral perfusion and control systemic circulation to maintain brain blood flow

Astrocytes provide neurons with essential metabolic and structural support, modulate neuronal circuit activity and may also function as versatile surveyors of brain milieu, tuned to sense conditions of potential metabolic insufficiency. Here we show that astrocytes detect falling cerebral perfusion pressure and activate CNS autonomic sympathetic control circuits to increase systemic arterial blood pressure and heart rate with the purpose of maintaining brain blood flow and oxygen delivery. Studies conducted in experimental animals (laboratory rats) show that astrocytes respond to acute decreases in brain perfusion with elevations in intracellular [Ca2+]. Blockade of Ca2+-dependent signaling mechanisms in populations of astrocytes that reside alongside CNS sympathetic control circuits prevents compensatory increases in sympathetic nerve activity, heart rate and arterial blood pressure induced by reductions in cerebral perfusion. These data suggest that astrocytes function as intracranial baroreceptors and play an important role in homeostatic control of arterial blood pressure and brain blood flow.

Imaging cAMP nanodomains in the heart

3′-5′-cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that modulates multiple cellular functions. It is now well established that cAMP can mediate a plethora of functional effects via a complex system of local regulatory mechanisms that result in compartmentalized signalling. The use of fluorescent probes to monitor cAMP in intact, living cells have been instrumental in furthering our appreciation of this ancestral and ubiquitous pathway and unexpected details of the nano-architecture of the cAMP signalling network are starting to emerge. Recent evidence shows that sympathetic control of cardiac contraction and relaxation is achieved via generation of multiple, distinct pools of cAMP that lead to differential phosphorylation of target proteins localized only tens of nanometres apart. The specific local control at these nanodomains is enabled by a distinct signalosome where effectors, targets, and regulators of the cAMP signal are clustered. In this review, we focus on recent advances using targeted fluorescent reporters for cAMP and how they have contributed to our current understanding of nanodomain cAMP signalling in the heart. We briefly discuss how this information can be exploited to design novel therapies and we highlight some of the questions that remain unanswered.