Abstract-Intermittent hypoxia (IH) is believed to contribute to the pathogenesis of hypertension in obstructive sleep apnea through mechanisms that include activation of the renin-angiotensin system. The objective of this study was to assess the role of the type I angiotensin II receptor in mediating an increase in arterial pressure associated with a single 6-hour IH exposure. Using a double-blind, placebo-controlled, randomized, crossover study design, we exposed 9 healthy male subjects to sham IH, IH with placebo medication, and IH with the type I angiotensin II receptor antagonist losartan. We measured blood pressure, cerebral blood flow, and ventilation at baseline and after exposure to 6 hours of IH. An acute isocapnic hypoxia experimental protocol was conducted immediately before and after exposure to IH. IH with placebo increased resting mean arterial pressure by 7.9Ϯ1.6 mm Hg, but mean arterial pressure did not increase with sham IH (1.9Ϯ1.5 mm Hg) or with losartan IH (Ϫ0.2Ϯ2.4 mm Hg; PϽ0.05). Exposure to IH prevented the diurnal decrease in the cerebral blood flow response to hypoxia, independently of the renin-angiotensin system. Finally, in contrast to other models of IH, the acute hypoxic ventilatory response did not change throughout the protocol. IH increases arterial blood pressure through activation of the type I angiotensin II receptor, without a demonstrable impact on the cerebrovascular or ventilatory response to acute hypoxia. (Hypertension. 2010;56:369-377.)Key Words: blood pressure Ⅲ cerebrovascular circulation Ⅲ hypoxia Ⅲ renin Ⅲ physiology P atients with obstructive sleep apnea (OSA) are exposed to chronic intermittent hypoxia (IH), which is thought to be the underlying mechanism that links OSA with an increased risk of cardiovascular disease. 1 The specific pathophysiologic mechanism whereby OSA causes hypertension has not been fully elucidated, but it has been proposed that persistent sympathoexcitation, oxidative stress, and endothelial dysfunction contribute. 2 Central to this concept is the important interaction between the sympathetic nervous system and the renin-angiotensin system (RAS). Renin release from the kidney is tightly controlled by activity in renal sympathetic nerves. 3 In OSA patients, sympathetic nerve activity, 4 the plasma concentration of angiotensin II (ANG-II), 5 and the vasoconstrictor response to ANG-II are elevated. 6 ANG-II has potent vasoconstrictor capabilities through its action on type I ANG-II receptors (AT 1 Rs) located on vascular smooth muscle cells. 7 ANG-II production can also regulate blood volume by increasing aldosterone production. The combined potential for the RAS to be stimulated by IH and its ability to regulate peripheral resistance and blood volume make it a credible pathway through which OSA can lead to the development of systemic hypertension. The role of the RAS in the IH-dependent increase in arterial blood pressure has yet to be addressed in human experiments.The primary objective of this study was to assess the role of the AT 1 R in ...

Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. This human study shows that reactive oxygen species overproduction modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with obstructive sleep apnea.

Objectives: We used functional MRI (fMRI), transcranial Doppler ultrasound, and visual evoked potentials (VEPs) to determine the nature of blood flow responses to functional brain activity and carbon dioxide (CO 2 ) inhalation in patients with cerebral amyloid angiopathy (CAA), and their association with markers of CAA severity.Methods: In a cross-sectional prospective cohort study, fMRI, transcranial Doppler ultrasound CO 2 reactivity, and VEP data were compared between 18 patients with probable CAA (by Boston criteria) and 18 healthy controls, matched by sex and age. Functional MRI consisted of a visual task (viewing an alternating checkerboard pattern) and a motor task (tapping the fingers of the dominant hand).Results: Patients with CAA had lower amplitude of the fMRI response in visual cortex compared with controls (p 5 0.01), but not in motor cortex (p 5 0.22). In patients with CAA, lower visual cortex fMRI amplitude correlated with higher white matter lesion volume (r 5 20.66, p 5 0.003) and more microbleeds (r 5 20.78, p , 0.001). VEP P100 amplitudes, however, did not differ between CAA and controls (p 5 0.45). There were trends toward reduced CO 2 reactivity in the middle cerebral artery (p 5 0.10) and posterior cerebral artery (p 5 0.08).Conclusions: Impaired blood flow responses in CAA are more evident using a task to activate the occipital lobe than the frontal lobe, consistent with the gradient of increasing vascular amyloid severity from frontal to occipital lobe seen in pathologic studies. Reduced fMRI responses in CAA are caused, at least partly, by impaired vascular reactivity, and are strongly correlated with other neuroimaging markers of CAA severity. Neurology ® 2013;81:1659-1665 GLOSSARY BOLD 5 blood oxygen level-dependent; CAA 5 cerebral amyloid angiopathy; CO 2 5 carbon dioxide; DEF 5 dynamic end-tidal forcing; DSM-IV 5 Diagnostic and Statistical Manual of Mental Disorders, 4th edition; fMRI 5 functional MRI; ICH 5 intracerebral hemorrhage; PETCO 2 5 partial pressure of end-tidal carbon dioxide; VEP 5 visual evoked potential; WMH 5 white matter hyperintensity.Cerebral amyloid angiopathy (CAA) is best recognized clinically as a cause of frequent recurrent intracerebral hemorrhages (ICHs) and microbleeds, reflecting loss of vascular integrity due to b-amyloid deposition.1 However, accumulating evidence suggests that impaired vascular reactivity is another feature of CAA. In a mouse model of severe CAA, there was decreased vasodilation in response to whisker barrel stimulation and to carbon dioxide (CO 2 ) inhalation, a vasodilatory stimulus.2 In a small study of patients with probable CAA, posterior cerebral artery flow velocity responses were lower than controls when viewing a visual stimulus, but middle cerebral artery flow velocity responses to CO 2 inhalation were relatively preserved.3 It was not clear whether the differential responses observed in the visual and CO 2 experiments were due to the different arteries tested, the different types of vasodilatory stimulus used, or wer...

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New, advanced quantitative neuroimaging techniques are not ready for routine radiological practice but are already being employed as monitoring biomarkers in the newest generation of trials for SVD.

Aging is associated with decreased vascular compliance and diminished neurovascular- and hypercapnia-evoked cerebral blood flow (CBF) responses. However, the interplay between arterial stiffness and reduced CBF responses is poorly understood. It was hypothesized that increased cerebral arterial stiffness is associated with reduced evoked responses to both, a flashing checkerboard visual stimulation (i.e., neurovascular coupling), and hypercapnia. To test this hypothesis, 20 older (64 ± 8 year; mean ± SD) and 10 young (30 ± 5 year) subjects underwent a visual stimulation (VS) and a hypercapnic test. Blood velocity through the posterior (PCA) and middle cerebral (MCA) arteries was measured concurrently using transcranial Doppler ultrasound (TCD). Cerebral and systemic vascular stiffness were calculated from the cerebral blood velocity and systemic blood pressure waveforms, respectively. Cerebrovascular (MCA: young = 76 ± 15%, older = 98 ± 19%, p = 0.004; PCA: young = 80 ± 16%, older = 106 ± 17%, p < 0.001) and systemic (young = 59 ± 9% and older = 80 ± 9%, p < 0.001) augmentation indices (AI) were higher in the older group. CBF responses to VS (PCA: p < 0.026) and hypercapnia (PCA: p = 0.018; MCA: p = 0.042) were lower in the older group. A curvilinear model fitted to cerebral AI and age showed AI increases until ~60 years of age, after which the increase levels off (PCA: R2 = 0.45, p < 0.001; MCA: R2 = 0.31, p < 0.001). Finally, MCA, but not PCA, hypercapnic reactivity was inversely related to cerebral AI (MCA: R2 = 0.28, p = 0.002; PCA: R2 = 0.10, p = 0.104). A similar inverse relationship was not observed with the PCA blood flow response to VS (R2 = 0.06, p = 0.174). In conclusion, older subjects had reduced neurovascular- and hypercapnia-mediated CBF responses. Furthermore, lower hypercapnia-mediated blood flow responses through the MCA were associated with increased vascular stiffness. These findings suggest the reduced hypercapnia-evoked CBF responses through the MCA, in older individuals may be secondary to vascular stiffening.

Hyperthermia-induced hyperventilation has been proposed to be a human thermolytic thermoregulatory response and to contribute to the disproportionate increase in exercise ventilation (VE) relative to metabolic needs during high-intensity exercise. In this study it was hypothesized that VE would adapt similar to human eccrine sweating (E(SW)) following a passive heat acclimation (HA). All participants performed an incremental exercise test on a cycle ergometer from rest to exhaustion before and after a 10-day passive exposure for 2 h/day to either 50 degrees C and 20% relative humidity (RH) (n = 8, Acclimation group) or 24 degrees C and 32% RH (n = 4, Control group). Attainment of HA was confirmed by a significant decrease (P = 0.025) of the esophageal temperature (T(es)) threshold for the onset of E(SW) and a significantly elevated E(SW) (P < or = 0.040) during the post-HA exercise tests. HA also gave a significant decrease in resting T(es) (P = 0.006) and a significant increase in plasma volume (P = 0.005). Ventilatory adaptations during exercise tests following HA included significantly decreased T(es) thresholds (P < or = 0.005) for the onset of increases in the ventilatory equivalents for O(2) (VE/VO(2)) and CO(2) (VE/VCO(2)) and a significantly increased VE (P < or = 0.017) at all levels of T(es). Elevated VE was a function of a significantly greater tidal volume (P = 0.003) at lower T(es) and of breathing frequency (P < or = 0.005) at higher T(es). Following HA, the ventilatory threshold was uninfluenced and the relationships between VO(2) and either VE/VO(2) or VE/VCO(2) did not explain the resulting hyperventilation. In conclusion, the results support that exercise VE following passive HA responds similarly to E(SW), and the mechanism accounting for this adaptation is independent of changes of the ventilatory threshold or relationships between VO(2) with each of VE/VO(2) and VE/VCO(2).

Study Objective: Intermittent hypoxia (IH) is associated with increased risk of cardiovascular disease. Exosomes are secreted by most cell types and released in biological fluids, including plasma, and play a role in modifying the functional phenotype of target cells. Using an experimental human model of IH, we investigated potential exosome-derived biomarkers of IH-induced vascular dysfunction. Methods: Ten male volunteers were exposed to room air (D0), IH (6 h/day) for 4 days (D4) and allowed to recover for 4 days (D8). Circulating plasma exosomes were isolated and incubated with human endothelial monolayer cultures for impedance measurements and RNA extracted and processed with messenger RNA (mRNA) arrays to identify gene targets. In addition, immunofluorescent assessments of endothelial nitric oxide synthase (eNOS) mRNA expression, ICAM-1 cellular distribution were conducted. Results: Plasma exosomal micro RNAs (miRNAs) were profiled. D4 exosomes, primarily from endothelial sources, disrupted impedance levels compared to D0 and D8. ICAM-1 expression was markedly upregulated in endothelial cells exposed to D4 exosomes along with significant reductions in eNOS expression. Microarray approaches identified a restricted and further validated signature of exosomal miRNAs in D4 exosomes, and mRNA arrays revealed putative endothelial gene target pathways. Conclusions:In humans, intermittent hypoxia alters exosome cargo in the circulation which promotes increased permeability and dysfunction of endothelial cells in vitro. A select number of circulating exosomal miRNAs may play important roles in the cardiovascular dysfunction associated with OSA by targeting specific effector pathways.