The need for specificity in quantifying neurocirculatory vs. respiratory effects of eucapnic hypoxia and transient hyperoxia.

Key Points: The carotid chemoreceptor mediates the ventilatory and muscle sympathetic nerve activity (MSNA) responses to hypoxia and contributes to tonic sympathetic and respiratory drives. It is often presumed that both excitatory and inhibitory tests of chemoreflex function show congruence in the end-organ responses. Ventilatory and neurocirculatory (MSNA, blood pressure and heart rate) responses to chemoreflex inhibition elicited by transient hyperoxia and to chemoreflex excitation produced by steady-state eucapnic hypoxia were measured in a cohort of 82 middle-aged individuals.

Effects of losartan and allopurinol on cardiorespiratory regulation in obstructive sleep apnoea.

New Findings: What is the central question of this study? In sleep apnoea, a putative link between intermittent hypoxia and hypertension is the generation of oxygen radicals by angiotensin II and xanthine oxidase within the chemoreflex arc and vasculature. We tested whether chemoreflex control of sympathetic outflow, hypoxic vasodilatation and blood pressure are altered by angiotensin blockade (losartan) and/or xanthine oxidase inhibition (allopurinol). What is the main finding and its importance? Both drugs lowered blood pressure without altering sympathetic outflow, reducing chemoreflex sensitivity or enhancing hypoxic vasodilatation.

Effect of Chronic Intermittent Hypoxia on Angiotensin II Receptors in the Central Nervous System.

Chronic intermittent hypoxia (CIH) increases basal sympathetic nervous system activity, augments chemoreflex-induced sympathoexcitation, and raises blood pressure. All effects are attenuated by systemic or intracerebroventricular administration of angiotensin II type 1 receptor (ATR) antagonists. This study aimed to quantify the effects of CIH on ATR- and ATR-like immunoreactivity in the rostroventrolateral medulla (RVLM) and paraventricular nucleus of the hypothalamus (PVN), central regions that are important components of the extended chemoreflex pathway.

Oxidative stress augments chemoreflex sensitivity in rats exposed to chronic intermittent hypoxia.

Chronic exposure to intermittent hypoxia (CIH) elicits plasticity of the carotid sinus and phrenic nerves via reactive oxygen species (ROS). To determine whether CIH-induced alterations in ventilation, metabolism, and heart rate are also dependent on ROS, we measured responses to acute hypoxia in conscious rats after 14 and 21 d of either CIH or normoxia (NORM), with or without concomitant administration of allopurinol (xanthine oxidase inhibitor), combined allopurinol plus losartan (angiotensin II type 1 receptor antagonist), or apocynin (NADPH oxidase inhibitor). Carotid body nitrotyrosine production was measured by immunohistochemistry.

Revisiting the Debate: Does Exercise Build Strong Bones in the Mature and Senescent Skeleton?

Traditional exercise programs seem to be less osteogenic in the mature and post-mature skeleton compared to the young skeleton. This is likely because of the decline in sensitivity of bone to mechanical loading that occurs with advancing age. Another factor contributing to the apparently diminished benefit of exercise in older adults is failure of widely used measurement techniques (i.

Peripheral Blood Flow Regulation in Human Obesity and Metabolic Syndrome.

Both obesity and metabolic syndrome are important cardiovascular disease risk factors. In this review, we will explore the hypothesis that young obese adults and adults with metabolic syndrome exhibit alterations in blood flow regulation that occur prior to the onset of overt cardiovascular dysfunction.

Chronic intermittent hypoxia alters ventilatory and metabolic responses to acute hypoxia in rats.

We determined the effects of chronic exposure to intermittent hypoxia (CIH) on chemoreflex control of ventilation in conscious animals. Adult male Sprague-Dawley rats were exposed to CIH [nadir oxygen saturation (SpO2), 75%; 15 events/h; 10 h/day] or normoxia (NORM) for 21 days. We assessed the following responses to acute, graded hypoxia before and after exposures: ventilation (V̇e, via barometric plethysmography), V̇o2 and V̇co2 (analysis of expired air), heart rate (HR), and SpO2 (pulse oximetry via neck collar).

Humans In Hypoxia: A Conspiracy Of Maladaptation?!

We address adaptive vs. maladaptive responses to hypoxemia in healthy humans and hypoxic-tolerant species during wakefulness, sleep, and exercise. Types of hypoxemia discussed include short-term and life-long residence at high altitudes, the intermittent hypoxemia attending sleep apnea, or training regimens prescribed for endurance athletes.

Quantifying hypoxia-induced chemoreceptor sensitivity in the awake rodent.

We evaluated several methods for characterizing hypoxic chemosensitivity in the conscious rat. Adult Sprague-Dawley rats (n = 30) were exposed to normobaric hypoxia [inspired oxygen fraction (Fio2) 0.15, 0.

Effects of chronic intermittent hypoxia on allergen-induced airway inflammation in rats.

Obstructive sleep apnea aggravates asthma, but its mechanisms are unknown. Chronic intermittent hypoxia is one hallmark feature of sleep apnea. In this study, we tested the effects of chronic intermittent hypoxia on allergen-induced inflammation in rats.

Mechanical and metabolic reflex activation of the sympathetic nervous system in younger adults with metabolic syndrome.

Aim: Based on reports of exaggerated blood pressure responses to whole-body exercise in patients with metabolic syndrome (MetSyn), we tested the hypothesis that MetSyn adults would exhibit augmented sympathetic and pressor responses to mechanoreflex and metaboreflex activation when compared with healthy, age-matched control subjects.

Methods: We studied 12 adults with MetSyn (34±3years) and 12 healthy control subjects (34±3years). Heart rate (HR; ECG), blood pressure (BP; finger photoplethysmography), and MSNA (microneurography of the peroneal nerve) were measured during: (1) static handgrip exercise at 15% of maximal voluntary contraction (MVC), and (2) static handgrip exercise at 30% MVC to fatigue, followed by post-exercise ischemia (PEI).

Neural control of blood flow during exercise in human metabolic syndrome.

α-Adrenergic-mediated vasoconstriction is greater during simulated exercise in animal models of metabolic syndrome (MetSyn) when compared with control animals. In an attempt to translate such findings to humans, we hypothesized that adults with MetSyn (n = 14, 35 ± 3 years old) would exhibit greater α-adrenergic responsiveness during exercise when compared with age-matched healthy control subjects (n = 16, 31 ± 3 years old). We measured muscle sympathetic nerve activity (MSNA; microneurography) and forearm blood flow (Doppler ultrasound) during dynamic forearm exercise (15% of maximal voluntary contraction).

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans.

The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) screened >300,000 compounds to evaluate their ability to restore fluconazole susceptibility in resistant Candida albicans isolates. Additional counter screens were incorporated to remove substances inherently toxic to either mammalian or fungal cells. A substituted indazole possessing the desired bioactivity profile was selected for further development, and initial investigation of structure-activity relationships led to the discovery of ML212.

Respiratory influences on muscle sympathetic nerve activity and vascular conductance in the steady state.

In patients with hypertension, volitional slowing of the respiratory rate has been purported to reduce arterial pressure via withdrawal of sympathetic tone. We examined the effects of paced breathing at 7, 14, and 21 breaths/min, with reciprocal changes in tidal volume, on muscle sympathetic nerve activity, forearm blood flow, forearm vascular conductance, and blood pressure in 21 men and women, 8 of whom had modest elevations in systemic arterial pressure. These alterations in breathing frequency and volume did not affect steady-state levels of sympathetic activity, blood flow, vascular conductance, or blood pressure (all P > 0.

Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.

A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.

Altered neurovascular control of the resting circulation in human metabolic syndrome.

Young healthy adults exhibit an inverse linear relationship between muscle sympathetic nerve activity (MSNA) and α-adrenergic responsiveness. This balance may be reversed in metabolic syndrome (MetSyn) as animal models exhibit increased sympathetic activity and α-mediated vasoconstriction. We hypothesized humans with MetSyn would demonstrate increased α-adrenergic vasoconstriction and the inverse relationship between MSNA and adrenergic responsiveness would be lost.

Impaired hypoxic cerebral vasodilation in younger adults with metabolic syndrome.

Metabolic syndrome (MetSyn) increases the risk of cerebrovascular disease and stroke; however, its impact on human cerebral circulation remains unclear. Reduced cerebral dilation is also associated with an increased risk of stroke and may occur in MetSyn adults. We hypothesised that MetSyn adults would exhibit reduced cerebral vasodilation to hypoxia and hypercapnia.

Perylenequinones: Isolation, Synthesis, and Biological Activity.

The perylenequinones are a novel class of natural products characterized by pentacyclic conjugated chromophore giving rise to photoactivity. Potentially useful light-activated biological activity, targeting protein kinase C (PKC), has been identified for several of the natural products. Recently discovered new members of this class of compound, as well as several related phenanthroperylenequinones, are reviewed.

Effect of AT1 receptor blockade on intermittent hypoxia-induced endothelial dysfunction.

Chronic intermittent hypoxia (CIH) raises arterial pressure, impairs vasodilator responsiveness, and increases circulating angiotensin II (Ang II); however, the role of Ang II in CIH-induced vascular dysfunction is unknown. Rats were exposed to CIH or room air (NORM), and a subset of these animals was treated with losartan (Los) during the exposure period. After 28 days, vasodilatory responses to acetylcholine or nitroprusside were measured in isolated gracilis arteries.