Cytoplasmic Dynein Transports Axonal Microtubules in a Polarity-Sorting Manner.

Axonal microtubules are predominantly organized into a plus-end-out pattern. Here, we tested both experimentally and with computational modeling whether a motor-based polarity-sorting mechanism can explain this microtubule pattern. The posited mechanism centers on cytoplasmic dynein transporting plus-end-out and minus-end-out microtubules into and out of the axon, respectively. When cytoplasmic dynein was acutely inhibited, the bi-directional transport of microtubules in the axon was disrupted in both directions, after which minus-end-out microtubules accumulated in the axon over time. Computational modeling revealed that dynein-mediated transport of microtubules can establish and preserve a predominantly plus-end-out microtubule pattern as per the details of the experimental findings, but only if a kinesin motor and a static cross-linker protein are also at play. Consistent with the predictions of the model, partial depletion of TRIM46, a protein that cross-links axonal microtubules in a manner that influences their polarity orientation, leads to an increase in microtubule transport.

Pharmacologically increasing microtubule acetylation corrects stress-exacerbated effects of organophosphates on neurons.

Many veterans of the 1990-1991 Gulf War contracted Gulf War Illness (GWI), a multisymptom disease that primarily affects the nervous system. Here, we treated cultures of human or rat neurons with diisopropyl fluorophosphate (DFP), an analog of sarin, one of the organophosphate (OP) toxicants to which the military veterans were exposed. All observed cellular defects produced by DFP were exacerbated by pretreatment with corticosterone or cortisol, which, in rat and human neurons, respectively, serves in our experiments to mimic the physical stress endured by soldiers during the war. To best mimic the disease, DFP was used below the level needed to inhibit acetylcholinesterase. We observed a diminution in the ratio of acetylated to total tubulin that was correctable by treatment with tubacin, a drug that inhibits HDAC6, the tubulin deacetylase. The reduction in microtubule acetylation was coupled with deficits in microtubule dynamics, which were correctable by HDAC6 inhibition. Deficits in mitochondrial transport and dopamine release were also improved by tubacin. Thus, various negative effects of the toxicant/stress exposures were at least partially correctable by restoring microtubule acetylation to a more normal status. Such an approach may have therapeutic benefit for individuals suffering from GWI or other neurological disorders linked to OP exposure.

The mGluR2 positive allosteric modulator, SAR218645, improves memory and attention deficits in translational models of cognitive symptoms associated with schizophrenia.

Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ35S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1neo-/- mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.

Axonal transport: The orderly motion of axonal structures.

Axonal transport is a constitutive process that supplies the axon and axon terminal with materials required to maintain their structure and function. Most materials are supplied via three rate components termed the fast component, slow component a, and slow component b. Each of these delivers a distinct set of materials with distinct transport kinetics. Understanding the basis for how materials sort among these rate components and the mechanisms that generate their distinctive transport kinetics have been long-standing goals in the field. An early view emphasized the relationships between axonally transported cargoes and cytological structures of the axon. In this article, I discuss key observations that led to this view and contemporary studies that have demonstrated its validity and thereby advanced the current understanding of the dynamics of axonal structure.

A novel role for doublecortin and doublecortin-like kinase in regulating growth cone microtubules.

Doublecortin (DCX) and doublecortin-like kinase (DCLK), closely related family members, are microtubule-associated proteins with overlapping functions in both neuronal migration and axonal outgrowth. In growing axons, these proteins appear to have their primary functions in the growth cone. Here, we used siRNA to deplete these proteins from cultured rat sympathetic neurons. Normally, microtubules in the growth cone exhibit a gently curved contour as they extend from the base of the cone toward its periphery. However, following depletion of DCX and DCLK, microtubules throughout the growth cone become much more curvy, with many microtubules exhibiting multiple prominent bends over relatively short distances, creating a configuration that we termed wave-like folds. Microtubules with these folds appeared as if they were buckling in response to powerful forces. Indeed, inhibition of myosin-II, which generates forces on the actin cytoskeleton to push microtubules in the growth cone back toward the axonal shaft, significantly decreases the frequency of these wave-like folds. In addition, in the absence of DCX and DCLK, the depth of microtubule invasion into filopodia is reduced compared with controls, and at a functional level, growth cone responses to substrate guidance cues are altered. Conversely, overexpression of DCX results in microtubules that are straighter than usual, suggesting that higher levels of these proteins can enable an even greater resistance to folding. These findings support a role for DCX and DCLK in enabling microtubules to overcome retrograde actin-based forces, thereby facilitating the ability of the growth cone to carry out its crucial path-finding functions.

SAR110894, a potent histamine H3-receptor antagonist, displays procognitive effects in rodents.

SAR110894 is a novel histamine H3-R ligand, displaying high and selective affinity for human, rat or mouse H3-Rs. SAR110894 is a potent H3-R antagonist at native receptors, reversing R-α-methylhistamine-induced inhibition of electrical field stimulation contraction in the guinea-pig ileum. Additionally, SAR110894 inhibited constitutive GTPγS binding at human H3-Rs demonstrating inverse agonist properties. In behavioral models addressing certain aspects of cognitive impairment associated with schizophrenia (CIAS) and attention deficit/hyperactivity disorder (ADHD), SAR110894 improved memory performances in several variants of the object recognition task in mice (0.3-3 mg/kg, p.o.) or rats (0.3-1 mg/kg, p.o.). Moreover, SAR110894 (1 mg/kg, p.o.) reversed a deficit in working memory in the Y-maze test, following an acute low dose of phencyclidine (PCP) (0.5 mg/kg, i.p.) in mice sensitized by repeated treatment with a high dose of PCP (10 mg/kg, i.p.). In the latent inhibition (LI) model, SAR110894 potentiated LI in saline-treated rats (1 and 3 mg/kg, i.p.) and reversed abnormally persistent LI induced by neonatal nitric oxide synthase (NOS) inhibition in rodents (0.3-3 mg/kg, i.p.). In a social novelty discrimination task in rats, SAR110894 attenuated selective attention deficit induced by neonatal PCP treatment (3 and 10 mg/kg, p.o.) or a parametric modification of the procedure (3 and 10 mg/kg, p.o.). SAR110894 showed efficacy in several animal models related to the cognitive deficits in Alzheimer's disease (AD). It prevented the occurrence of episodic memory deficit induced by scopolamine in rats (0.01-10 mg/kg, p.o.) or by the central infusion of the toxic amyloid fragment ß25₋35 in the object recognition test in mice (1 and 3 mg/kg, p.o.). Altogether, these findings suggest that SAR110894 may be of therapeutic interest for the treatment of the cognitive symptoms of AD, schizophrenia and certain aspects of ADHD.

The cytoskeleton of the neuron--an essay in celebration of Paul Letourneau's career.

The neuronal cytoskeleton consists of microtubules, actin filaments, neurofilaments, and an array of accessory proteins that regulate and modify these three main filament systems. This essay celebrates the career of Paul Letourneau, a pioneer of the neuronal cytoskeleton, to whom the community owes a debt of gratitude.

Influence of cold water immersion on limb and cutaneous blood flow at rest.

BACKGROUND: Cold water immersion reduces exercise-induced muscle damage. Benefits may partly arise from a decline in limb blood flow; however, no study has comprehensively investigated the influence of different degrees of cooling undertaken via cold water immersion on limb blood flow responses. PURPOSE: To determine the influence of cold (8°C) and cool (22°C) water immersion on lower limb and cutaneous blood flow. STUDY DESIGN: Controlled laboratory study. METHODS: Nine men were placed in a semireclined position and lowered into 8°C or 22°C water to the iliac crest for two 5-minute periods interspersed with 2 minutes of nonimmersion. Rectal and thigh skin temperature, deep and superficial muscle temperature, heart rate, mean arterial pressure, thigh cutaneous blood velocity (laser Doppler), and superficial femoral artery blood flow (duplex ultrasound) were measured during immersion and for 30 minutes after immersion. Indices of vascular conductance were calculated (flux and blood flow/mean arterial pressure). RESULTS: Reductions in rectal temperature (8°C, 0.2° ± 0.1°C; 22°C, 0.1° ± 0.1°C) and thigh skin temperature (8°C, 6.2° ± 0.5°C; 22°C, 3.2° ± 0.2°C) were greater in 8°C water than in 22°C (P < .01). Femoral artery conductance was reduced to a similar extent immediately after immersion (~30%) and 30 minutes after immersion (~40%) under both conditions (P < .01). In contrast, there was less thigh cutaneous vasoconstriction during and after immersion in 8°C water compared with 22°C (P = .01). CONCLUSION: These data suggest that immersion at both temperatures resulted in similar whole limb blood flow but, paradoxically, more blood was distributed to the skin in the colder water. This suggests that colder temperatures may be associated with reduced muscle blood flow, which could provide an explanation for the benefits of cold water immersion in alleviating exercise-induced muscle damage in sports and athletic contexts. CLINICAL RELEVANCE: Colder water temperatures may be more effective in the treatment of exercise-induced muscle damage and injury rehabilitation because of greater reductions in muscle blood flow.

Assessment of flow-mediated dilation in humans: a methodological and physiological guideline.

Endothelial dysfunction is now considered an important early event in the development of atherosclerosis, which precedes gross morphological signs and clinical symptoms. The assessment of flow-mediated dilation (FMD) was introduced almost 20 years ago as a noninvasive approach to examine vasodilator function in vivo. FMD is widely believed to reflect endothelium-dependent and largely nitric oxide-mediated arterial function and has been used as a surrogate marker of vascular health. This noninvasive technique has been used to compare groups of subjects and to evaluate the impact of interventions within individuals. Despite its widespread adoption, there is considerable variability between studies with respect to the protocols applied, methods of analysis, and interpretation of results. Moreover, differences in methodological approaches have important impacts on the response magnitude, can result in spurious data interpretation, and limit the comparability of outcomes between studies. This review results from a collegial discussion between physiologists with the purpose of developing considered guidelines. The contributors represent several distinct research groups that have independently worked to advance the evidence base for improvement of the technical approaches to FMD measurement and analysis. The outcome is a series of recommendations on the basis of review and critical appraisal of recent physiological studies, pertaining to the most appropriate methods to assess FMD in humans.

AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia: improvement in cognitive function and reduction of antipsychotic-side effects in rodents.

RATIONALE: The psychotomimetic effects of cannabis are believed to be mediated via cannabinoid CB1 receptors. Furthermore, studies have implicated CB1 receptors in the pathophysiology of schizophrenia. OBJECTIVE: These studies investigated the effects of the CB1 receptor antagonist, AVE1625, in acute pharmacological and neurodevelopmental models of schizophrenia. AVE1625 was administered to rodents alone or as a co-treatment with clinically used antipsychotic drugs (APDs). METHODS: The antipsychotic potential of AVE1625 was tested using psychotomimetic-induced hyperactivity and latent inhibition (LI) deficit models. The procognitive profile was assessed using hole board, novel object recognition, auditory evoked potential, and LI techniques. In addition, the side-effect profile was established by measuring catalepsy, antipsychotic-induced weight gain, plasma levels of prolactin, and anxiogenic potential. RESULTS: AVE1625 (1, 3, and 10 mg/kg ip), reversed abnormally persistent LI induced by MK-801 or neonatal nitric oxide synthase inhibition in rodents, and improved both working and episodic memory. AVE1625 was not active in positive symptom models but importantly, it did not diminish the efficacy of APDs. It also decreased catalepsy and weight gain induced by APDs, suggesting that it may decrease APD-induced extrapyramidal side effects (EPS) and compliance. Unlike other CB1 antagonists, AVE1625 did not produce anxiogenic-like effects. CONCLUSIONS: These preclinical data suggest that AVE1625 may be useful to treat the cognitive deficits in schizophrenia and as a co-treatment with currently available antipsychotics. In addition, an improved side-effect profile was seen, with potential to ameliorate the EPS and weight gain issues with currently available treatments.

Impact of age, sex and exercise on brachial and popliteal artery remodelling in humans.

OBJECTIVE: To examine the impact of age, sex and exercise on wall thickness and remodelling in the popliteal and brachial arteries. METHODS: We compared wall thickness, lumen diameter and wall:lumen ratios in the brachial and popliteal arteries of 15 young (Y, 25.4+/-0.8 yr; 7M 8W) and 16 older sedentary (OS, 58.8+/-1.1 yr; 8M 8W) subjects, with 12 of the OS group also studied following 12 and 24 weeks exercise training. RESULTS: Wall thickness and lumen diameter were higher in the popliteal than the brachial artery for both groups (P<0.05); wall:lumen ratio was similar between arteries. Comparison of the Y and OS groups revealed no impact on wall thickness, whereas diameter values were higher in OS subjects (P<0.05). Whilst there were no significant differences in wall thickness between men and women in the Y or OS groups, diameter was larger in men than in women for both arteries (P<0.05). After 24 weeks of training the wall thickness of both arteries decreased (P<0.01) and the wall:lumen ratio of the brachial (P<0.01) and the popliteal (P<0.05) decreased. CONCLUSION: The cross-sectional results suggest that ageing was associated with increased lumen diameter, although wall:lumen ratio remained unchanged. Wall:lumen ratio was higher in women than men, irrespective of subject age or the artery studied. This related primarily to differences in lumen diameter between the sexes, as wall thickness did not significantly differ between men and women. Our longitudinal data strongly suggest that exercise training is associated with beneficial effects on conduit artery wall thickness and wall:lumen ratio in both upper and lower limbs in humans.

Profiling of energy metabolism in olanzapine-induced weight gain in rats and its prevention by the CB1-antagonist AVE1625.

This is the first study to examine the effect of subchronic olanzapine (OLZ) on energy homeostasis in rats, covering all aspects of energy balance, including energy intake as metabolizable energy, storage, and expenditure. We further analyzed whether, and by which mechanism, the CB1-antagonist AVE1625 might attenuate OLZ-induced body weight gain. For this purpose, we selected juvenile female Hanover Wistar rats that robustly and reproducibly demonstrated weight gain on OLZ treatment, accepting limitations to model the aberrations on lipid and carbohydrate metabolism. Rats received 2 mg/kg OLZ orally twice daily for 12 days. Body weight and body composition were analyzed. Moreover daily food intake, energy expenditure, and substrate oxidation were determined in parallel to motility and body core temperature. OLZ treatment resulted in substantial body weight gain, in which lean and fat mass increased significantly. OLZ-treated rats showed hyperphagia that manifested in increased carbohydrate oxidation and lowered fat oxidation (FO). Energy expenditure was increased, motility decreased, but there was no indication for hypothermia in OLZ-treated rats. Coadministration of OLZ and AVE1625 (10 mg/kg orally once daily) attenuated body weight gain, diminishing the enhanced food intake while maintaining increased energy expenditure and decreased motility. Our data reveal that energy expenditure was enhanced in OLZ-treated rats, an effect not critically influenced by motility. Energy uptake, however, exceeded energy expenditure and led to a positive energy balance, confirming hyperphagia as the major driving factor for OLZ-induced weight gain. Combination of OLZ treatment with the CB1-antagonist AVE1625 attenuated body weight gain in rats.

Genomic and biological analysis of phage Xfas53 and related prophages of Xylella fastidiosa.

We report the plaque propagation and genomic analysis of Xfas53, a temperate phage of Xylella fastidiosa. Xfas53 was isolated from supernatants of X. fastidiosa strain 53 and forms plaques on the sequenced strain Temecula. Xfas53 forms short-tailed virions, morphologically similar to podophage P22. The 36.7-kb genome is predicted to encode 45 proteins. The Xfas53 terminase and structural genes are related at a protein and gene order level to P22. The left arm of the Xfas53 genome has over 90% nucleotide identity to multiple prophage elements of the sequenced X. fastidiosa strains. This arm encodes proteins involved in DNA metabolism, integration, and lysogenic control. In contrast to Xfas53, each of these prophages encodes head and DNA packaging proteins related to the siphophage lambda and tail morphogenesis proteins related to those of myophage P2. Therefore, it appears that Xfas53 was formed by recombination between a widespread family of X. fastidiosa P2-related prophage elements and a podophage distantly related to phage P22. The lysis cassette of Xfas53 is predicted to encode a pinholin, a signal anchor and release (SAR) endolysin, and Rz and Rz1 equivalents. The holin gene encodes a pinholin and appears to be subject to an unprecedented degree of negative regulation at both the level of expression, with rho-independent transcriptional termination and RNA structure-dependent translational repression, and the level of holin function, with two upstream translational starts predicted to encode antiholin products. A notable feature of Xfas53 and related prophages is the presence of 220- to 390-nucleotide degenerate tandem direct repeats encoding putative DNA binding proteins. Additionally, each phage encodes at least two BroN domain-containing proteins possibly involved in lysogenic control. Xfas53 exhibits unusually slow adsorption kinetics, possibly an adaptation to the confined niche of its slow-growing host.

Is the ratio of flow-mediated dilation and shear rate a statistically sound approach to normalization in cross-sectional studies on endothelial function?

It has been deemed important to normalize flow-mediated dilation (FMD), a marker of endothelial function, for between-subject differences in the eliciting shear rate (SR) stimulus. Conventionally, FMD is divided by the area under the curve of the SR stimulus. In the context of a cross-sectional comparison across different age cohorts, we examined whether this ratio approach adhered to established statistical assumptions necessary for reliable normalization. To quantify brachial artery FMD and area under the curve of SR, forearm cuff inflation to suprasystolic pressure was administered for 5 min to 16 boys aged 10.9 yr (SD 0.3), 48 young men aged 25.3 yr (SD 4.2), and 15 older men aged 57.5 yr (SD 4.3). Mean differences between age groups were statistically significant (P < 0.001) for nonnormalized FMD [children: 10.4% (SD 5.4), young adults: 7.5% (SD 2.9), older adults: 5.6% (SD 2.0)] but not for ratio-normalized FMD (P = 0.10). Moreover, all assumptions necessary for reliable use of ratio-normalization were violated, including regression slopes between SR and FMD that had y-intercepts greater than zero (P < 0.05), nonlinear and unstable relations between the normalized ratios and SR, skewed data distributions, and heteroscedastic variance. Logarithmic transformation of SR and FMD before ratio calculation improved adherence to these assumptions and resulted in age differences similar to the nonnormalized data (P = 0.03). In conclusion, although ratio normalization of FMD altered findings about age differences in endothelial function, this could be explained by violation of statistical assumptions. We recommend that exploration of these assumptions should be routine in future research. If the relationship between SR and FMD is generally found to be weak or nonlinear or variable between samples, then ratio normalization should not be applied.

Doublecortin associates with microtubules preferentially in regions of the axon displaying actin-rich protrusive structures.

Here we studied doublecortin (DCX) in cultured hippocampal and sympathetic neurons during axonal development. In both types of neurons, DCX is abundant in the growth cone, in which it primarily localizes with microtubules. Its abundance is lowest on microtubules in the neck region of the growth cone and highest on microtubules extending into the actin-rich lamellar regions. Interestingly, the microtubule polymer richest in DCX is also deficient in tau. In hippocampal neurons but not sympathetic neurons, discrete focal patches of microtubules rich in DCX and deficient in tau are present along the axonal shaft. Invariably, these patches have actin-rich protrusions resembling those of growth cones. Many of the DCX/actin filament patches exhibit vigorous protrusive activity and also undergo a proximal-to-distal redistribution within the axon at average rates approximately 2 microm/min and thus closely resemble the growth-cone-like waves described by previous authors. Depletion of DCX using small interfering RNA had little effect on the appearance of the growth cone or on axonal growth in either type of neuron. However, DCX depletion significantly delayed collateral branching in hippocampal neurons and also significantly lowered the frequency of actin-rich patches along hippocampal axons. Branching by sympathetic neurons, which occurs by growth cone splitting, was not impaired by DCX depletion. These findings reveal a functional relationship between the DCX/actin filament patches and collateral branching. Based on the striking resemblance of these patches to growth cones, we discuss the possibility that they reflect a mechanism for locally boosting morphogenetic activity to facilitate axonal growth and collateral branching.

Impact of age, sex, and exercise on brachial artery flow-mediated dilatation.

Flow-mediated dilatation (%FMD), an index of nitric oxide (NO)-mediated vasodilator function, is regarded as a surrogate marker of cardiovascular disease. Aging is associated with endothelial dysfunction, but underlying sex-related differences may exist and the effects of fitness and exercise on endothelial dysfunction in men (M) and women (W) are poorly understood. We compared %FMD of the brachial artery in 18 young [Y, 26 +/- 1 yr; 9 M and 9 W], 12 older fit (OF, 57 +/- 2 yr; 6 M and 6 W), and 16 older sedentary (OS, 59 +/- 2 yr; 8 M and 8 W) subjects. Glyceryl trinitrate (GTN) administration was used to assess endothelium-independent vasodilatation, and the FMD-to-GTN ratio was calculated to characterize NO dilator function in the context of smooth muscle cell sensitivity. Brachial %FMD in Y (7.1 +/- 0.8%) was significantly higher compared with OS (4.8 +/- 0.7%, P < 0.05), but not OF (6.4 +/- 0.7%). Differences between Y and OS subjects were due primarily to lower FMD in the OS women (4.3 +/- 0.6%). OS women exhibited significantly lower FMD-to-GTN ratios compared with Y (P < 0.05) and OF women (P < 0.05), whereas these differences were not apparent in men. Exercise training improved brachial artery NO dilator function (FMD-to-GTN ratio) after 24 wk (P < 0.05) in OS women, but not men. These findings indicate that maintaining a high level of fitness, or undertaking exercise training, prevents the age-related decline in the brachial artery vasodilator function evident in women. In OS men, who had relatively preserved NO dilator function, no training adaptations were observed. This study has potential implications for the prevention of conduit artery endothelial dysfunction in men and women.

Impact of shear rate modulation on vascular function in humans.

Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow-mediated dilation, a largely NO-mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling, and bilateral handgrip exercise. During each intervention, a cuff inflated to 60 mm Hg was placed on 1 arm to unilaterally manipulate the shear rate stimulus. In the noncuffed arm, antegrade flow and shear increased similarly in response to each intervention (ANOVA; P<0.001, no interaction between interventions; P=0.71). Baseline flow-mediated dilation (4.6%, 6.9%, and 6.7%) increased similarly in response to heating, handgrip, and cycling (8.1%, 10.4%, and 8.9%, ANOVA; P<0.001, no interaction; P=0.89). In contrast, cuffed arm antegrade shear rate was lower than in the noncuffed arm for all of the conditions (P<0.05), and the increase in flow-mediated dilation was abolished in this arm (4.7%, 6.7%, and 6.1%; 2-way ANOVA: all conditions interacted P<0.05). These results suggest that differences in the magnitude of antegrade shear rate transduce differences in endothelial vasodilator function in humans, a finding that may have relevance for the impact of different exercise interventions on vascular adaptation in humans.

Evidence for a greater elevation in vascular shear stress after morning exercise.

INTRODUCTION: The vascular endothelium plays an important role in the maintenance of vascular health and the modulation of vascular tone and blood pressure. Recently, it has been demonstrated that blood pressure reactivity to physical activity is greater in the morning, and possibly, diurnal variation in vascular function may also be evident. The aim of this study was to assess vascular responses after exercise at different times of day. METHODS: After 45 min of supine rest, 12 male normotensives completed a 30-min bout of cycling at 70% peak oxygen uptake beginning on separate days at 0800 and 1600 h. Edge detection and wall tracking of high-resolution arterial B-mode ultrasound images combined with synchronized Doppler waveform analysis were used to measure brachial and femoral conduit artery diameter and to calculate blood flow and shear rate. Measurements were recorded before and 20 min after exercise. RESULTS: At 5 min after exercise, the mean +/- SE brachial shear rate was 72 +/- 21 arbitrary unit (AU) higher in the morning compared with the afternoon (P = 0.05), but this was not compensated for by enlargement of arterial diameter (P = 0.59). No diurnal variation was observed in the femoral artery measurements. CONCLUSION: Diurnal difference in conduit artery regulatory control manifests as an elevated intravascular shear stress after morning exercise. Potentially, higher postexercise shear rate in the morning in at-risk individuals could contribute to the elevated cardiovascular risk evident in the postwaking hours.

The impact of exercise on derived measures of central pressure and augmentation index obtained from the SphygmoCor device.

The purpose of this study was to investigate whether measures derived from the SphygmoCor device and its associated transfer function are influenced by exercise-induced alterations in vascular tone. Measurements were taken from either the exercised or the contralateral nonexercised limb during repeated and identical incremental hand-grip protocols. Eight male subjects performed three 3-min bouts of hand-grip exercise on two occasions. The exercise intensities were set at 3 kg, 5 kg, with a final 1.5-kg bout performed during cuff ischemia (1.5Isch). Blood pressure waveforms were recorded from the radial artery of either the exercised or nonexercised limb using applanation tonometry (SphygmoCor) during a 90-s rest period immediately after each exercise bout. Central blood pressures and augmentation indexes (AIx), an index of arterial stiffness, were derived using the peripheral waveform and the inbuilt SphygmoCor transfer function (TF). AIx was consistently approximately 10% higher in the exercised arm during all trials compared with the nonexercised limb. Similarly, there was a consistent and significant difference ( approximately 3 mmHg; P < 0.05) between exercised and nonexercised arms for the derived central systolic and mean arterial blood pressures. Despite identical bouts of exercise, AIx and central systolic and mean arterial blood pressures derived from applanation tonometry at the peripheral radial artery were statistically different when assessed at the exercising arm vs. the nonexercising arm. Changes in vascular tone with exercise may modify the intrinsic characteristics of the vessel wall and could compromise the assumptions underlying transfer functions used to derive central measures using applanation tonometry.

Brachial artery blood flow responses to different modalities of lower limb exercise.

INTRODUCTION/PURPOSE: Cycling is associated with a reproducible systolic anterograde and diastolic retrograde flow pattern in the brachial artery (BA) of the inactive upper limb, which results in endothelial nitric oxide (NO) release. The purpose of this study was to examine the impact of different types and intensities of lower limb exercise on the BA flow pattern. METHODS: We examined BA blood flow and shear rate patterns during cycling, leg kicking, and walking exercise in 12 young subjects (24 +/- 3 yr). BA diameter, blood flow, and shear rate were assessed at baseline (1 min) and at three incremental intensity levels of cycling (60, 80, and 120 W), bilateral leg kicking (5, 7.5, and 10 kg), and walking (3, 4, and 5 km x h(-1)), performed for 3 min each. Edge detection and wall tracking of high-resolution B-mode arterial ultrasound images, combined with synchronized Doppler waveform envelope analysis, were used to calculate conduit artery diameter and anterograde/retrograde blood flow and shear rate continuously across the cardiac cycle. RESULTS: BA mean blood flow and shear rate increased significantly throughout each exercise protocol (P < 0.001), and BA anterograde blood flow and shear rate showed comparable increases throughout each protocol (P < 0.001). Retrograde blood flow and shear rate, however, demonstrated a significant increase during cycling and walking (P < 0.001) but not during leg kicking. CONCLUSION: Rhythmic lower limb exercise (cycling and walking) results in an increase in BA systolic anterograde blood flow and shear rate, directly followed by a large retrograde flow and shear rate. This typical pattern, previously linked with endothelial NO release, is not present during a different type of exercise such as leg kicking.