Interaction of macro- and microvascular function underlies brachial artery flow-mediated dilation in humans.

Brachial artery flow-mediated dilation (BAFMD) is induced by hyperemic wall shear rate (WSR) following forearm ischemia. In older adults, there appears to be a reduced brachial hyperemic WSR and altered stimulus-response relationship compared with young adults. However, it is unclear if an altered forearm microvascular response to ischemia influences brachial hyperemic WSR in older adults. We determined associations between brachial hyperemic WSR and forearm skeletal muscle oxygen saturation in young and older adults. Healthy young (n = 17, 29 ± 7 yr) and older (n = 32, 65 ± 4 yr) adults participated in the study. BAFMD by a multigate spectral Doppler system and forearm skeletal muscle oxygen saturation by near-infrared spectroscopy were concurrently measured. When compared with the young, older adults showed reduced oxygen extraction kinetics (OE, 0.15 [0.12-0.17] vs. 0.09 [0.05-0.12]%s-1) and magnitude (So2deficit, 3,810 ± 1,420 vs. 2,723 ± 1,240%s) during ischemia, as well as oxygen resaturation kinetics (So2slope, 2.5 ± 0.7 vs. 1.7 ± 0.7%s-1) upon reperfusion (all P < 0.05). When OE in the young and So2slope in older adults were stratified by their median values, young adults with OE above the median had greater hyperemic WSR parameters compared with those below the median (P < 0.05), but So2slope in older adults did not show clear differences in hyperemic WSR parameters between those above/below the median. This study demonstrates that, in addition to a reduced microvascular response to ischemia, there may be a dissociation between microvascular response to ischemia and brachial hyperemic WSR in older adults, which may result in a further impairment of BAFMD in this cohort.NEW & NOTEWORTHY Microvascular response to ischemia and subsequent reperfusion is diminished in older adults compared with the young. Furthermore, there appears to be a dissociation between the microvascular response to ischemia and brachial hyperemic WSR in older adults, which may further disturb the BAFMD process in this cohort. A reduced BAFMD in older adults may be a result of multiple alterations occurring both at macro- and microcirculation.

Age and sex differences in microvascular responses during reactive hyperaemia.

Microvascular impairments are typical of several cardiovascular diseases. Near-infrared spectroscopy (NIRS) combined with a vascular occlusion test provides non-invasive insights into microvascular responses by monitoring skeletal muscle oxygenation changes during reactive hyperaemia. Despite increasing interest in the effects of sex and ageing on microvascular responses, evidence remains inconsistent. Therefore, the present study aimed to investigate the effects of sex and age on microvascular responsiveness. Twenty-seven participants (seven young men and seven young women; seven older men and six older women; aged 26 ± 1, 26 ± 4, 67 ± 3 and 69 ± 4 years, respectively) completed a vascular occlusion test consisting of 5 min of arterial occlusion followed by 5 min reperfusion. Oxygenation changes in the vastus lateralis were monitored by near-infrared spectroscopy. The findings revealed that both women (referring to young and older women) and older participants (referring to both men and women) exhibited lower microvascular responsiveness. Notably, both women and older participants demonstrated reduced desaturation (-38% and -59%, respectively) and reperfusion rates (-24% and -40%, respectively) along with a narrower range of tissue oxygenation (-39% and -39%, respectively) and higher minimal tissue oxygenation levels (+34% and +21%, respectively). Women additionally displayed higher values in resting (+12%) and time-to-peak (+15%) tissue oxygenation levels. In conclusion, this study confirmed decreased microvascular responses in women and older individuals. These results emphasize the importance of considering sex and age when studying microvascular responses. Further research is needed to uncover the underlying mechanisms and clinical relevance of these findings, enabling the development of tailored strategies for preserving vascular health in diverse populations.

PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity.

Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis. The capillary endothelial cell strong inward-rectifier K+ channel Kir2.1, which senses neuronal activity and initiates a propagating electrical signal that dilates upstream arterioles, is a cornerstone of functional hyperemia. Here, using a genetic SVD mouse model, we show that impaired functional hyperemia is caused by diminished Kir2.1 channel activity. We link Kir2.1 deactivation to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2), a membrane phospholipid essential for Kir2.1 activity. Systemic injection of soluble PIP2 rapidly restored functional hyperemia in SVD mice, suggesting a possible strategy for rescuing functional hyperemia in brain disorders in which blood flow is disturbed.

Sex Differences in Test-Retest Reliability of Near-Infrared Spectroscopy During Postocclusive Reactive Hyperemia of the Vastus Lateralis.

ABSTRACT: Shoemaker, ME, Smith, CM, Gillen, ZM, and Cramer, JT. Sex differences in test-retest reliability of near-infrared spectroscopy during postocclusive reactive hyperemia of the vastus lateralis. J Strength Cond Res 38(2): e40-e48, 2024-The purpose of this study was to determine test-retest reliability for vascular reactivity measures and ranges for normalization of near-infrared spectroscopy (NIRS) variables from the vastus lateralis using postocclusive reactive hyperemia (PORH) procedure in male subjects, female subjects, and combined. Concentrations of oxygenated hemoglobin (Hb) + myoglobin (Mb) (O 2 Hb) and deoxygenated Hb + Mb (HHb) to derive total Hb + Mb (THb), difference in Hb + Mb signal (Hbdiff), and muscle tissue oxygen saturation (StO 2 ) from the vastus lateralis were measured during the PORH in 12 male subjects (age: 23.17 ± 1.77 years; stature: 180.88 ± 4.59 cm; and mass: 81.47 ± 9.68 kg) and 10 female subjects (age: 23.80 ± 2.07 years; stature: 165.95 ± 4.92 cm; and mass: 70.93 ± 10.55 kg) on 2 separate days. Adipose tissue thickness at the NIRS site was measured with ultrasonography. There were no significant differences between the mean values from visit 1 to visit 2 ( p > 0.076-0.985). In the composite sample, intraclass correlation coefficient (ICC) and coefficient of variation (CV) ranged from 0.35 to 0.91 and 4.74 to 39.18%, respectively. In male subjects, ICC and CV values ranged from 0.57 to 0.89 and 2.44 to 28.55%, respectively. In female subjects, ICC and CV values ranged from -0.05 to 0.75 and 7.83 to 61.19%, respectively. Although NIRS variables were overall reliable during PORH, when separated by sex, reliability in male subjects generally increased, whereas female subjects were not reliable, suggesting adipose tissue thickness may be a contributing factor. Understanding sex differences in reliability is important when using this technique for normalization or examining vascular reactivity during athletic performance. With greater utilization of NIRS monitoring in athletes to examine training adaptations, it is important for practitioners to understand the capabilities and potential limitations of the tool.

Reactive hyperemia half-time response is associated with skeletal muscle oxygen saturation changes during cycling exercise.

We investigated the relationship between muscle microvascular responses during reactive hyperemia as assessed using near-infrared spectroscopy (NIRS) with changes in skeletal muscle oxygen saturation during exercise. Thirty young untrained adults (M/W: 20/10; 23 ± 5 years) completed a maximal cycling exercise test to determine exercise intensities performed on a subsequent visit separated by seven days. At the second visit, post-occlusive reactive hyperemia was measured as changes in NIRS-derived tissue saturation index (TSI) at the left vastus lateralis muscle. Variables of interest included desaturation magnitude, resaturation rate, resaturation half-time, and hyperemic area under the curve. Afterwards, two 4-minute bouts of moderate intensity cycling followed by one bout of severe intensity cycling to fatigue took place while TSI was measured at the vastus lateralis muscle. TSI was averaged across the last 60-s of each moderate intensity bout then averaged together for analysis, and at 60-s into severe exercise. The change in TSI (∆TSI) during exercise is expressed relative to a 20 W cycling baseline. On average, the ΔTSI was -3.4 ± 2.4 % and -7.2 ± 2.8 % during moderate and severe intensity cycling, respectively. Resaturation half-time was correlated with the ΔTSI during moderate (r = -0.42, P = 0.01) and severe (r = -0.53, P = 0.002) intensity exercise. No other reactive hyperemia variable was found to correlate with ΔTSI. These results indicate that resaturation half-time during reactive hyperemia represents a resting muscle microvascular measure that associates with the degree of skeletal muscle desaturation during exercise in young adults.

Developmental toxicity of a pymetrozine photo-metabolite, 3-pyridinecarboxaldehyde, in zebrafish (Danio rerio) embryos: Abnormal cardiac development and occurrence of heart dysfunction via differential expression of heart formation-related genes.

Pymetrozine (PYM) is worldwide used to control sucking insect pests in rice-cultivated fields and it is degraded into various metabolites including 3-pyridinecarboxaldehyde (3-PCA). These two pyridine compounds were used to determine their impacts on aquatic environments, particularly on the aquatic animal model zebrafish (Danio rerio). PYM did not show acute toxicities in terms of lethality, hatching rate, and phenotypic changes in zebrafish embryos in the tested ranges up to a concentration of 20 mg/L. 3-PCA exhibited acute toxicity with LC50 and EC50 values of 10.7 and 2.07 mg/L, respectively. 3-PCA treatment caused phenotypic changes including pericardial edema, yolk sac edema, hyperemia, and curved spine, at a concentration of 10 mg/L after 48 h of exposure. Abnormal cardiac development was observed in 3-PCA-treated zebrafish embryos at a concentration of 5 mg/L with reduced heart function. In a molecular analysis, cacna1c, encoding a voltage-dependent calcium channel, was significantly down-regulated in the 3-PCA-treated embryos, indicating synaptic and behavioral defects. Hyperemia and incomplete intersegmental vessels were observed in 3-PCA-treated embryos. Based on these results, it is necessary to generate scientific information on the acute and chronic toxicity of PYM and its metabolites with regular monitoring of their residues in aquatic environments.

Mechanisms that underlie blood flow regulation at rest and during exercise.

The cardiovascular system must distribute oxygen and nutrients to the body while maintaining appropriate blood pressure. This is achieved through a combination of central and peripheral mechanisms that influence cardiac output and vasomotor tone throughout the vascular system. Furthermore, the capability to preferentially direct blood to tissues with increased metabolic demand (i.e., active hyperemia) is crucial to exercise tolerance. However, the interaction between these systems is difficult to understand without real-life examples. Fortunately, monitoring blood flow, blood pressure, and heart rate during a series of laboratory protocols will allow students to partition the contributions of these central and peripheral factors. The three protocols include 1) reactive hyperemia in the forearm, 2) small muscle mass handgrip exercise, and 3) large muscle mass cycling exercise. In addition to providing a detailed description of the required equipment, specific protocols, and expected outcomes, this report also reviews some of the common student misconceptions that are associated with the observed physiological responses.NEW & NOTEWORTHY Blood flow regulation during exercise is a complicated process that involves many overlapping mechanisms. This laboratory will help students better understand how the body regulates blood flow to the active muscles using three separate protocols: 1) reactive hyperemia, 2) small muscle mass exercise, and 3) large muscle mass exercise.

Global REACH 2018: increased adrenergic restraint of blood flow preserves coupling of oxygen delivery and demand during exercise at high-altitude.

Chronic exposure to hypoxia (high-altitude, HA; >4000 m) attenuates the vasodilatory response to exercise and is associated with a persistent increase in basal sympathetic nerve activity (SNA). The mechanism(s) responsible for the reduced vasodilatation and exercise hyperaemia at HA remains unknown. We hypothesized that heightened adrenergic signalling restrains skeletal muscle blood flow during handgrip exercise in lowlanders acclimatizing to HA. We tested nine adult males (n = 9) at sea-level (SL; 344 m) and following 21-28 days at HA (∼4300 m). Forearm blood flow (FBF; duplex ultrasonography), mean arterial pressure (MAP; brachial artery catheter), forearm vascular conductance (FVC; FBF/MAP), and arterial and venous blood sampling (O2 delivery ( DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ ) and uptake ( V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ )) were measured at rest and during graded rhythmic handgrip exercise (5%, 15% and 25% of maximum voluntary isometric contraction; MVC) before and after local α- and ß-adrenergic blockade (intra-arterial phentolamine and propranolol). HA reduced ΔFBF (25% MVC: SL: 138.3 ± 47.6 vs. HA: 113.4 ± 37.1 ml min-1 ; P = 0.022) and Δ V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ (25% MVC: SL: 20.3 ± 7.5 vs. HA: 14.3 ± 6.2 ml min-1 ; P = 0.014) during exercise. Local adrenoreceptor blockade at HA restored FBF during exercise (25% MVC: SLα-ß blockade : 164.1 ± 71.7 vs. HAα-ß blockade : 185.4 ± 66.6 ml min-1 ; P = 0.947) but resulted in an exaggerated relationship between DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ and V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ ( DO2${D}_{{{\rm{O}}}_{\rm{2}}}$ / V̇O2${\dot{V}}_{{{\rm{O}}}_{\rm{2}}}$ slope: SL: 1.32; HA: slope: 1.86; P = 0.037). These results indicate that tonic adrenergic signalling restrains exercise hyperaemia in lowlanders acclimatizing to HA. The increase in adrenergic restraint is necessary to match oxygen delivery to demand and prevent over perfusion of contracting muscle at HA. KEY POINTS: In exercising skeletal muscle, local vasodilatory signalling and sympathetic vasoconstriction integrate to match oxygen delivery to demand and maintain arterial blood pressure. Exposure to chronic hypoxia (altitude, >4000 m) causes a persistent increase in sympathetic nervous system activity that is associated with impaired functional capacity and diminished vasodilatation during exercise. In healthy male lowlanders exposed to chronic hypoxia (21-28 days; ∼4300 m), local adrenoreceptor blockade (combined α- and ß-adrenergic blockade) restored skeletal muscle blood flow during handgrip exercise. However, removal of tonic adrenergic restraint at high altitude caused an excessive rise in blood flow and subsequently oxygen delivery for any given metabolic demand. This investigation is the first to identify greater adrenergic restraint of blood flow during acclimatization to high altitude and provides evidence of a functional role for this adaptive response in regulating oxygen delivery and demand.

Endothelial NMDA receptors mediate activity-dependent brain hemodynamic responses in mice.

Dynamic coupling of blood supply with energy demand is a natural brain property that requires signaling between synapses and endothelial cells. Our previous work showed that cortical arteriole lumen diameter is regulated by N-methyl-d-aspartate receptors (NMDARs) expressed by brain endothelial cells. The purpose of this study was to determine whether endothelial NMDARs (eNMDARs) regulate functional hyperemia in vivo. In response to whisker stimulation, regional cerebral blood flow (rCBF) and hemodynamic responses were assessed in barrel cortex of awake wild-type or eNMDAR loss-of-function mice using two-photon microscopy. Hyperemic enhancement of rCBF and vasodilation throughout the vascular network was observed in wild-type mice. eNMDAR loss of function reduced hyperemic responses in rCBF and plasma flux in individual vessels. Discovery of an endothelial receptor that regulates brain hyperemia provides insight into how neuronal activity couples with endothelial cells.

PECULIARITIES OF VASOR-REGULATING FUNCTIONS OF THE VASCULAR ENDOTHELIUM IN ADAPTATION OF THE YOUTH BODY TO SYSTEMATIC PHYSICAL LOADS.

OBJECTIVE: The aim: To analyze the features of changes in the functional state of the vascular endothelium of handball players in the dynamics of the training process, at different levels of the body's hypoxic state. PATIENTS AND METHODS: Materials and methods: Theoretical methods, the method of Corretti et al. with the use of high-resolution ultrasound, Fisher test with the calculation of the Fisher criterion and the Bland-Altman method. The study of the vasomotor function of the vascular endothelium was carried out of young men 18-20 y.o., who did not go in for sports and which were systematically played handball. The brachial artery diameter, maximum linear blood flow velocity, volumetric blood flow velocity were registered in the state of relative rest after artificially created reactive hyperemia. RESULTS: Results: The primary results obtained showed that in the process of long-term adaptation to systematic muscular work, a pronounced vasodilation effect was observed. Subsequent analyze of changes in the functional state of the vascular endothelium of young sportsmen during the macrocycle preparation different levels of the body's hypoxic state manifested the following. The young men-athletes had more pronounced vasodilation effect, the values of the linear and volumetric blood flow velocity both in the state of relative rest and at the peak of the artificially created hyperemia were significantly higher than in the young men, who did not go in for sports. CONCLUSION: Conclusions: Suggested that the systematic muscular work contributes to a significant intensification of the oxidation pathway of nitric oxide formation from L-arginine with the participation of endothelial NO-synthase.

TRPV4 channel blockade does not modulate skin vasodilation and sweating during hyperthermia or cutaneous postocclusive reactive and thermal hyperemia.

Transient receptor potential vanilloid 4 (TRPV4) channels exist on vascular endothelial cells and eccrine sweat gland secretory cells in human skin. Here, we assessed whether TRPV4 channels contribute to cutaneous vasodilation and sweating during whole body passive heat stress (protocol 1) and to cutaneous vasodilation during postocclusive reactive hyperemia and local thermal hyperemia (protocol 2). Intradermal microdialysis was employed to locally deliver pharmacological agents to forearm skin sites, where cutaneous vascular conductance (CVC) and sweat rate were assessed. In protocol 1 (12 young adults), CVC and sweat rate were increased by passive whole body heating, resulting in a body core temperature elevation of 1.2 ± 0.1°C. The elevated CVC and sweat rate assessed at sites treated with TRPV4 channel antagonist (either 200 µM HC-067047 or 125 µM GSK2193874) were not different from the vehicle control site (5% dimethyl sulfoxide). After whole body heating, the TRPV4 channel agonist (100 µM GSK1016790A) was administered to each skin site, eliciting elevations in CVC. Relative to control, this response was partly attenuated by both TRPV4 channel antagonists, confirming drug efficacy. In protocol 2 (10 young adults), CVC was increased following a 5-min arterial occlusion and during local heating from 33 to 42°C. These responses did not differ between the control and the TRPV4 channel antagonist sites (200 µM HC-067047). We show that TRPV4 channels are not required for regulating cutaneous vasodilation or sweating during a whole body passive heat stress. Furthermore, they are not required for regulating cutaneous vasodilation during postocclusive reactive hyperemia and local thermal hyperemia.

Greater α1-adrenergic-mediated vasoconstriction in contracting skeletal muscle of patients with type 2 diabetes.

Patients with type 2 diabetes mellitus (T2DM) exhibit diminished exercise capacity likely attributable to reduced skeletal muscle blood flow (i.e., exercise hyperemia). A potential underlying mechanism of the impaired hyperemic response to exercise could be inadequate blunting of sympathetic-mediated vasoconstriction (i.e., poor functional sympatholysis). Therefore, we studied the hyperemic and vasodilatory responses to handgrip exercise in patients with T2DM as well as vasoconstriction to selective α-agonist infusion. Forearm blood flow (FBF) and vascular conductance (FVC) were examined in patients with T2DM (n = 30) as well as nondiabetic controls (n = 15) with similar age (59 ± 9 vs. 60 ± 9 yr, P = 0.69) and body mass index (31.4 ± 5.2 vs. 29.5 ± 4.6 kg/m2, P = 0.48). Intra-arterial infusion of phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were used to induce vasoconstriction: [(FVCwith drug - FVCpredrug)/FVCpredrug × 100%]. Subjects completed rest and dynamic handgrip exercise (20% of maximum) trials per α-agonist. Patients with T2DM had smaller increases (Δ from rest) in FBF (147 ± 71 vs. 199 ± 63 ml/min) and FVC (126 ± 58 vs. 176 ± 50 ml·min-1·100 mmHg-1, P < 0.01 for both) during exercise compared with controls, respectively. During exercise, patients with T2DM had greater α1- (-16.9 ± 5.9 vs. -11.3 ± 3.8%) and α2-mediated vasoconstriction (-23.5 ± 7.1 vs. -19.0 ± 6.5%, P < 0.05 for both) versus controls. The magnitude of sympatholysis (Δ in %vasoconstriction between exercise and rest) for PE was lower (worse) in patients with T2DM versus controls (14.9 ± 12.2 vs. 23.1 ± 8.1%, P < 0.05) whereas groups were similar during DEX trials (24.6 ± 12.3 vs. 27.6 ± 13.4%, P = 0.47). Our data suggest patients with T2DM have attenuated hyperemic and vasodilatory responses to exercise, which could be attributable to greater α1-mediated vasoconstriction in contracting skeletal muscle.NEW & NOTEWORTHY Findings presented in this article are the first to show patients with type 2 diabetes mellitus have blunted hyperemic and vasodilatory responses to dynamic handgrip exercise. Moreover, we illustrate greater α1-adrenergic-mediated vasoconstriction may contribute to our initial observations. Collectively, these data suggest patients with type 2 diabetes may have impaired functional sympatholysis, which can contribute to their reduced exercise capacity.

Tetraethylammonium, glibenclamide, and 4-aminopyridine modulate post-occlusive reactive hyperemia in non-glabrous human skin with no roles of NOS and COX.

OBJECTIVES: Post-occlusive reactive hyperemia (PORH) following arterial occlusion is widely used to assess cutaneous microvascular function, though the underlying mechanisms remain to be fully elucidated. We evaluated the hypothesis that Ca2+ -activated, ATP-sensitive, and voltage-gated K+ channels (KCa , KATP , and KV channels, respectively) contribute to PORH while nitric oxide synthase (NOS) and cyclooxygenase (COX) do not. METHODS: On separate occasions, cutaneous blood flow (laser Doppler flowmetry) was monitored before and following 5-min arterial occlusion at forearm skin sites treated via microdialysis with the following: Experiment 1 (n = 11): (a) lactated Ringer solution (Control), (b) 10 mM Nω -nitro-L -arginine (NOS inhibitor), (c) 10 mM ketorolac (COX inhibitor), and (d) combined NOS+COX inhibition; Experiment 2 (n = 14): (a) lactated Ringer solution (Control), (b) 50 mM tetraethylammonium (non-selective KCa channel blocker), (c) 5 mM glibenclamide (non-specific KATP channel blocker), and (d) 10 mM 4-aminopyridine (non-selective KV channel blocker). RESULTS: Separate and combined NOS and COX inhibition did not influence PORH. Conversely, tetraethylammonium and glibenclamide attenuated, whereas 4-aminopyridine augmented PORH. CONCLUSIONS: We showed that tetraethylammonium, glibenclamide, and 4-aminopyridine modulate PORH with no roles of NOS and COX in human non-glabrous forearm skin in vivo. Thus, cutaneous PORH changes could reflect altered K+ channel function.

Assessment of microvascular function in vivo using flow mediated skin fluorescence (FMSF) in patients with obstructive lung diseases: A preliminary study.

BACKGROUND: Cardiovascular diseases play an important role in the morbidity and mortality of patients with obstructive lung diseases. Impaired vascular endothelial function seems to be a key element linking obstructive lung disease and cardiovascular disease. Recently developed technique named flow mediated skin fluorescence (FMSF) is a novel, non-invasive tool to study microvascular function. METHODS: Total of 69 volunteers including 26 patients with chronic obstructive pulmonary disease (COPD), 23 patients with asthma and 20 healthy subjects underwent microvascular function assessments using FMSF. FMSF assessments were composed of measurements of reduced form of nicotinamide adenine dinucleotide (NADH) fluorescence intensity signal during brachial artery occlusion - ischemic response (IRmax) and immediately after release of occlusion - hyperemic response (HRmax). Associations of microvascular function with clinical and biochemical characteristics of studied subjects were also evaluated. RESULTS: The median value of IRmax was significantly lower in COPD subjects (2.4 [1.0-6.7] %) compared with healthy subjects (9.6 [3.7-13.5] %; p < 0.01). The mean value of HRmax was also significantly reduced in COPD subjects (9.7 (4.5) %) compared with both asthma subjects (12.1 (3.5) %; p < 0.05) and healthy control subjects (13.4 (2.9) %; p < 0.01). CONCLUSIONS: The FMSF technique makes it possible to identify impairments of the microvascular function in patients with COPD, but not in asthma patients. These exploratory findings require further validation in a larger patients cohort.

Noninvasive assessment of increases in microvascular endothelial function following repeated bouts of hyperaemia.

OBJECTIVE: Spectral analyses of laser-Doppler signal can delineate underlying mechanisms in response to pharmacological agents and in cross-sectional studies of healthy and clinical populations. We tested whether spectral analyses can detect acute changes in endothelial function in response to a 6-week intervention of repeated bouts of hyperaemia. METHODS: Eleven males performed forearm occlusion (5 s with 10 s rest) for 30 min, 5 times/week for 6 weeks on one arm; the other was an untreated control. Skin blood flow was measured using laser-Doppler fluxmetry (LDF), and endothelial function was assessed with and without nitric oxide (NO) synthase-inhibition with L-NAME in response to local heating (42 °C and 44 °C) and acetylcholine. A wavelet transform was used for spectral analysis of frequency intervals associated with physiological functions. RESULTS: Basal measures were all unaffected by the hyperaemia intervention (all P > 0.05). In response to local skin heating to 42 °C, the 6 weeks hyperaemia intervention increased LDF, endothelial NO-independent and NO-dependent activity (all P ≤ 0.038). In response to peak local heating (44 °C) endothelial NO-independent and NO-dependent activity increased (both P ≤ 0.01); however, LDF did not (P > 0.2). In response to acetylcholine, LDF, endothelial NO-independent and NO-dependent activity all increased (all P ≤ 0.003) post-intervention. CONCLUSIONS: Spectral analysis appears sufficiently sensitive to measure changes over time in cutaneous endothelial activity that are consistent with standard physiological (local heating) and pharmacological (acetylcholine) interventions of assessing cutaneous endothelial function, and may be useful not only in research but also clinical diagnosis and treatment.

Protective effects of Chrysin against memory impairment, cerebral hyperemia and oxidative stress after cerebral hypoperfusion and reperfusion in rats.

Stroke is devastating and a leading cause of morbidity and mortality worldwide. Cerebral ischemia-reperfusion and its subsequent reactive hyperemia lead to neuronal damage in the hippocampus and cognitive decline. Chrysin (5, 7-dihydroxyflavone) is a well-known member of the flavonoid family with antioxidant and neuroprotective effects. Therefore, in the present study, the aim was to investigate whether chrysin will be able to recover the brain function caused by ischemia-reperfusion (I/R) in rats. Adult male Wistar rats (250-300 g) were randomly divided into five groups: and submitted to cerebral I/R or a sham surgery after three-weeks of pretreatment with chrysin (CH; 10, 30 and 100 mg/kg; P.O.) and/or normal saline containing %5 DMSO. Subsequently, sensorimotor scores, cognition, local cerebral blood flow, extracellular single unit, and histological parameters were evaluated following I/R. Hippocampus was used to evaluate biomarkers including: oxidative stress parameters and prostaglandin E2 (PGE2) using ELISA kits. Data showed that pretreatment with chrysin significantly improved sensorimotor signs, passive avoidance memory, and attenuated reactive hyperemia, and increased the average number of spikes/bin (p < 0.001). Furthermore, chrysin pre-treatment significantly decreased the levels of MDA, NO, and PGE2 (p < 0. 001), while increased the levels of GPX and the number of surviving cells in the hippocampal CA1 region (p < 0.01, p < 0.001; respectively). This study demonstrates that chrysin may have beneficial effects in the treatment of cognitive impairment and help recover the brain dysfunction induced by I/R.

Contribution of prostaglandins to exercise hyperaemia: workload, ethnicity and sex matter!

The contribution of prostaglandins (PGs) to exercise hyperaemia is controversial. In this review, we argue this is partly explained by differences in exercise intensity between studies. The effects of cyclooxygenase (COX) inhibition and PG assays indicate that PGs contribute more at moderate to heavy than at light workloads and are mainly released by low tissue O2 . But, the release and actions of PGs also depend on other O2 -dependent dilators including ATP, adenosine and NO. K+ may inhibit the action of PGs and other mediators by causing hyperpolarization, but contributes to the hyperaemia. Thus, at lighter loads, the influence of PGs may be blunted by K+ , while COX inhibition leads to compensatory increases in other O2 -dependent dilators. In addition, we show that other sources of variability are sex and ethnicity. Our findings indicate that exercise hyperaemia following rhythmic contractions at 60% maximum voluntary contraction, is smaller in young black African (BA) men and women than in their white European (WE) counterparts, but larger in men than in women of both ethnicities. We propose the larger absolute force in men causes greater vascular occlusion and accumulation of dilators, while blunted hyperaemia in BAs may reflect lower oxidative capacity and O2 requirement. Nevertheless, COX inhibition attenuated peak hyperaemia by ∼30% in WE, BA men and WE women, indicating PGs make a substantial contribution in all three groups. There was no effect in BA women. Lack of PG involvement may provide early evidence of endothelial dysfunction, consistent in BA women with their greater risk of cardiovascular disease.

Pericyte constriction underlies capillary derecruitment during hyperemia in the setting of arterial stenosis.

Capillary derecruitment distal to a coronary stenosis is implicated as the mechanism of reversible perfusion defect and potential myocardial ischemia during coronary hyperemia; however, the underlying mechanisms are not defined. We tested whether pericyte constriction underlies capillary derecruitment during hyperemia under conditions of stenosis. In vivo two-photon microscopy (2PM) and optical microangiography (OMAG) were used to measure hyperemia-induced changes in capillary diameter and perfusion in wild-type and pericyte-depleted mice with femoral artery stenosis. OMAG demonstrated that hyperemic challenge under stenosis produced capillary derecruitment associated with decreased RBC flux. 2PM demonstrated that hyperemia under control conditions induces 26 ± 5% of capillaries to dilate and 19 ± 3% to constrict. After stenosis, the proportion of capillaries dilating to hyperemia decreased to 14 ± 4% (P = 0.05), whereas proportion of constricting capillaries increased to 32 ± 4% (P = 0.05). Hyperemia-induced changes in capillary diameter occurred preferentially in capillary segments invested with pericytes. In a transgenic mouse model featuring partial pericyte depletion, only 14 ± 3% of capillaries constricted to hyperemic challenge after stenosis, a significant reduction from 33 ± 4% in wild-type littermate controls (P = 0.04). These results provide for the first time direct visualization of hyperemia-induced capillary derecruitment distal to arterial stenosis and demonstrate that pericyte constriction underlies this phenomenon in vivo. These results could have important therapeutic implications in the treatment of exercise-induced ischemia. NEW & NOTEWORTHY In the setting of coronary arterial stenosis, hyperemia produces a reversible perfusion defect resulting from capillary derecruitment that is believed to underlie cardiac ischemia under hyperemic conditions. We use optical microangiography and in vivo two-photon microscopy to visualize capillary derecruitment distal to a femoral arterial stenosis with cellular resolution. We demonstrate that capillary constriction in response to hyperemia in the setting of stenosis is dependent on pericytes, contractile mural cells investing the microcirculation.

The association between near-infrared spectroscopy-derived and flow-mediated dilation assessment of vascular responsiveness in the arm.

INTRODUCTION: Following a period of blood flow occlusion, the near-infrared spectroscopy (NIRS)-derived reperfusion slope of the oxygen saturation signal (StO2) is a measure of microvascular responsiveness that has been shown to be positively correlated with flow-mediated dilation (FMD) assessment of conduit artery function in the lower limb vasculature. Given that previously established differences in structure and function of the vessels in the upper compared to the lower limbs may change this relationship, investigating whether this correlation between the reperfusion slope of the StO2 and the FMD response is maintained in upper limbs is important. Accordingly, this study investigated the correlation between the reperfusion slope of the StO2 and FMD in the arm vasculature. METHODS: 18 physically active individuals were submitted to a vascular occlusion test (VOT). Microvascular responsiveness was calculated as the NIRS-derived reperfusion slope assessed in a forearm muscle. Macrovascular responsiveness was assessed at the brachial artery and calculated as a percent of change in FMD (%FMD). RESULTS: A statistically significant correlation (r = 0.66; P = 0.001) was found between the reperfusion slope and %FMD response. CONCLUSION: The significant correlation between the reperfusion slope in the forearm muscle and %FMD in the brachial artery, reinforces the relationship between downstream and upstream vascular reactivity in healthy human limbs.

Reliability of microvascular responsiveness measures derived from near-infrared spectroscopy across a variety of ischemic periods in young and older individuals.

BACKGROUND: Cardiovascular disease (CVD) is associated with impairments in microvascular responsiveness. Therefore, reliably assessing microvascular function is clinically relevant. Thus, this study aimed to examine the reliability of the near-infrared spectroscopy (NIRS)-derived oxygen saturation (StO2) reperfusion slope, a measure of microvascular responsiveness, to four different vascular occlusion tests (VOT) of different durations in young and older participants. METHODS: Eight healthy young (29 ±â€¯5 yr) and seven older (67 ±â€¯4 yr) men participated in four NIRS combined with VOT (NIRS-VOT; 30 s, 1, 3, and 5 min) in the leg microvasculature on two visits separated by 1-2 weeks. Vascular responsiveness was determined by the StO2 reperfusion slope. The coefficient of variation (CV), repeatability, reliability (ICC), and the limits of agreement (LOA) were calculated for the NIRS-derived reperfusion slopes for each occlusion duration and visit. RESULTS: CV for the StO2 reperfusion slope following 30 s, 1, 3 and 5 min of occlusion were 33 ±â€¯29%, 19 ±â€¯21%, 14 ±â€¯12%, and 12 ±â€¯10%, respectively. Repeatability values following 30 s, 1, 3 and 5 min occlusions were 20%, 1%, 4% and 21%, respectively. The ICC for the StO2 reperfusion slopes for each occlusion duration were 0.29, 0.42, 0.84, and 0.88 following 30 s, 1, 3 and 5 min of occlusion, respectively. LOA values between visit 1 and 2 for occlusions were not different from zero. There were no age-related differences for all variables of the study. CONCLUSION: NIRS-derived StO2 reperfusion slope, has good reliability across a range of occlusion durations with the strongest reliability during longer occlusion durations.