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New Findings What is the central question of this study? Does ageing influence the respiratory-related bursting of muscle sympathetic nerve activity (MSNA) and the association between the rhythmicfluctuations in MSNA and blood pressure (Traube‐Hering waves) that occur with respiration? What is the mainfinding and its importance? Despitetheage-relatedelevationinMSNA,thecyclicalinhibitionofMSNAduringrespiration issimilarbetweenyoungandolderindividuals.Furthermore,centralrespiratory‐sympathetic coupling plays a role in the generation of Traube‐Hering waves in both young and older humans. Healthy ageing and alterations in respiratory‐sympathetic coupling have been independently linked with heightened sympathetic neural vasoconstrictor activity. We investigated how age influences the respiratory-related modulation of muscle sympathetic nerve activity (MSNA) and the association between the rhythmic fluctuations in MSNA and blood pressure that occur with respiration (Traube‐Hering waves; THW). Ten young (22 ± 2 years; mean ± SD) and 10 older healthy men (58 ± 6 years) were studied while resting supine and breathing spontaneously. MSNA, blood pressure and respiration were recorded simultaneously. Resting values were ascertained and respiratory cycle-triggered averaging of MSNA and blood pressure measurementsperformed.TheMSNAburstincidencewashigherinolderindividuals[22.7±9.2 versus 42.2 ± 13.7 bursts (100 heart beats) �1 , P < 0.05], and was reduced to a similar extent in the inspiratory to postinspiratory period in young and older subjects (by25% compared with mid- to late expiration). A similar attenuation of MSNA burst frequency (in bursts per minute), amplitude and total activity (burst frequency × mean burst amplitude) was also observed in the inspiratory to postinspiratory period in both groups. A significant positive correlation between respiratory-related MSNA and the magnitude of Traube‐Hering waves was observed in all young (100%) and most older subjects (80%). These data suggest that the strength of the cyclical inhibition of MSNA during respiration is similar between young and older individuals; thus,alterationsinrespiratory‐sympatheticcouplingappearnottocontributetotheage-related

New Findings What is the topic of this review? This review highlights the importance of increased vascular insulin sensitivity for maintaining glycaemic control and cardiovascular health. What advances does it highlight? We discuss the role of habitual physical activity in modulating vascular actions of insulin. Type 2 diabetes and cardiovascular disease commonly coexist. Current evidence suggests that impaired insulin signalling in the vasculature may be a common link between metabolic and cardiovascular diseases, including glycaemic dysregulation and atherosclerosis. Herein, we highlight the importance of the actions of insulin on the vasculature for glycaemic control and arterial health. In addition, we summarize and discuss findings from our group and others demonstrating that increased physical activity may be an effective approach to enhancing vascular insulin sensitivity. Furthermore, in light of the existing literature, we formulate the hypothesis that increased shear stress may be a prime mechanism through which habitual physical activity improves insulin signalling in the vasculature. Ultimately, we propose that targeting vascular insulin resistance may represent a viable strategy for improving glycaemic control and reducing cardiovascular risk in patients with type 2 diabetes.

New Findings What is the central question of this study? The prevalence of sedentary behaviour in the workplace and increased daily sitting time have been associated with the development of cardiovascular disease; however, studies investigating the impact of sitting on vascular function remain limited. What is the main finding and its importance? We demonstrate that there is a marked vulnerability of the vasculature in the lower and upper limbs to prolonged sitting and highlight the importance of physical activity in restoring vascular function in a limb-specific manner. Sedentary behaviour in the workplace and increased daily sitting time are on the rise; however, studies investigating the impact of sitting on vascular function remain limited. Herein, we hypothesized that 6 h of uninterrupted sitting would impair limb micro- and macrovascular dilator function and that this impairment could be improved with a bout of walking. Resting blood flow, reactive hyperaemia to 5 min cuff occlusion (microvascular reactivity) and associated flow-mediated dilatation (FMD; macrovascular reactivity) were assessed in popliteal and brachial arteries of young men at baseline (Pre Sit) and after 6 h of uninterrupted sitting (Post Sit). Measures were then repeated after a 10 min walk (∼1000 steps). Sitting resulted in a marked reduction of resting popliteal artery mean blood flow and mean shear rate (6 h mean shear rate, −52 ± 8 s−1 versus Pre Sit, P

A cholinergic (muscarinic) contribution to the initial circulatory response to exercise in humans remains controversial. Herein, we posit that this may be due to exercise mode with a cholinergic contribution being important during isometric handgrip exercise, where the hyperemic response of the muscle is relatively small compared with the onset of leg cycling, where a marked increase in muscle blood flow rapidly occurs as a consequence of multiple redundant mechanisms. We recorded blood pressure (BP; brachial artery), stroke volume (pulse contour analysis), cardiac output, and systemic vascular resistance (SVR) in young healthy males, while performing either 20 s of isometric handgrip contraction at 40% maximum voluntary contraction ( protocol 1; n = 9) or 20 s of low-intensity leg cycling exercise ( protocol 2; n = 8, 42 ± 8 W). Exercise trials were conducted under control (no drug) conditions and following cholinergic blockade (glycopyrrolate). Under control conditions, isometric handgrip elicited an initial increase in BP (+5 ± 2 mmHg at 3 s and +3 ± 1 mmHg at 10 s, P < 0.05), while SVR dropped after 3 s (−27 ± 6% at 20 s; P < 0.05). Cholinergic blockade abolished the isometric handgrip-induced fall in SVR and, thereby, augmented the pressor response (+13 ± 3 mmHg at 10 s; P < 0.05 vs. control). In contrast, cholinergic blockade had a nonsignificant effect on changes in BP and SVR at the onset of leg cycling exercise. These findings suggest that a cholinergic mechanism is important for the BP and SVR responses at the onset of isometric handgrip exercise in humans.

Type 2 diabetes mellitus patients (T2D) have elevated risk of stroke, suggesting that cerebrovascular function is impaired. Herein, we examined dynamic cerebral autoregulation (CA) at rest and during exercise in T2D patients and determined whether underlying systemic oxidative stress is associated with impairments in CA. Middle cerebral artery blood velocity and arterial blood pressure (BP) were measured at rest and during 2-min bouts of low- and high-intensity isometric handgrip performed at 20% and 40% maximum voluntary contraction, respectively, in seven normotensive and eight hypertensive T2D patients and eight healthy controls. Dynamic CA was estimated using the rate of regulation (RoR). Total reactive oxygen species (ROS) and superoxide levels were measured at rest. There were no differences in RoR at rest or during exercise between normotensive and hypertensive T2D patients. However, when compared with controls, T2D patients exhibited lower RoR at rest and during low-intensity handgrip indicating impaired dynamic CA. Moreover, the RoR was further reduced by 29 ± 4% during high-intensity handgrip in T2D patients (0.307 ± 0.012/s rest vs. 0.220 ± 0.014/s high intensity; P < 0.01), although well maintained in controls. T2D patients demonstrated greater baseline total ROS and superoxide compared with controls, both of which were negatively related to RoR during handgrip (e.g., total ROS: r = −0.71, P < 0.05; 40% maximum voluntary contraction). Collectively, these data demonstrate impaired dynamic CA at rest and during isometric handgrip in T2D patients, which may be, in part, related to greater underlying systemic oxidative stress. Additionally, dynamic CA is blunted further with high intensity isometric contractions potentially placing T2D patients at greater risk for cerebral events during such activities.

Autonomic nervous system adjustments to the heart and blood vessels are necessary for mediating the cardiovascular responses required to meet the metabolic demands of working skeletal muscle during exercise. These demands are met by precise exercise intensity-dependent alterations in sympathetic and parasympathetic nerve activity. The purpose of this review is to examine the contributions of the sympathetic and parasympathetic nervous systems in mediating specific cardiovascular and hemodynamic responses to exercise. These changes in autonomic outflow are regulated by several neural mechanisms working in concert, including central command (a feed forward mechanism originating from higher brain centers), the exercise pressor reflex (a feed-back mechanism originating from skeletal muscle), the arterial baroreflex (a negative feed-back mechanism originating from the carotid sinus and aortic arch), and cardiopulmonary baroreceptors (a feed-back mechanism from stretch receptors located in the heart and lungs). In addition, arterial chemoreceptors and phrenic afferents from respiratory muscles (i.e., respiratory metaboreflex) are also capable of modulating the autonomic responses to exercise. Our goal is to provide a detailed review of the parasympathetic and sympathetic changes that occur with exercise distinguishing between the onset of exercise and steady-state conditions, when appropriate. In addition, studies demonstrating the contributions of each of the aforementioned neural mechanisms to the autonomic changes and ensuing cardiac and/or vascular responses will be covered.

Investigations of human myogenic responses typically use maneuvers that evoke robust changes in transmural pressure. Although this strategy has demonstrated peripheral myogenic responsiveness in the limbs, particularly in glabrous skin of the hand or foot, it has not considered the potential influence of the myogenic mechanism in beat-to-beat blood flow (BF) control during unprovoked rest. In the present study, we examined the interactions of spontaneous beat-to-beat mean arterial pressure (MAP; Finapres) with BF (Doppler ultrasound) supplying the forearm (brachial artery), lower leg (popliteal artery), and hand (ulnar artery) during 10 min of supine rest in healthy young men. Cross-correlation analyses revealed a negative association between MAP and BF, which was more prominent in the forearm than lower leg. The strongest correlation resulted when a −2-heart beat offset of MAP was applied ( R = −0.53 ± 0.04 in the forearm and −0.23 ± 0.05 in the leg, P < 0.05), suggesting an ∼2-s delay from instances of high/low MAP to low/high BF. Negatively associated episodes (high MAP/low BF and low MAP/high BF) outnumbered positively associated data ( P < 0.05). BF during low MAP values was greater than the steady-state average BF and vice versa. Wrist and ankle occlusion blunted the strength of correlations, homogenized the incidence of MAP and BF pairings, and reduced the magnitude of deviation from steady-state values. In contrast, these relationships were matched or accentuated for hand BF. Overall, these results suggest that myogenic responses are present and occur rapidly in human limbs during rest, overwhelm perfusion pressure gradient influences, and are primarily mediated by the distal limb circulation.

Abundant evidence obtained largely from male human and animal subjects indicates that obesity increases sympathetic nerve activity (SNA), which contributes to hypertension development. However, recent studies that included women reported that the strong relationships between muscle SNA and waist circumference or body mass index (BMI) found in men are not present in overweight and obese women. A similar sex difference in the association between adiposity and hypertension development has been identified in animal models of obesity. In this brief review, we consider two possible mechanisms for this sex difference. First, visceral adiposity, leptin, insulin, and angiotensin II have been identified as potential culprits in obesity-induced sympathoexcitation in males. We explore if these factors wield the same impact in females. Second, we consider if sex differences in vascular reactivity to sympathetic activation contribute. Our survey of the literature suggests that premenopausal females may be able to resist obesity-induced sympathoexcitation and hypertension in part due to differences in adipose disposition as well as its muted inflammatory response and reduced production of pressor versus depressor components of the renin-angiotensin system. In addition, vascular responsiveness to increased SNA may be reduced. However, more importantly, we identify the urgent need for further study, not only of sex differences per se, but also of the mechanisms that may mediate these differences. This information is required not only to refine treatment options for obese premenopausal women but also to potentially reveal new therapeutic avenues in obese men and women.

Background Postmenopausal women represent the largest cohort of patients with heart failure with preserved ejection fraction, and vascular dementia represents the most common form of dementia in patients with heart failure with preserved ejection fraction. Therefore, we tested the hypotheses that the combination of cardiac pressure overload (aortic banding [ AB ]) and the loss of female sex hormones (ovariectomy [ OVX ]) impairs cerebrovascular control and spatial memory. Methods and Results Female Yucatan miniswine were separated into 4 groups (n=7 per group): (1) control, (2) AB , (3) OVX , and (4) AB ‐ OVX . Pigs underwent OVX and AB at 7 and 8 months of age, respectively. At 14 months, cerebral blood flow velocity and spatial memory (spatial hole‐board task) were lower in the OVX groups ( P AB ‐ OVX group ( P AB ‐ OVX group ( P OVX groups ( P AB ‐ OVX group ( P 2+ ‐activated potassium channel α‐subunit agonist NS ‐1619 was impaired in both AB groups ( P 2+ ‐activated potassium channel α‐subunit protein was increased in AB groups ( P Conclusions Mechanistically, impaired cerebral blood flow control in experimental heart failure may be the result of heightened neuropeptide Y–induced vasoconstriction along with reduced vasodilation associated with decreased Ca 2+ ‐activated potassium channel function and impaired nitric oxide signaling, the effects of which are exacerbated in the absence of female sex hormones.

NEW FINDINGS What is the central question of this study? To understand better the effects of acute hyperglycaemia on arterial stiffness in healthy young individuals, we assessed arterial stiffness in physically active men before and after reduced ambulatory physical activity to decrease insulin sensitivity. What is the main finding and its importance? During an oral glucose tolerance test, we identified an increase in leg arterial stiffness (i.e. reduced femoral artery compliance) only when subjects were inactive for 5 days ( 10,000 steps day-1 ). These results demonstrate the deleterious consequence of acute reductions in daily physical activity on the response of the peripheral vasculature to acute hyperglycaemia. ABSTRACT Acute hyperglycaemia has been shown to augment indices of arterial stiffness in patients with insulin resistance and other co-morbidities; however, conflicting results exist in healthy young individuals. We examined whether acute hyperglycaemia after an oral glucose tolerance test (OGTT) increases arterial stiffness in healthy active men before and after reduced ambulatory physical activity to decrease insulin sensitivity. High-resolution arterial diameter traces acquired from Doppler ultrasound allowed an arterial blood pressure (BP) waveform to be obtained from the diameter trace within a cardiac cycle. In 24 subjects, this method demonstrated sufficient agreement with the traditional approach for assessing arterial compliance using applanation tonometry. In 10 men, continuous recordings of femoral and brachial artery diameter and beat-to-beat BP (Finometer) were acquired at rest, 60 and 120 min of an OGTT before and after 5 days of reduced activity (from >10,000 to

The incidence of chronic kidney disease (CKD) is increasing worldwide, with more than 26 million people suffering from CKD in the United States alone. More patients with CKD die of cardiovascular complications than progress to dialysis. Over 80% of CKD patients have hypertension, which is associated with increased risk of cardiovascular morbidity and mortality. Another common, perhaps underappreciated, feature of CKD is an overactive sympathetic nervous system. This elevation in sympathetic nerve activity (SNA) not only contributes to hypertension but also plays a detrimental role in the progression of CKD independent of any increase in blood pressure. Indeed, high SNA is associated with poor prognosis and increased cardiovascular morbidity and mortality independent of its effect on blood pressure. This brief review will discuss some of the consequences of sympathetic overactivity and highlight some of the potential pathways contributing to chronically elevated SNA in CKD. Mechanisms leading to chronic sympathoexcitation in CKD are complex, multifactorial and to date, not completely understood. Identification of the mechanisms and/or signals leading to sympathetic overactivity in CKD are crucial for development of effective therapeutic targets to reduce the increased cardiovascular risk in this patient group.

For the first time, we obtained direct intra-neural measurements of muscle sympathetic nerve activity (MSNA) in relapsing–remitting multiple sclerosis (MS) patients to test the hypothesis that spontaneous resting MSNA is reduced in MS patients compared to age, sex-matched healthy controls. Spontaneous MSNA (microneurography; peroneal nerve), plasma norepinephrine, arterial blood pressure (finger photoplethysmography), and heart rate were measured at rest in three groups: 1) relapsing–remitting MS patients on disease modifying therapy only (MS-DT; n = 6); 2) relapsing–remitting MS patients on disease modifying therapy and medications for MS-related symptoms that are known to effect the central nervous system (MS-DT/ST; n = 5), and 3) healthy age and sex-matched controls (CON; n = 6). Compared to the CON group, MSNA burst frequency (bursts/min) was significantly lower in both MS-DT (P = 0.027) and MS-DT/ST groups (P = 0.003). Similarly, MSNA burst incidence (bursts/100 heartbeats) was significantly reduced in both MS-DT (P = 0.049) and MS-DT/ST groups (P = 0.004) compared to the CON group. Burst frequency and burst incidence were not different between MS-DT and MS-DT/ST groups. Resting plasma norepinephrine was also significantly lower in both MS-DT (P = 0.039) and MS-DT/ST groups (P = 0.021) compared to the CON group. Reduced MSNA may signify an important dysfunction in autonomic control of cardiovascular function in patients with MS.

Recent work suggests that β-adrenergic vasodilation offsets α-adrenergic vasoconstriction in young women, but this effect is lost after menopause. Given these age-related vascular changes, we tested the hypothesis that older women would exhibit a greater change in vascular conductance following baroreflex perturbation compared with young women. In 10 young (21 ± 1 yr) and 10 older (62 ± 2 yr) women, mean arterial pressure (MAP; Finometer), heart rate (HR), cardiac output (CO; Modelflow), total vascular conductance (TVC), and leg vascular conductance (LVC, duplex-Doppler ultrasound) were continuously measured in response to 5-s pulses of neck suction (NS; −60 Torr) and neck pressure (NP; +40 Torr) to simulate carotid hypertension and hypotension, respectively. Following NS, decreases in MAP were similar between groups; however, MAP peak response latency was slower in older women ( P < 0.05). Moreover, at the time of peak MAP, increases in LVC (young, −11.5 ± 3.9%LVC vs. older, +19.1 ± 7.0%LVC; P < 0.05) and TVC were greater in older women, whereas young women exhibited larger decreases in HR and CO (young, −10 ± 3% CO vs. older, +0.8 ± 2% CO; P < 0.05). Following NP, increases in MAP were blunted (young, +14 ± 1 mmHg vs. older, +8 ± 1 mmHg; P < 0.05) in older women, whereas MAP response latencies were similar. Interestingly, decreases in LVC and TVC were similar between groups, but HR and CO (young, +7.0 ± 2% CO vs. older, −4.0 ± 2% CO; P < 0.05) responses were attenuated in older women. These findings suggest that older women have greater reliance on vascular conductance to modulate MAP via carotid baroreflex, whereas young women rely more on cardiac responsiveness. Furthermore, older women demonstrate a blunted ability to increase MAP to hypotensive stimuli.

Ultrasound Doppler and near-infrared spectroscopy (NIRS) are routinely used for noninvasive monitoring of peripheral hemodynamics in both clinical and experimental settings. However, the comparative ability of these methodologies to detect changes in microvascular and whole limb hemodynamics during pharmacological manipulation of vascular smooth muscle receptors located at varied locations within the arterial tree is unknown. Thus, in 10 healthy subjects (25 ± 2 yr), changes in resting leg blood flow (ultrasound Doppler; femoral artery) and muscle oxygenation (oxyhemoglobin + oxymyoglobin; vastus lateralis) were simultaneously evaluated in response to intra-arterial infusions of phenylephrine (PE, 0.025–0.8 μg·kg−1·min−1), BHT-933 (2.5–40 μg·kg−1·min−1), and angiotensin II (ANG II, 0.5–8 ng·kg−1·min−1). All drugs elicited significant dose-dependent reductions in leg blood flow and oxyhemoglobin + oxymyoglobin. Significant relationships were found between ultrasound Doppler and NIRS changes across doses of PE ( r2 = 0.37 ± 0.08), BHT-933 ( r2 = 0.74 ± 0.06), and ANG II ( r2 = 0.68 ± 0.13), with the strongest relationships evident with agonists for receptors located preferentially “downstream” in the leg microcirculation (BHT-933 and ANG II). Analyses of drug potency revealed similar EC50 between ultrasound Doppler and NIRS measurements for PE (0.06 ± 0.02 vs. 0.10 ± 0.01), BHT-933 (5.0 ± 0.9 vs. 4.5 ± 1.3), and ANG II (1.4 ± 0.8 vs. 1.3 ± 0.3). These data provide evidence that both ultrasound Doppler and NIRS track pharmacologically induced changes in peripheral hemodynamics and are equally capable of determining drug potency. However, considerable disparity was observed between agonist infusions targeting different levels of the arterial tree, suggesting that receptor landscape is an important consideration for proper interpretation of hemodynamic monitoring with these methodologies.

Sympathetic vasoconstriction is attenuated in exercising muscles to assist in matching of blood flow with metabolic demand. This “functional sympatholysis” may be impaired in young obese individuals due to greater sympathetic activation and/or reduced local vasodilatory capacity of both small and large arteries, but this remains poorly understood. We tested the hypothesis that functional sympatholysis is impaired in obese individuals compared with normal‐weight counterparts. In 36 obese and normal‐weight young healthy adults (n = 18/group), we measured forearm blood flow and calculated forearm vascular conductance (FVC) responses to reflex increases in sympathetic nerve activity induced by lower body negative pressure (LBNP) at rest and during rhythmic handgrip exercise at 15% and 30% of the maximal voluntary contraction (MVC). FVC was normalized to lean forearm mass. In normal‐weight individuals, LBNP evoked a decrease in FVC (−16.1 ± 5.7%) in the resting forearm, and the reduction in FVC (15%MVC: −8.1 ± 3.3%; 30%MVC: −1.0 ± 4.0%) was blunted during exercise in an intensity‐dependent manner (P 0.05) and was intensity‐dependent (P

New Findings What is the central question of this study? The normal ability of sympathetic nerves to cause vasoconstriction is blunted in exercising skeletal muscle, a phenomenon termed ‘functional sympatholysis’. Animal studies suggest that functional sympatholysis appears to occur preferentially in fast-twitch type II glycolytic compared with slow-twitch type I oxidative skeletal muscle. We asked whether these findings can be extended to humans. What is the main finding and its importance? We show that skeletal muscles composed largely of fast-twitch type II fibres may also be more sensitive to functional sympatholysis in humans, particularly at lower exercise intensities. Additionally, independent of muscle fibre type composition, the magnitude of sympatholysis is strongly related to exercise-induced increases in metabolic demand. Animal studies suggest that functional sympatholysis appears to occur preferentially in glycolytic (largely type II) compared with oxidative (largely type I) skeletal muscle. Whether these findings can be extended to humans currently remains unclear. In 12 healthy male subjects, vasoconstrictor responses in gastrocnemius (i.e. primarily type II) and soleus muscles (i.e. primarily type I) were measured using near-infrared spectroscopy to detect decreases in muscle oxygenation (HbO2) in response to sympathetic activation evoked by a cold pressor test (CPT). The HbO2 responses to a CPT at rest were compared with responses during steady-state plantar flexion exercise (30 repetitions min−1) performed at 10, 20 and 40% maximal voluntary contraction (MVC) for 6 min. In resting conditions, HbO2 at the gastrocnemius (−14 ± 1%) and soleus muscles (−16 ± 1%) decreased significantly during CPT, with no differences between muscles. During planter flexion at 20% MVC, the change in HbO2 in response to the CPT was blunted in gastrocnemius but not soleus, whereas during 40% MVC both muscles exhibited a significant attenuation to sympathetic activation. The decreases in HbO2 in response to the CPT during exercise were significantly correlated with the metabolic demands of exercise (the decreases in HbO2 in response to steady-state plantar flexion) in both gastrocnemius and soleus muscles. Collectively, these results suggest that skeletal muscles composed mainly of glycolytic type II fibres are more sensitive to functional sympatholysis, particularly at lower intensities of exercise. Moreover, the blunting of sympathetic vasoconstriction during exercise is strongly related to metabolic demand; an effect that appears independent of fibre type composition.

Physical inactivity promotes the development of cardiovascular diseases. However, few data exist examining the vascular consequences of short-term reductions in daily physical activity. Thus we tested the hypothesis that popliteal and brachial artery flow-mediated dilation (FMD) would be reduced and concentrations of endothelial microparticles (EMPs) would be elevated following reduced daily physical activity. To examine this, popliteal and brachial artery FMD and plasma levels of EMPs suggestive of apoptotic and activated endothelial cells (CD31+/CD42b− and CD62E+ EMPs, respectively) were measured at baseline and during days 1, 3, and 5 of reduced daily physical activity in 11 recreationally active men (25 ± 2 yr). Subjects were instructed to reduce daily physical activity by taking +/CD42b− EMPs were significantly elevated with reduced activity (baseline: 17.6 ± 9.4, reduced activity day 5: 104.1 ± 43.1 per μl plasma, P < 0.05), whereas CD62E+ EMPs were unaltered. Collectively, our results provide evidence for the early and robust deleterious impact of reduced daily activity on vascular function and highlight the vulnerability of the vasculature to a sedentary lifestyle.

Many diseases associated with sympathoexcitation also exhibit elevated reactive oxygen species (ROS). A recent animal study indicated that exogenous administration of the sympathetic neurotransmitter norepinephrine (NE) increased systemic ROS via circulating leukocytes. The mechanisms contributing to this effect of NE and whether these findings can be translated to humans is unknown. Thus we tested the hypothesis that NE increases superoxide production in human peripheral blood mononuclear cells (PBMCs) via NADPH oxidase. Primary human PBMCs were freshly isolated from healthy young men and placed in culture. After NE (50 pg/ml, 50 ng/ml, and 50 μg/ml concentrations) or control treatments, NADPH oxidase mRNA expression (gp91phox, p22phox, and p67phox) was assessed using real-time RT-PCR, and intracellular superoxide production was measured using dihydroethidium fluorescence. PBMCs were also treated with selective adrenergic agonists-antagonists to determine the receptor population involved. In addition, CD14+monocyte-endothelial cell adhesion was determined using a fluorescent-based assay. NE significantly increased NADPH oxidase gene expression and intracellular superoxide production in a time-dependent manner (superoxide: 0.9 ± 0.2 fold, 6 h vs. 3.0 ± 0.3 fold, 36 h; NE, 50 μg/ml; P < 0.05). The sustained increase in NE-induced superoxide production was primarily mediated via α-adrenergic receptors, preferentially α2-receptors. The NADPH oxidase blocker diphenylene iodonium and protein kinase C inhibitor Staurosporine significantly attenuated NE-induced increases in superoxide production. Importantly, NE treatment increased CD14+monocyte-endothelial cell adhesion. These findings indicate for the first time that NE increases superoxide production in freshly isolated primary human PBMCs via NADPH oxidase through α-adrenergic receptors, an effect facilitating monocyte adhesion to the endothelium.

ObjectivesThis study sought to determine if simvastatin impairs exercise training adaptations.BackgroundStatins are commonly prescribed in combination with therapeutic lifestyle changes, including exercise, to reduce cardiovascular disease risk in patients with metabolic syndrome. Statin use has been linked to skeletal muscle myopathy and impaired mitochondrial function, but it is unclear whether statin use alters adaptations to exercise training.MethodsThis study examined the effects of simvastatin on changes in cardiorespiratory fitness and skeletal muscle mitochondrial content in response to aerobic exercise training. Sedentary overweight or obese adults with at least 2 metabolic syndrome risk factors (defined according to National Cholesterol Education Panel Adult Treatment Panel III criteria) were randomized to 12 weeks of aerobic exercise training or to exercise in combination with simvastatin (40 mg/day). The primary outcomes were cardiorespiratory fitness and skeletal muscle (vastus lateralis) mitochondrial content (citrate synthase enzyme activity).ResultsThirty-seven participants (exercise plus statins: n = 18; exercise only: n = 19) completed the study. Cardiorespiratory fitness increased by 10% (p < 0.05) in response to exercise training alone, but was blunted by the addition of simvastatin resulting in only a 1.5% increase (p < 0.005 for group by time interaction). Similarly, skeletal muscle citrate synthase activity increased by 13% in the exercise-only group (p < 0.05), but decreased by 4.5% in the simvastatin-plus-exercise group (p < 0.05 for group-by-time interaction).ConclusionsSimvastatin attenuates increases in cardiorespiratory fitness and skeletal muscle mitochondrial content when combined with exercise training in overweight or obese patients at risk of the metabolic syndrome. (Exercise, Statins, and the Metabolic Syndrome; NCT01700530)

Dysfunction of the endothelium is proposed as the primary initiator of atherosclerotic peripheral artery disease, which occurs mainly in medium- to large-sized conduit arteries of the lower extremities (e.g., iliac, femoral, popliteal arteries). In this review article, we propose the novel concept that conduit artery endothelial cell phenotype is determined, in part, by microvascular tone in skeletal muscle resistance arteries through both changes in arterial blood pressure as well as upstream conduit artery shear stress patterns. First, we summarize the literature supporting the involvement of sympathetic nerve activity (SNA) and nitric oxide (NO) in the modulation of microvascular tone and arterial blood pressure. We then focus on the role of elevated blood pressure and shear stress profiles in modulating conduit artery endothelial cell phenotype. Last, we discuss findings from classic and emerging studies indicating that increased vascular resistance, as it occurs in the context of increased SNA and/or reduced NO bioavailability, is associated with greater oscillatory shear stress (e.g., increased retrograde shear) in upstream conduit arteries. The ideas put forth in this review set the stage for a new paradigm concerning the mechanistic link between increased microvascular tone and development of conduit artery endothelial dysfunction and thus increased risk for peripheral artery disease. Indeed, a vast amount of evidence supports the notion that excessive blood pressure and oscillatory shear stress are potent pro-atherogenic signals to the endothelium.

New Findings • What is the central question of this study?Sympathetic baroreflex sensitivity increases during isolated skeletal muscle metaboreflex activation in young adults, but whether this neural interaction between the arterial baroreflex and the muscle metaboreflex is altered in healthy ageing remains unclear. • What is the main finding and its importance?The collective findings indicate that the neural interaction between the arterial baroreflex and the skeletal muscle metaboreflex in the regulation of muscle sympathetic nerve activity is preserved in healthy ageing. This has potential implications for the regulation of blood pressure during exercise in older adults. Sympathetic baroreflex sensitivity is increased during selective activation of the skeletal muscle metaboreflex with postexercise ischaemia (PEI) in young adults. However, to date, there are no data demonstrating this neural interaction between the arterial baroreflex and the muscle metaboreflex in healthy older adults. Therefore, the goal of the present study was to examine the influence of healthy ageing on the metabolic component of the exercise pressor reflex and its interaction with the arterial baroreflex in the control of sympathetic outflow. Postexercise ischaemia following static hand grip performed at 30% maximal voluntary contraction was used to isolate muscle metaboreflex activation in young [n= 10; 24 ± 1 years old; resting blood pressure (BP) 116 ± 3/64 ± 3 mmHg] and older men (n= 9; 59 ± 2 years old; resting BP 120 ± 2/77 ± 2 mmHg). Arterial BP (Finometer) and muscle sympathetic nerve activity (MSNA) were measured continuously. Weighted linear regression analysis between MSNA and diastolic BP was used to estimate arterial baroreflex MSNA gain. There were no age-related differences in the increase in mean BP (young, Δ14 ± 3 mmHg versus older, Δ15 ± 2 mmHg; P > 0.05) or MSNA burst frequency (young, Δ11 ± 2 bursts min−1 versus older, Δ9 ± 1 bursts min−1; P > 0.05) during PEI. Likewise, the gain of arterial baroreflex control of total MSNA increased to a similar extent in both groups during PEI (young, −4.2 ± 0.9 baseline versus−6.3 ± 1.1 PEI a.u. beat−1 mmHg−1; and older, −3.7 ± 1.1 baseline versus−6.7 ± 1.4 PEI a.u. beat−1 mmHg−1; P < 0.05 for both). Collectively, these findings indicate that the neural interaction between the arterial baroreflex and the skeletal muscle metaboreflex in the regulation of MSNA is preserved in healthy ageing.

Sympathetic vascular transduction is commonly understood to act as a basic relay mechanism, but under basal conditions, competing dilatory signals may interact with and alter the ability of sympathetic activity to decrease vascular conductance. Thus, we determined the extent to which spontaneous bursts of muscle sympathetic nerve activity (MSNA) mediate decreases in forearm vascular conductance (FVC) and the contribution of local α-adrenergic receptor-mediated pathways to the observed FVC responses. In 19 young men, MSNA (microneurography), arterial blood pressure and brachial artery blood flow (duplex Doppler ultrasound) were continuously measured during supine rest. These measures were also recorded in seven men during intra-arterial infusions of normal saline, phentolamine (PHEN) and PHEN with angiotensin II (PHEN+ANG). The latter was used to control for increases in resting blood flow with α-adrenergic blockade. Spike-triggered averaging was used to characterize beat-by-beat changes in FVC for 15 cardiac cycles following each MSNA burst and a peak response was calculated. Following MSNA bursts, FVC initially increased by +3.3 ± 0.3% (P = 0.016) and then robustly decreased to a nadir of -5.8 ± 1.6% (P < 0.001). The magnitude of vasoconstriction appeared graded with the number of consecutive MSNA bursts; while individual burst size only had a mild influence. Neither PHEN nor PHEN+ANG infusions affected the initial rise in FVC, but both infusions significantly attenuated the subsequent decrease in FVC (-2.1 ± 0.7% and -0.7 ± 0.8%, respectively; P < 0.001 vs. normal saline). These findings indicate that spontaneous MSNA bursts evoke robust beat-by-beat decreases in FVC that are exclusively mediated via α-adrenergic receptors.

Previous studies in humans attempting to assess sympathetic vascular transduction have related large reflex-mediated increases in muscle sympathetic nerve activity (MSNA) to associated changes in limb vascular resistance. However, such procedures do not provide insight into the ability of MSNA to dynamically control vascular tone on a beat-by-beat basis. Thus we examined the influence of spontaneous MSNA bursts on leg vascular conductance (LVC) and how variations in MSNA burst pattern (single vs. multiple bursts) and burst size may affect the magnitude of the LVC response. In 11 young men, arterial blood pressure, common femoral artery blood flow, and MSNA were continuously recorded during 20 min of supine rest. Signal averaging was used to characterize percent changes in LVC for 15 cardiac cycles following heartbeats associated with and without MSNA bursts. LVC significantly decreased following MSNA bursts, reaching a nadir during the 6th cardiac cycle (single bursts, −2.9 ± 1.1%; and multiple bursts, −11.0 ± 1.4%; both, P < 0.001). Individual MSNA burst amplitudes and the total amplitude of consecutive bursts were related to the magnitude of peak decreases in LVC. In contrast, cardiac cycles without MSNA bursts were associated with a significant increase in LVC (+3.1 ± 0.5%; P < 0.001). Total vascular conductance decreased in parallel with LVC also reaching a nadir around the peak rise in arterial blood pressure following an MSNA burst. Collectively, these data are the first to assess beat-by-beat sympathetic vascular transduction in resting humans, demonstrating robust and dynamic decreases in LVC following MSNA bursts, an effect that was absent for cardiac cycles without MSNA bursts.

What is the central question of this study? Patients with type 2 diabetes exhibit increased oxidative stress in peripheral blood mononuclear cells, including monocytes; however, the mechanisms remain unknown. What is the main finding and its importance? The main finding of this study is that factors contained within the plasma of patients with type 2 diabetes can contribute to increased oxidative stress in monocytes, making them more adherent to endothelial cells. We show that these effects are largely mediated by the interaction between endoplasmic reticulum stress and NADPH oxidase activity. Recent evidence suggests that exposure of human monocytes to glucolipotoxic media to mimic the composition of plasma of patients with type 2 diabetes (T2D) results in the induction of endoplasmic reticulum (ER) stress markers and formation of reactive oxygen species (ROS). The extent to which these findings translate to patients with T2D remains unclear. Thus, we first measured ROS (dihydroethidium fluorescence) in peripheral blood mononuclear cells (PBMCs) from whole blood of T2D patients (n = 8) and compared the values with age-matched healthy control subjects (n = 8). The T2D patients exhibited greater basal intracellular ROS (mean ± SD, +3.4 ± 1.4-fold; P 0.05) compared with control subjects. Next, the increase in ROS in PBMCs isolated from T2D patients was partly recapitulated in cultured human monocytes (THP-1 cells) exposed to plasma from T2D patients for 36 h (+1.3 ± 0.08-fold versus plasma from control subjects; P 0.05). In addition, we found that increased ROS formation in THP-1 cells treated with T2D plasma was NADPH oxidase derived and led to increased endothelial cell adhesion (+1.8 ± 0.5-fold; P 0.05) and lipid uptake (+1.3 ± 0.3-fold; P 0.05). Notably, we found that T2D plasma-induced monocyte ROS and downstream functional effects were abolished by treating cells with tauroursodeoxycholic acid, a chemical chaperone known to inhibit ER stress. Collectively, these data indicate that monocyte ROS production with T2D can be attributed, in part, to signals from the circulating environment. Furthermore, an interplay between ER stress and NADPH oxidase activity contributes to ROS production and may be a mechanism mediating endothelial cell adhesion and foam cell formation in T2D.

Despite standard drug therapy, sympathetic nerve activity (SNA) remains high in heart failure (HF) patients making the sympathetic nervous system a primary drug target in the treatment of HF. Studies in rabbits with pacing-induced HF have demonstrated that statins reduce resting SNA, in part, due to reductions in reactive oxygen species (ROS). Whether these findings can be extended to the clinical setting of human HF remains unclear. We first performed a study in seven statin-naïve HF patients (56 ± 2 yr; ejection fraction: 31 ± 4%) to determine if 1 mo of simvastatin (40 mg/day) reduces muscle SNA (MSNA). Next, to control for possible placebo effects and determine the effect of simvastatin on ROS, a double-blinded, placebo-controlled crossover design study was performed in six additional HF patients (51 ± 3 yr; ejection fraction: 22 ± 4%), and MSNA, ROS, and superoxide were measured. We tested the hypothesis that statin therapy decreases resting MSNA in HF patients and this would be associated with reductions in ROS. In study 1, simvastatin reduced resting MSNA (75 ± 5 baseline vs. 65 ± 5 statin bursts/100 heartbeats; P < 0.05). Likewise, in study 2, simvastatin also decreased resting MSNA (59 ± 5 placebo vs. 45 ± 6 statin bursts/100 heartbeats; P < 0.05). In addition, statin therapy significantly reduced total ROS and superoxide. As expected, cholesterol was reduced after simvastatin. Collectively, these findings indicate that short-term statin therapy concomitantly reduces resting MSNA and total ROS and superoxide in HF patients. Thus, in addition to lowering cholesterol, statins may also be beneficial in reducing sympathetic overactivity and oxidative stress in HF patients.

To date, no studies have examined whether there are either sex- or ovarian hormone-related alterations in arterial baroreflex resetting and function during dynamic exercise. Thus we studied 16 young men and 18 young women at rest and during leg cycling at 50% heart rate (HR) reserve. In addition, 10 women were studied at three different phases of the menstrual cycle. Five-second pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr were applied to determine full carotid baroreflex (CBR) stimulus response curves. An upward and rightward resetting of the CBR function curve was observed during exercise in all groups with a similar magnitude of CBR resetting for mean arterial pressure (MAP) and HR between sexes ( P > 0.05) and at different phases of the menstrual cycle ( P > 0.05). For CBR control of MAP, women exhibited augmented pressor responses to NP at rest and exercise during mid-luteal compared with early and late follicular phases. For CBR control of HR, there was a greater bradycardic response to NS in women across all menstrual cycle phases with the operating point (OP) located further away from centering point (CP) on the CBR-HR curve during rest (OP-CP; in mmHg: −13 ± 3 women vs. −3 ± 3 men; P < 0.05) and exercise (in mmHg: −31 ± 2 women vs. −15 ± 3 men; P < 0.05). Collectively, these findings suggest that sex and fluctuations in ovarian hormones do not influence exercise resetting of the baroreflex. However, women exhibited greater CBR control of HR during exercise, specifically against acute hypertension, an effect that was present throughout the menstrual cycle.

Non-technical summary Activation of sympathetic nerves decreases blood flow to resting skeletal muscle, but this vasoconstrictor effect normally is blunted during exercise so that blood flow can increase to the working muscles. In rats and humans treated with nitroglycerin for 1 week, we show that overproduction of reactive oxygen species prevents the usual attenuation of sympathetic vasoconstriction in the working muscles, resulting in muscle ischaemia during exercise. Improved knowledge about the effect that reactive oxygen species has on muscle blood flow regulation may help us to better understand the decreased exercise tolerance that occurs with age as well as with chronic disease.

We and others have recently reported that prolonged sitting impairs endothelial function in the leg vasculature; however, the mechanism(s) remain unknown. Herein, we tested the hypothesis that a sustained reduction in flow-induced shear stress is the underlying mechanism by which sitting induces leg endothelial dysfunction. Specifically, we examined whether preventing the reduction in shear stress during sitting would abolish the detrimental effects of sitting on popliteal artery endothelial function. In 10 young healthy men, bilateral measurements of popliteal artery flow-mediated dilation were performed before and after a 3-h sitting period during which one foot was submerged in 42°C water (i.e., heated) to increase blood flow and thus shear stress, whereas the contralateral leg remained dry and served as internal control (i.e., nonheated). During sitting, popliteal artery mean shear rate was reduced in the nonheated leg (pre-sit, 42.9 ± 4.5 s−1; and 3-h sit, 23.6 ± 3.3 s−1; P < 0.05) but not in the heated leg (pre-sit, 38.9 ± 3.4 s−1; and 3-h sit, 63.9 ± 16.9 s−1; P > 0.05). Popliteal artery flow-mediated dilation was impaired after 3 h of sitting in the nonheated leg (pre-sit, 7.1 ± 1.4% vs. post-sit, 2.8 ± 0.9%; P < 0.05) but not in the heated leg (pre-sit: 7.3 ± 1.5% vs. post-sit, 10.9 ± 1.8%; P > 0.05). Collectively, these data suggest that preventing the reduction of flow-induced shear stress during prolonged sitting with local heating abolishes the impairment in popliteal artery endothelial function. Thus these findings are consistent with the hypothesis that sitting-induced leg endothelial dysfunction is mediated by a reduction in shear stress.

See related article, pp 970–976 The importance of nitric oxide (NO) for normal cardiovascular regulation and health has been well established. However, the large majority of the focus and knowledge about NO has revolved around the endothelium and endothelial derived NO. Aside from its importance for blood flow and blood pressure via endothelium-dependent vasodilation,1,2 endothelial NO synthase (eNOS) has been shown to have numerous other vascular protective effects including, but not limited to, inhibition of platelet aggregation and adhesion, promotion of angiogenesis, anti-inflammation, and inhibition of the atherosclerotic process.3,4 In addition, eNOS has important cardiac effects. Thus, it is clear that impairments in eNOS-derived NO can have deleterious consequences and play a role in the disease process. Although the aforementioned functions of eNOS cannot be overstated, the synthesis of NO via neuronal NOS (nNOS) may also be critical for cardiovascular regulation and health. Indeed, nNOS along with eNOS is constitutively expressed in mammalian cells, and an emerging body of research, mainly performed in animals, has indicated that nNOS may also be important for the regulation of vasomotor tone and blood pressure.5 However, much less is known about nNOS in humans. In the current issue of Hypertension , Shabeeh et al6 report results from the first human study to systemically infuse the …

It is presently unknown whether there are sex differences in the magnitude of blood pressure (BP) responses to baroreceptor perturbation or if the relative contribution of cardiac output (CO) and total vascular conductance (TVC) to baroreflex-mediated changes in BP differs in young women and men. Since sympathetic vasoconstrictor tone is attenuated in women, we hypothesized that carotid baroreflex-mediated BP responses would be attenuated in women by virtue of a blunted vascular response (i.e., an attenuated TVC response). BP, heart rate (HR), and stroke volume were continuously recorded during the application of 5-s pulses of neck pressure (NP; carotid hypotension) and neck suction (NS; carotid hypertension) ranging from +40 to −80 Torr in women ( n = 20, 21 ± 0.5 yr) and men ( n = 20, 21 ± 0.4 yr). CO and TVC were calculated on a beat-to-beat basis. Women demonstrated greater depressor responses to NS (e.g., −60 Torr, −17 ± 1%baseline in women vs. −11 ± 1%baseline in men, P < 0.05), which were driven by augmented decreases in HR that, in turn, contributed to larger reductions in CO (−60 Torr, −15 ± 2%baseline in women vs. −6 ± 2%baseline in men, P < 0.05). In contrast, pressor responses to NP were similar in women and men (e.g., +40 Torr, +14 ± 2%baseline in women vs. +10 ± 1%baseline in men, P > 0.05), with TVC being the primary mediating factor in both groups. Our findings indicate that sex differences in the baroreflex control of BP are evident during carotid hypertension but not carotid hypotension. Furthermore, in contrast to our hypothesis, young women exhibited greater BP responses to carotid hypertension by virtue of a greater cardiac responsiveness.

After considerable debate and key experimental evidence, the importance of the arterial baroreflex in contributing to and maintaining the appropriate neural cardiovascular adjustments to exercise is now well accepted. Indeed, the arterial baroreflex resets during exercise in an intensity-dependent manner to continue to regulate blood pressure as effectively as at rest. Studies have indicated that the exercise resetting of the arterial baroreflex is mediated by both the feedforward mechanism of central command and the feedback mechanism associated with skeletal muscle afferents (the exercise pressor reflex). Another perhaps less appreciated neural mechanism involved in evoking and maintaining neural cardiovascular responses to exercise is the cardiopulmonary baroreflex. The limited information available regarding the cardiopulmonary baroreflex during exercise provides evidence for a role in mediating sympathetic nerve activity and blood pressure responses. In addition, recent investigations have demonstrated an interaction between cardiopulmonary baroreceptors and the arterial baroreflex during dynamic exercise, which contributes to the magnitude of exercise-induced increases in blood pressure as well as the resetting of the arterial baroreflex. Furthermore, neural inputs from the cardiopulmonary baroreceptors appear to play an important role in establishing the operating point of the arterial baroreflex. This symposium review highlights recent studies in these important areas indicating that the interactions of four neural mechanisms (central command, the exercise pressor reflex, the arterial baroreflex and cardiopulmonary baroreflex) are integral in mediating the neural cardiovascular adjustments to exercise.

We recently observed a marked increase in brachial artery (BA) diameter during prolonged leg cycling exercise. The purpose of the present study was to test the hypothesis that this increase in BA diameter during lower limb exercise is shear stress mediated. Accordingly, we determined whether recapitulation of cycling-induced BA shear rate with forearm heating, a known stimulus evoking shear-induced conduit artery dilatation, would elicit comparable profiles and magnitudes of BA vasodilatation to those observed during cycling. In 12 healthy men, BA diameter and blood velocity were measured simultaneously using Doppler ultrasonography at baseline and every 5 min during 60 min of either steady-state semi-recumbent leg cycling (120 W) or forearm heating. At the onset of cycling, the BA diameter was reduced (−3.9 ± 1.2% at 5 min; P 0.05). Herein, we found that in the absence of exercise the extent of the BA vasodilator response was reproduced when the BA was exposed to comparable magnitudes of shear rate via forearm heating. These results are consistent with the hypothesis that shear stress plays a key role in signalling brachial artery vasodilatation during dynamic leg exercise.

Aging has been recently associated with increased retrograde and oscillatory shear in peripheral conduit arteries, a hemodynamic environment that favors a proatherogenic endothelial cell phenotype. We evaluated whether nitric oxide (NO) bioavailability in resistance vessels contributes to age-related differences in shear rate patterns in upstream conduit arteries at rest and during rhythmic muscle contraction. Younger (n=11, age 26±2 years) and older (n=11, age 61±2 years) healthy subjects received intra-arterial saline (control) and the NO synthase inhibitor N G -Monomethyl- l -arginine. Brachial artery diameter and velocities were measured via Doppler ultrasound at rest and during a 5-minute bout of rhythmic forearm exercise. At rest, older subjects exhibited greater brachial artery retrograde and oscillatory shear (−13.2±3.0 s −1 and 0.11±.0.02 arbitrary units, respectively) compared with young subjects (−4.8±2.3 s −1 and 0.04±0.02 arbitrary units, respectively; both P P P >0.05). From rest to steady-state exercise, older subjects decreased retrograde and oscillatory shear (both P P >0.05). Inhibition of NO synthase in the forearm circulation did not affect retrograde and oscillatory shear during exercise in either group (all P >0.05). These data demonstrate for the first time that reduced NO bioavailability in the resistance vessels contributes, in part, to age-related discrepancies in resting shear patterns, thus identifying a potential mechanism for increased risk of atherosclerotic disease in conduit arteries.

Limited information is available regarding cerebral vascular responses to dynamic exercise in older adults. We examined the influence of age on exercise-induced changes in the critical closing pressure (CCP) of the cerebral vasculature. Twelve young and twelve older subjects performed two bouts of steady-state cycling at low and moderate intensities (30 and 50% heart rate reserve). Mean arterial pressure (MAP), middle cerebral artery blood velocity (MCA V) and partial pressure of end-tidal carbon dioxide () were measured. The CCP was estimated by linear extrapolation of pairs of systolic and diastolic blood pressure and MCA V waveforms. Exercise-induced increases in MAP were greater in older subjects (P < 0.01), while mean MCA V (MCA Vmean) responses to exercise were similar between groups (P= 0.59). The CCP was elevated from rest during low- and moderate-intensity exercise in both groups (moderate exercise: young, +13 ± 2 mmHg and older, +22 ± 2 mmHg; P < 0.01), with the older subjects exhibiting greater increases in CCP during both exercise intensities (moderate exercise: young, +43 ± 9% rest versus older, +153 ± 45% rest; P= 0.04). In contrast, cerebral vascular conductance index (MCA Vmean/MAP; CVCi) was only decreased during moderate exercise in older subjects (P < 0.01) and CVCi was not altered from rest in young subjects during low- or moderate-intensity cycling. No age-group differences were observed in at rest or during two intensities of exercise (P= 0.40). These data demonstrate that older subjects exhibit larger exercise-induced increases in CCP and decreases in CVCi. Thus, ageing is associated with greater increases in cerebral vascular tone during low- and moderate-intensity dynamic exercise.

The arterial baroreflex is fundamental for evoking and maintaining appropriate cardiovascular adjustments to exercise. We sought to investigate how aging influences carotid baroreflex regulation of blood pressure (BP) during dynamic exercise. BP and heart rate (HR) were continuously recorded at rest and during leg cycling performed at 50% HR reserve in 15 young (22 ± 1 yr) and 11 older (61 ± 2 yr) healthy subjects. Five-second pulses of neck pressure and neck suction from +40 to −80 Torr were applied to determine the full carotid baroreflex stimulus response curve and examine baroreflex resetting during exercise. Although the maximal gain of the modeled stimulus response curve was similar in both groups at rest and during exercise, in older subjects the operating point (OP) was located further away from the centering point (CP) and toward the reflex threshold, both at rest (OP minus CP; −10 ± 3 older vs. 0 ± 2 young mmHg, P < 0.05) and during exercise (OP minus CP; −10 ± 2 older vs. 1 ± 3 young mmHg, P < 0.05). In agreement, older subjects demonstrated a reduced BP response to neck pressure (simulated carotid hypotension) and a greater BP response to neck suction (simulated carotid hypertension). In addition, the magnitude of the upward and rightward resetting of the carotid baroreflex-BP stimulus response curve with exercise was ∼40% greater in older individuals. These data indicate that despite a maintained maximal gain, the ability of the carotid baroreflex to defend against a hypotensive challenge is reduced, whereas responses to hypertensive stimuli are greater with advanced age, both at rest and during exercise.

The mechanism(s) for the increased occurrence of a grayout or blackout, syncope, immediately after heavy resistance exercise are unclear. It is well‐known that orthostatic stress increases the occurrence of postexercise syncope. In addition, previous findings have suggested that hypo‐perfusion, especially in the posterior cerebral circulation rather than anterior cerebral circulation, may be associated with the occurrence of syncope. Herein, we hypothesized that the postexercise decrease in posterior, but not anterior, cerebral blood flow (CBF) would be greater during orthostatic stress. Nine healthy subjects performed 3‐min isometric handgrip (HG) at 30% maximum voluntary contraction without (CONTROL) and during lower body negative pressure (LBNP; −40 Torr) while vertebral artery (VA) blood flow, as an index of posterior CBF, and middle cerebral artery blood velocity (MCAv), as an index of anterior CBF, were measured. Immediately after HG (0 to 15 sec of recovery phase), mean arterial pressure decreased but there was no difference in this reduction between CONTROL and LBNP conditions (−15.4 ± 4.0% and −17.0 ± 6.2%, P = 0.42). Similarly, MCAv decreased following exercise and was unaffected by the application of LBNP (P = 0.22). In contrast, decreases in VA blood flow immediately following HG during LBNP were significantly greater compared to CONTROL condition (−24.2 ± 9.5% and ‐13.4 ± 6.6%, P = 0.005). These findings suggest that the decrease in posterior CBF immediately following exercise was augmented by LBNP, whereas anterior CBF appeared unaffected. Thus, the posterior cerebral circulation may be more sensitive to orthostatic stress during the postexercise period.

Recent animal studies indicate that insulin increases arterial baroreflex control of lumbar sympathetic nerve activity; however, the extent to which these findings can be extrapolated to humans is unknown. To begin to address this, muscle sympathetic nerve activity (MSNA) and arterial blood pressure were measured in 19 healthy subjects (27 ± 1 years) before, and for 120 min following, two common methodologies used to evoke sustained increases in plasma insulin: a mixed meal and a hyperinsulinaemic euglycaemic clamp. Weighted linear regression analysis between MSNA and diastolic blood pressure was used to determine the gain (i.e. sensitivity) of arterial baroreflex control of MSNA. Plasma insulin was significantly elevated within 30 min following meal intake (Δ34 ± 6 uIU ml−1; P < 0.05) and remained above baseline for up to 120 min. Similarly, after meal intake, arterial baroreflex-MSNA gain for burst incidence and total MSNA was increased and remained elevated for the duration of the protocol (e.g. burst incidence gain: −3.29 ± 0.54 baseline vs.−5.64 ± 0.67 bursts (100 heart beats)−1 mmHg−1 at 120 min; P < 0.05). During the hyperinsulinaemic euglycaemic clamp, in which insulin was elevated to postprandial concentrations (Δ42 ± 6 μIU ml−1; P < 0.05), while glucose was maintained constant, arterial baroreflex-MSNA gain was similarly enhanced (e.g. burst incidence gain: −2.44 ± 0.29 baseline vs.−4.74 ± 0.71 bursts (100 heart beats)−1 mmHg−1 at 120 min; P < 0.05). Importantly, during time control experiments, with sustained fasting insulin concentrations, the arterial baroreflex-MSNA gain remained unchanged. These findings demonstrate, for the first time in healthy humans, that increases in plasma insulin enhance the gain of arterial baroreflex control of MSNA.

Brain blood vessels contain muscarinic receptors that are important for cerebral blood flow (CBF) regulation, but whether a cholinergic receptor mechanism is involved in the exercise-induced increase in cerebral perfusion or affects cerebral metabolism remains unknown. We evaluated CBF and cerebral metabolism (from arterial and internal jugular venous O(2), glucose and lactate differences), as well as the middle cerebral artery mean blood velocity (MCA V(mean); transcranial Doppler ultrasound) during a sustained static handgrip contraction at 40% of maximal voluntary contraction (n = 9) and the MCA V(mean) during ergometer cycling (n = 8). Separate, randomized and counterbalanced trials were performed in control (no drug) conditions and following muscarinic cholinergic receptor blockade by glycopyrrolate. Glycopyrrolate increased resting heart rate from approximately 60 to approximately 110 beats min(-1) (P < 0.01) and cardiac output by approximately 40% (P < 0.05), but did not affect mean arterial pressure. The central cardiovascular responses to exercise with glycopyrrolate were similar to the control responses, except that cardiac output did not increase during static handgrip with glycopyrrolate. Glycopyrrolate did not significantly affect cerebral metabolism during static handgrip, but a parallel increase in MCA V(mean) (approximately 16%; P < 0.01) and CBF (approximately 12%; P < 0.01) during static handgrip, as well as the increase in MCA V(mean) during cycling (approximately 15%; P < 0.01), were abolished by glycopyrrolate (P < 0.05). Thus, during both cycling and static handgrip, a cholinergic receptor mechanism is important for the exercise-induced increase in cerebral perfusion without affecting the cerebral metabolic rate for oxygen.

The pathogenesis of hypertension and its mode of progression are complex, multifactoral and incompletely understood. However, there is accumulating evidence from humans and animal models of hypertension indicating that excessive central sympathetic nerve activity (SNA) plays a pathogenic role in triggering and sustaining the essential hypertensive state (the so-called 'neuroadrenergic hypothesis'). Importantly, augmented central sympathetic outflow has also been implicated in the initiation and progression of a plethora of pathophysiological processes independent of any increase in blood pressure, such as left ventricular hypertrophy and cardiac arrhythmias. Thus, the sympathetic nervous system constitutes an important putative drug target in hypertension. However, traditional pharmacological approaches for the management of essential hypertension appear ineffective in reducing central sympathetic outflow. Recently, several new and promising therapeutic strategies targeting neurogenic hypertension have been developed. The present report will provide a brief update of this topic with a particular emphasis on human studies examining the efficacy of novel pharmacological approaches (central sympatholytics and statins), lifestyle modification (aerobic exercise training, weight loss and stress reduction) and surgical intervention (renal denervation, chronic carotid baroreflex stimulation and deep brain stimulation) in reducing excessive central sympathetic activation in hypertension.

Escalating evidence indicates that disturbed flow patterns, characterized by the presence of retrograde and oscillatory shear stress, induce a proatherogenic endothelial cell phenotype; however, the mechanisms underlying oscillatory shear profiles in peripheral conduit arteries are not fully understood. We tested the hypothesis that acute elevations in muscle sympathetic nerve activity (MSNA) are accompanied by increases in conduit artery retrograde and oscillatory shear. Fourteen healthy men (25 ± 1 yr) performed three sympathoexcitatory maneuvers: graded lower body negative pressure (LBNP) from 0 to −40 Torr, cold pressor test (CPT), and 35% maximal voluntary contraction handgrip followed by postexercise ischemia (PEI). MSNA (microneurography; peroneal nerve), arterial blood pressure (finger photoplethysmography), and brachial artery velocity and diameter (duplex Doppler ultrasound) in the contralateral arm were recorded continuously. All maneuvers elicited significant increases in MSNA total activity from baseline ( P < 0.05). Retrograde shear (−3.96 ± 1.2 baseline vs. −8.15 ± 1.8 s−1, −40 LBNP, P < 0.05) and oscillatory shear index (0.09 ± 0.02 baseline vs. 0.20 ± 0.02 arbitrary units, −40 LBNP, P < 0.05) were progressively augmented during graded LBNP. In contrast, during CPT and PEI, in which MSNA and blood pressure were concomitantly increased ( P < 0.05), minimal or no changes in retrograde and oscillatory shear were noted. These data suggest that acute elevations in MSNA are associated with an increase in conduit artery retrograde and oscillatory shear, an effect that may be influenced by concurrent increases in arterial blood pressure. Future studies should examine the complex interaction between MSNA, arterial blood pressure, and other potential modulatory factors of shear rate patterns.

Nutrient intake is accompanied by increases in central sympathetic outflow, a response that has been mainly attributed to insulin. Insulin-mediated sympathoexcitation appears to be blunted in insulin-resistant conditions, suggesting that aside from peripheral insulin insensitivity, such conditions may also impair the central action of insulin in mediating sympathetic activation. What remains unclear is whether an insulin-sensitive state, such as that induced by chronic endurance training, alters the central sympathetic effects of insulin during postprandial conditions. To examine this question plasma insulin and glucose, muscle sympathetic nerve activity (MSNA), heart rate, and arterial blood pressure were measured in 11 high-fit [HF; peak oxygen uptake (V̇o2peak) 65.9 ± 1.4 ml·kg−1·min−1] and 9 average-fit (AF; V̇o2peak 43.6 ± 1.3 ml·kg−1·min−1) male subjects before and for 120 min after ingestion of a mixed meal drink. As expected, the insulin response to meal ingestion was lower in HF than AF participants (insulin area under the curve0–120: 2,314 ± 171 vs. 4,028 ± 460 μIU·ml−1·120−1, HF vs. AF, P < 0.05), with similar plasma glucose responses between groups. Importantly, following consumption of the meal, the HF subjects demonstrated a greater rise in MSNA compared with the AF subjects (e.g., 120 min: Δ21 ± 1 vs. 8 ± 3 bursts/100 heart beats, HF vs. AF, P < 0.05). Furthermore, when expressed relative to plasma insulin, HF subjects exhibited a greater change in MSNA for any given change in insulin. Arterial blood pressure responses following meal intake were similar between groups. Collectively, these data suggest that, in addition to improved peripheral insulin sensitivity, endurance training may enhance the central sympathetic effect of insulin to increase MSNA following consumption of a mixed meal.

Isolated activation of metabolically sensitive skeletal muscle afferents (muscle metaboreflex) using post-exercise ischaemia (PEI) following handgrip partially maintains exercise-induced increases in arterial blood pressure (BP) and muscle sympathetic nerve activity (SNA), while heart rate (HR) declines towards resting values. Although masking of metaboreflex-mediated increases in cardiac SNA by parasympathetic reactivation during PEI has been suggested, this has not been directly tested in humans. In nine male subjects (23 ± 5 years) the muscle metaboreflex was activated by PEI following moderate (PEI-M) and high (PEI-H) intensity isometric handgrip performed at 25% and 40% maximum voluntary contraction, under control (no drug), parasympathetic blockade (glycopyrrolate) and β-adrenergic blockade (metoprolol or propranalol) conditions, while beat-to-beat HR and BP were continuously measured. During control PEI-M, HR was slightly elevated from rest (+3 ± 2 beats min−1); however, this HR elevation was abolished with β-adrenergic blockade (P 0.05 vs. control). BP was similarly increased from rest during PEI-M and further elevated during PEI-H (P < 0.05) in all conditions. Collectively, these findings suggest that the muscle metaboreflex increases cardiac SNA during PEI in humans; however, it requires a robust muscle metaboreflex activation to offset the influence of cardiac parasympathetic reactivation on heart rate.

Animal studies have indicated that nitric oxide is a key signalling molecule involved in the tonic restraint of central sympathetic outflow from the brainstem. Extension of these findings to humans has been difficult because systemic infusion of nitric oxide synthase (NOS) inhibitors increases blood pressure due to inhibition of endothelial NOS, resulting in activation of the arterial baroreflex and subsequent inhibition of central sympathetic outflow. To overcome this confounding inhibitory influence of the baroreflex, in the current study we directly measured skin sympathetic nerve activity (SNA), which is not under baroreceptor control. Healthy, normotensive humans were studied before, during a 60 min intravenous infusion of the NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 4 mg kg−1), and for 120 min following the infusion (i.e. 180 min total). Skin SNA and arterial blood pressure (BP) were continuously measured. BP was increased from baseline at the end of the l-NAME infusion (Δ14 ± 2 mmHg; P < 0.05) and remained significantly elevated for the remainder of the experiment (Δ18 ± 3 mmHg; P < 0.05). Similarly, systemic NOS inhibition produced time-dependent increases in skin SNA, such that skin SNA was elevated at the end of the l-NAME infusion (total activity, 200 ± 22% baseline; P= 0.08) and was further increased at the end of the study protocol (total activity, 350 ± 41% baseline; P < 0.05). Importantly, skin SNA remained unchanged during time and hypertensive (phenylephrine) control experiments. These findings indicate that pharmacological inhibition of NOS causes sympathetic activation and support a role of nitric oxide in central sympathetic control in humans.

The dynamic relationship between ‘spontaneous’ fluctuations in arterial blood pressure (BP) and heart rate (HR) is increasingly being used to provide an estimate of resting cardiac baroreflex sensitivity. Given the ease of use and clinical utility, spontaneous methods are now also being used to examine cardiac baroreflex sensitivity in distinct subject groups during various laboratory stressors and tasks encountered during daily life, such as physical activity. However, the utility of such spontaneous measures to estimate cardiac baroreflex function during exercise remains unclear, particularly when comparing groups. Therefore, we tested the ability of spontaneous indices to detect age-related differences in cardiac baroreflex function during dynamic exercise. Beat-to-beat HR and BP were measured in eighteen healthy young subjects (24 ± 1 years) and sixteen healthy middle-aged subjects (59 ± 1 years) at rest and during steady-state leg cycling. Estimates of spontaneous cardiac baroreflex sensitivity using the sequence technique (GSEQ) and low-frequency transfer function gain (GTF) were compared with the operating point (GOP) and maximal gain (GMAX) of the full carotid–cardiac baroreflex function curve. At rest GSEQ, GTF, GOP and GMAX were all significantly lower in older subjects. During moderate-intensity steady-state exercise no differences were observed in GSEQ and GTF (older 0.26 ± 0.03 beats min−1 mmHg−1versus younger 0.32 ± 0.04 beats min−1 mmHg−1; P > 0.05), whereas GOP and GMAX (older −0.21 ± 0.02 beats min−1 mmHg−1versus younger −0.39 ± 0.03 beats min−1 mmHg−1; P < 0.05) remained lower in older subjects. These data indicate that spontaneous measures of cardiac baroreflex sensitivity alone provide limited information when comparing age-groups during exercise, which makes genuine differences in baroreflex function difficult to identify.

Arterial baroreceptors originating in the carotid arteries and aorta play a pivotal role in the rapid reflex adjustments that accompany acute cardiovascular stressors. There is now ample evidence to indicate that the arterial baroreflex remains functional during exercise by resetting in direct relation to the intensity of exercise from rest to maximum. Moreover, there is convincing evidence that a properly functioning arterial baroreflex is requisite for an appropriate neural cardiovascular response to exercise. Importantly, an understanding of the underlying means by which the baroreflex responds to changes in blood pressure has been elucidated. In this regard, both at rest and during exercise, alterations in stroke volume do not appear to contribute to the maintenance of arterial blood pressure (ABP) by the carotid baroreceptors (CBR), and therefore, any reflex-induced changes in cardiac output are the result of CBR-mediated changes in heart rate (HR). More importantly, it appears that CBR-induced changes in ABP are primarily mediated by alterations in vascular conductance with only minimal contributions from cardiac output. Therefore, the capacity of the CBR to regulate ABP depends critically on its ability to alter vascular tone both at rest and during exercise. Indeed, studies have clearly indicated that active and inactive skeletal muscle vascular beds contribute to mediating CBR-induced changes in ABP. The purpose of this review is to describe the mechanisms by which the CBR responds to alterations in ABP both at rest and during exercise in humans with a particular emphasis on the importance of baroreflex-mediated vascular responses.