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NEW FINDINGS What is the central question of this study? The prevalence of hypertension in black individuals exceeds that in other racial groups. Despite this well-known heightened risk, the underlying contributory factors remain incompletely understood. We hypothesized that young black men would exhibit augmented beat-to-beat blood pressure variability compared with white men and that black men would exhibit augmented total peripheral resistance variability. What is the main finding and its importance? We demonstrate that young, healthy black men exhibit greater resting beat-to-beat blood pressure variability compared with their white counterparts, which is accompanied by greater variability in total peripheral resistance. These swings in blood pressure over time might contribute to the enhanced cardiovascular risk profile in black individuals. ABSTRACT The prevalence of hypertension in black (BL) individuals exceeds that in other racial groups. Recently, resting beat-to-beat blood pressure (BP) variability has been shown to predict cardiovascular risk and detect target organ damage better than ambulatory BP monitoring. Given the heightened risk in BL individuals, we hypothesized young BL men would exhibit augmented beat-to-beat BP variability compared with white (WH) men. Furthermore, given studies reporting reduced vasodilatation and augmented vasoconstriction in BL individuals, we hypothesized that BL men would exhibit augmented variability in total peripheral resistance (TPR). In 45 normotensive men (24 BL), beat-to-beat BP (Finometer) was measured during 10-20 min of quiet rest. Cardiac output and TPR were estimated (Modelflow method). Despite similar resting BP, BL men exhibited greater BP standard deviation (e.g. systolic BP SD; BL, 7.1 ± 2.2 mmHg; WH, 5.4 ± 1.5 mmHg; P = 0.006) compared with WH men, which was accompanied by a greater TPR SD (P = 0.003), but not cardiac output SD (P = 0.390). Other traditional measures of variability provided similar results. Histogram analysis indicated that BL men exhibited a greater percentage of cardiac cycles with BPs higher (> +10 mmHg higher) and lower (< -8 mmHg lower) than mean systolic BP compared with WH men (interaction, P

NEW FINDINGS What is the central question of this study? Water drinking increases muscle sympathetic nerve activity (MSNA), and it increases arterial blood pressure (ABP) in older populations but not in young healthy subjects. Does an increase in gain of arterial baroreflex control of MSNA contribute to maintenance of ABP after water drinking in healthy young subjects? What is the main finding and its importance? The gain of arterial baroreflex control of MSNA was increased and remained elevated 60 min after water drinking (500 ml) but remained unchanged after saline intake. An enhancement in gain of arterial baroreflex control of MSNA contributes to the maintenance of ABP after water drinking in young healthy subjects, probably via osmosensitive mechanisms. ABSTRACT Water drinking increases muscle sympathetic nerve activity (MSNA), which is accompanied by a profound pressor response in patients with impaired arterial baroreflex function and in older populations, but not in healthy young subjects. We tested the hypothesis that an enhancement in the gain of arterial baroreflex control of MSNA contributes to the maintenance of arterial blood pressure after water drinking in healthy young subjects. The MSNA, arterial blood pressure and heart rate were measured in 10 healthy men (24 ± 2 years old; mean ± SD) before and for 60 min after ingestion of 500 ml of bottled water or saline solution. 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. After water drinking, MSNA was significantly elevated within 15 min and remained above baseline for up to 60 min [e.g. 21 ± 10 bursts (100 heart beats)-1 mmHg-1 at baseline versus 35 ± 14 bursts (100 heart beats)-1 mmHg-1 at 30 min; P < 0.01], whereas mean arterial blood pressure (e.g. 87 ± 7 mmHg at baseline versus 89 ± 7 mmHg at 30 min; P = 0.34) and heart rate were unchanged. The arterial baroreflex-MSNA gain for bursts incidence was increased and remained elevated throughout the protocol [e.g. -2.25 ± 0.99 bursts (100 heart beats)-1 mmHg-1 at baseline versus -4.32 ± 1.53 bursts (100 heart beats)-1 mmHg-1 at 30 min; P < 0.01]. Importantly, saline intake had no effect on arterial baroreflex-MSNA gain or any neurocardiovascular variables. These findings demonstrate that water drinking enhances the gain of arterial baroreflex control of MSNA in healthy young men, which may contribute to buffering the pressor response after water drinking, probably via osmosensitive mechanisms.

NEW FINDINGS What is the central question of this study? We aimed to examine leg vascular responses to brief periods of inactivity. What is the main finding and its importance? We demonstrate that a mere 10 min of sitting is sufficient to impair leg microvascular function (reactive hyperaemia). However, conduit artery vasodilatation (flow-mediated dilatation) was unaffected, indicating maintained macrovascular function. Interestingly, immobile supine rest also resulted in a reduction in microvascular function alone that was prevented when calf muscle contractions were performed. Collectively, these data highlight the susceptibility of the microcirculation to short periods of inactivity and the beneficial role of skeletal muscle contraction for vascular health. ABSTRACT Prolonged sitting for 1-6 h has been shown to impair leg macrovascular [i.e. reduced flow-mediated dilatation (FMD)] and microvascular (i.e. reduced reactive hyperaemia) function. These impairments appear to be mediated through reductions in shear stress. Interestingly, a reduction in shear rate has been observed as early as 10 min into sitting. However, it is unknown whether this acute reduction in shear stress is sufficient to affect vascular function. Accordingly, we studied 18 young men and assessed popliteal artery FMD and reactive hyperaemia before (Baseline) and after (PostSit) a 10 min sitting period. Popliteal artery shear rate was significantly reduced during sitting (Baseline, 62 ± 35 s-1 ; 10 min sitting, 27 ± 13 s-1 ; P

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 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 to age matched healthy controls (n = 8). T2D patients exhibited greater basal intracellular ROS (mean±SD, +3.4 ± 1.4 fold; P

New findings What is the topic of this review? This review summarizes and synthesizes what is known about the contribution of inflammation to age-related arterial dysfunction. What advances does it highlight? This review details observational evidence for the relationship of age-related inflammation and arterial dysfunction, insight from autoimmune inflammatory diseases and their effects on arterial function, interventional evidence linking inflammation and age-related arterial dysfunction, insight into age-related arterial inflammation from preclinical models and interventions to ameliorate age-related inflammation and arterial dysfunction. Abstract Advanced age is a primary risk factor for cardiovascular disease, the leading cause of death in the industrialized world. Two major components of arterial ageing are stiffening of the large arteries and impaired endothelium-dependent dilatation in multiple vascular beds. These two alterations are major contributors to the development of overt cardiovascular disease. Increasing inflammation with advanced age is likely to play a role in this arterial dysfunction. The purpose of this review is to synthesize what is known about inflammation and its relationship to age-related arterial dysfunction. This review discusses both the initial observational evidence for the relationship of age-related inflammation and arterial dysfunction and the evidence that inflammatory autoimmune diseases are associated with a premature arterial ageing phenotype. We next discuss interventional and mechanistic evidence linking inflammation and age-related arterial dysfunction in older adults. We also attempt to summarize the relevant evidence from preclinical models. Lastly, we discuss interventions in both humans and animals that have been shown to ameliorate age-related arterial inflammation and dysfunction. The available evidence provides a strong basis for the role of inflammation in both large artery stiffening and impairment of endothelium-dependent dilatation; however, the specific inflammatory mediators, the initiating factors and the relative importance of the endothelium, smooth muscle cells, perivascular adipose tissue and immune cells in arterial inflammation are not well understood. With the expansion of the ageing population, ameliorating age-related arterial inflammation represents an important potential strategy for preserving vascular health in the elderly.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

Central command and the exercise pressor reflex can independently reset the carotid baroreflex (CBR) during exercise. The present investigation assessed the interactive relationship between these two neural mechanisms in mediating baroreflex resetting during exercise. Six men performed static leg exercise at 20% maximal voluntary contraction under four conditions: control, no perturbation; neuromuscular blockade (NMB) induced by administration of the neuromuscular blocking agent Norcuron (central command activation); MAST, application of medical antishock trousers inflated to 100 mmHg (exercise pressor reflex activation); and Combo, NMB plus MAST (concomitant central command and exercise pressor reflex activation). With regard to CBR control of heart rate (HR), both NMB and Combo conditions resulted in a further resetting of the carotid-cardiac stimulus-response curve compared to control conditions, suggesting that CBR-HR resetting is predominately mediated by central command. In contrast, it appears that CBR control of blood pressure can be mediated by signals from either central command or the exercise pressor reflex, since both NMB and MAST conditions equally augmented the resetting of the carotid-vasomotor stimulus-response curve. With regard to the regulation of both HR and blood pressure, the extent of CBR resetting was greater during the Combo condition than during overactivation of either central command or the exercise pressor reflex alone. Therefore, we suggest that central command and the exercise pressor reflex interact such that signals from one input facilitate signals from the other, resulting in an enhanced resetting of the baroreflex during exercise.

Within the past 20 years numerous animal and human experiments have provided supportive evidence of arterial baroreflex resetting during exercise. In addition, it has been demonstrated that both the feedforward mechanism of central command and the feedback mechanism associated with skeletal muscle afferents (the exercise pressor reflex) play both independent and interactive roles in the resetting of the arterial baroreflex with exercise. A fundamental alteration associated with baroreflex resetting during exercise is the movement of the operating point of the reflex away from the centring point and closer to the threshold, thereby increasing the ability of the reflex to buffer hypertensive stimuli. Recent studies suggest that central command and the cardiopulmonary baroreceptors may play a role in this movement of the operating point on the baroreflex-heart rate and baroreflex-blood pressure curve, respectively. Current research is focusing on the investigation of central neural mechanisms involved in cardiovascular control, including use of electrophysiological and molecular biological techniques in rat and mouse models to investigate baroreflex resetting as well as use of state of the art brain imaging techniques in humans. However, the purpose of this review is to describe the role of the arterial baroreflex in the regulation of arterial blood pressure during physical activity from a historical perspective with a particular emphasis on human investigations.

The autonomic adjustments to exercise are mediated by central signals from the higher brain (central command) and by a peripheral reflex arising from working skeletal muscle (exercise pressor reflex), with further modulation provided by the arterial baroreflex. Although it is clear that central command, the exercise pressor reflex and the arterial baroreflex are all requisite for eliciting appropriate cardiovascular adjustments to exercise, this review will be limited primarily to discussion of central command. Central modulation of the cardiovascular system via descending signals from higher brain centres has been well recognized for over a century, yet the specific regions of the human brain involved in this exercise-related response have remained speculative. Brain mapping studies during exercise as well as non-exercise conditions have provided information towards establishing the cerebral cortical structures in the human brain specifically involved in cardiovascular control. The purpose of this review is to provide an update of current concepts on central command in humans, with a particular emphasis on the regions of the brain identified to alter autonomic outflow and result in cardiovascular adjustments.

The variable pressure neck chamber has provided an invaluable research tool for the non-invasive assessment of carotid baroreflex (CBR) function in human investigations. The ability to construct complete stimulus-response curves and define specific parameters of the reflex function curve permits statistical comparisons of baroreflex function between different experimental conditions, such as rest and exercise. Results have convincingly indicated that the CBR stimulus-response curve is reset during exercise in an intensity-dependent manner to functionally operate around the prevailing pressure elicited by the exercise workload. Furthermore, both at rest and during exercise, alterations in stroke volume do not contribute importantly to the maintenance of arterial blood pressure by the carotid baroreceptors, and therefore, any reflex-induced changes in cardiac output (Q) are the result of CBR-mediated changes in heart rate. However, more importantly, the CBR-induced changes in mean arterial pressure (MAP) are primarily mediated by alterations in vascular conductance with only minimal contributions from Q to the initial reflex MAP response. Thus, the capacity of the CBR to regulate blood pressure depends critically on its ability to alter vascular tone both at rest and during exercise. This review will emphasize the utility of the variable pressure neck chamber to assess CBR function in human experimental investigations and the mechanisms by which the CBR responds to alterations in arterial blood pressure both at rest and during exercise.

Although square-wave sustained and R wave-triggered pulsatile stimuli have been used to assess carotid baroreflex (CBR) function in humans, it remains unclear whether these different stimulus protocols elicit comparable responses and whether CBR responses adapt during prolonged stimulation. Thus, we measured muscle sympathetic nerve activity (MSNA), heart rate (HR) and mean arterial pressure (MAP) in response to +30 Torr neck pressure (NP) and -30 Torr neck suction (NS) delivered for 20 s either as a sustained or pulsatile stimulus. CBR-mediated changes in MSNA, HR and MAP were similar with sustained and pulsatile stimuli. The time course of MSNA and HR responses identified that significant changes occurred during the initial 5 s and were better maintained over 20 s with NP than with NS. Changes in MAP exhibited a slower onset with the peak increase during NP occurring at 10 s (sustained, 7 +/- 1 mmHg; pulsatile, 7 +/- 1 mmHg; P > 0.05) and the nadir during NS occurring at 20 s (sustained, -7 +/- 1 mmHg; pulsatile, -9 +/- 2 mmHg; P > 0.05). These data demonstrate that sustained and pulsatile NP and NS produce comparable CBR-mediated responses. Furthermore, despite MSNA and HR returning towards baseline during NS, CBR-mediated changes in MAP are well maintained over 20 s of NS and NP.

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; P0.05) or MSNA burst frequency (young, Δ11 ± 2 bursts min(-1) versus older, Δ9 ± 1 bursts min(-1); P0.05) 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); P0.05 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.

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 (P0.01), while mean MCA V (MCA V(mean)) 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; P0.01), 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 V(mean)/MAP; CVCi) was only decreased during moderate exercise in older subjects (P0.01) 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.

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) (P0.01) and cardiac output by approximately 40% (P0.05), 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%; P0.01) and CBF (approximately 12%; P0.01) during static handgrip, as well as the increase in MCA V(mean) during cycling (approximately 15%; P0.01), were abolished by glycopyrrolate (P0.05). 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.

Central command and the exercise pressor reflex can independently reset the carotid baroreflex (CBR) during exercise. The present investigation assessed the interactive relationship between these two neural mechanisms in mediating baroreflex resetting during exercise. Six men performed static leg exercise at 20% maximal voluntary contraction under four conditions: control, no perturbation; neuromuscular blockade (NMB) induced by administration of the neuromuscular blocking agent Norcuron (central command activation); MAST, application of medical antishock trousers inflated to 100 mmHg (exercise pressor reflex activation); and Combo, NMB plus MAST (concomitant central command and exercise pressor reflex activation). With regard to CBR control of heart rate (HR), both NMB and Combo conditions resulted in a further resetting of the carotid-cardiac stimulus-response curve compared to control conditions, suggesting that CBR-HR resetting is predominately mediated by central command. In contrast, it appears that CBR control of blood pressure can be mediated by signals from either central command or the exercise pressor reflex, since both NMB and MAST conditions equally augmented the resetting of the carotid-vasomotor stimulus-response curve. With regard to the regulation of both HR and blood pressure, the extent of CBR resetting was greater during the Combo condition than during overactivation of either central command or the exercise pressor reflex alone. Therefore, we suggest that central command and the exercise pressor reflex interact such that signals from one input facilitate signals from the other, resulting in an enhanced resetting of the baroreflex during exercise.

Within the past 20 years numerous animal and human experiments have provided supportive evidence of arterial baroreflex resetting during exercise. In addition, it has been demonstrated that both the feedforward mechanism of central command and the feedback mechanism associated with skeletal muscle afferents (the exercise pressor reflex) play both independent and interactive roles in the resetting of the arterial baroreflex with exercise. A fundamental alteration associated with baroreflex resetting during exercise is the movement of the operating point of the reflex away from the centring point and closer to the threshold, thereby increasing the ability of the reflex to buffer hypertensive stimuli. Recent studies suggest that central command and the cardiopulmonary baroreceptors may play a role in this movement of the operating point on the baroreflex-heart rate and baroreflex-blood pressure curve, respectively. Current research is focusing on the investigation of central neural mechanisms involved in cardiovascular control, including use of electrophysiological and molecular biological techniques in rat and mouse models to investigate baroreflex resetting as well as use of state of the art brain imaging techniques in humans. However, the purpose of this review is to describe the role of the arterial baroreflex in the regulation of arterial blood pressure during physical activity from a historical perspective with a particular emphasis on human investigations.