Passive Limb Movement: Evidence of Mechanoreflex Sex Specificity

Previous studies have determined that premenopausal women exhibit an attenuated metaboreflex; however, little is known about sex specificity of the mechanoreflex. Thus, we sought to determine if sex differences exist in the central and peripheral hemodynamic responses to passive limb movement. Second-by-second measurements of heart rate, stroke volume, cardiac output (CO), mean arterial pressure, and femoral artery blood flow (FBF) were recorded during 3 min of supine passive knee extension in 24 young healthy subjects (12 women and 12 men). Normalization of CO and stroke volume to body surface area, expressed as cardiac index and stroke index, eliminated differences in baseline central hemodynamics, whereas, peripherally, basal FBF and femoral vascular conductance were similar between the sexes. In response to passive limb movement, women displayed significantly attenuated peak central hemodynamic responses compared with men (heart rate: 9.0 ± 1 vs. 14.8 ± 2% change, stroke index: 4.5 ± 0.6 vs. 7.8 ± 1.2% change, cardiac index: 9.6 ± 1 vs. 17.2 ± 2% change, all P \u3c 0.05), whereas movement induced similar increases in peak FBF (167 ± 32 vs. 193 ± 17% change) and femoral vascular conductance (172 ± 31 vs. 203 ± 16% change) in both sexes (women vs. men, respectively). Additionally, there was a significant positive relationship between individual peak FBF and peak CO response to passive movement in men but not in women. Thus, although both sexes exhibited similar movement-induced hyperemia and peripheral vasodilatory function, the central hemodynamic response was blunted in women, implying an attenuated mechanoreflex. Therefore, this study reveals that, as already recognized with the metaboreflex, there is likely a sex-specific attenuation of the mechanoreflex in women

Heart Failure and Movement-induced Hemodynamics: Partitioning the Impact of Central and Peripheral Dysfunction

BACKGROUND: The complex pathophysiology of heart failure (HF) creates a challenging paradigm to differentiate the role of central and peripheral hemodynamic dysfunction during conventional exercise. Adopting a novel reductionist approach with potential clinical relevance, we studied the central and peripheral contributors to both continuous and single passive leg movement (PLM)-induced hyperemia in 14 HF patients with reduced ejection fraction (HFrEF) and 13 controls. METHODS: Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure (MAP), and femoral artery blood flow (FBF) were recorded during PLM. RESULTS: The FBF response (area under the curve; AUC) to 60s of continuous PLM was attenuated in the HFrEF (25±15ml AUC) compared to controls (199±34ml AUC) as were peak changes from baseline for FBF, leg vascular conductance (LVC), CO, and HR. During single PLM, increases in CO and HR were smaller and no longer different between groups, supporting the use of this modality to assess groups with disparate central hemodynamics. Interestingly, single PLM-induced hyperemia, likely predominantly driven by flow-mediated vasodilation due to minimal vessel deformation, was essentially nonexistent in the HFrEF (-9±10ml AUC) in contrast to the controls (43±25ml AUC). CONCLUSIONS: These data fail to support a HFrEF-associated exaggeration in the mechanoreceptor driven component of the exercise pressor response. In fact, by exhibiting limited central hemodynamic responses compared to the controls, the observed attenuation in movement-induced FBF in HFrEF appears largely due to peripheral vascular dysfunction, particularly flow-mediated vasodilation

Acute, Quercetin-Induced Reductions in Blood Pressure in Hypertensive Individuals Are Not Secondary to Lower Plasma Angiotensin-Converting Enzyme Activity or Endothelin-1: Nitric Oxide

Quercetin (Q) reduces blood pressure (BP) in hypertensive individuals, but the mechanism is unknown. We hypothesized that acute Q aglycone administration reduces BP in hypertensive men by decreasing angiotensin-converting enzyme (ACE) activity and/or by lowering the ratio of circulating endothelin-1 (ET-1) to nitric oxide and that these alterations will improve endothelial function. Using a double-blind, placebo-controlled, crossover design Q or placebo (P) was administered to normotensive men (n = 5; 24 ± 3 years; 24 ± 4 kg/m(2)) and stage 1 hypertensive men (n = 12; 41 ± 12 years; 29 ± 5 kg/m(2)). As anticipated, ingesting 1095 mg Q did not affect BP in normotensive men but resulted in maximal plasma Q (2.3 ± 1.8 μmol/L) at approximately 10 hours, with Q returning to baseline concentrations (0.4 ± 0.08 μmol/L) by approximately 17 hours. Results from this study provided rationale for determining end-points of interest in stage 1 hypertensive men 10 hours after ingesting Q or P. In stage 1 hypertensive individuals, plasma Q increased(0.6 ± 0.4 vs. 0.05 ± 0.02 μmol/L), and mean BP decreased (103 ± 7 vs 108 ± 7 mm Hg; both P \u3c .05) 10 hours after Q vs P, respectively. Plasma ACE activity (16 ± 10 vs 18 ± 10 U/L), ET-1 (1.6 ± 0.9 vs 1.6 ± 0.8 pg/ml), nitrites (57.0 ± 3.0 vs 56.7 ± 2.6 μmol/L), and brachial artery flow-mediated dilation (6.2 ± 2.9 vs. 6.3 ± 3.2%) were unaffected by Q. A single dose of Q aglycone reduces BP in hypertensive men through a mechanism that is independent of changes in ACE activity, ET-1, or nitric oxide bioavailability and without affecting vascular reactivity

Does Brachial Artery Flow-Mediated Vasodilation Provide a Bioassay for NO?

This study sought to better define the role of NO in brachial artery flow-mediated vasodilation (FMD) in young, healthy humans. Brachial artery blood velocity and diameter were determined (ultrasound Doppler) in 8 volunteers (26 ± 1 year) before and after 5-minute forearm circulatory occlusion with and without intra-arterial infusion of the endothelial NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 0.48 mg/dL per minute). Control (CON) and L-NMMA trials were performed with the occlusion cuff placed in the traditional distal position, as well as proximal to the measurement site. FMD was significantly reduced, but not abolished, by L-NMMA in the distal cuff trial (8.9 ± 1.3%-6.0 ± 0.7%, CON versus L-NMMA; P=0.02), with no effect of L-NMMA on FMD with proximal cuff placement (10.6 ± 1.2%-12.4 ± 1.7%, CON versus L-NMMA; P=0.39). When the reduction in shear stimulus after L-NMMA was taken into account, no drug difference was observed for either distal (0.26 ± 0.02-0.23 ± 0.03, CON versus L-NMMA; P=0.40) or proximal (0.23 ± 0.08-0.23 ± 0.03, CON versus L-NMMA; P=0.89) FMD trials. These findings challenge the assertion that NO is obligatory for brachial artery FMD and call into question the sensitivity of this procedure for noninvasive determination of NO bioavailability in young, healthy humans

Vascular Dysfunction and Chronic Obstructive Pulmonary Disease: The Role of Redox Balance

Chronic obstructive pulmonary disease is characterized by low pulmonary function, inflammation, free-radical production, vascular dysfunction and subsequently a greater incidence of cardiovascular disease. By administering an acute oral antioxidant cocktail to patients with chronic obstructive pulmonary disease (n=30) and controls (n=30), we sought to determine the role of redox balance in the vascular dysfunction of these patients. Using a double blind, randomized, placebo controlled, crossover design, patients with chronic obstructive pulmonary disease and controls ingested placebo or the antioxidant cocktail (Vitamin-C, Vitamin-E, α-lipoic acid) after which brachial artery flow mediated dilation and carotid-radial pulse wave velocity were assessed using ultrasound Doppler. The patients exhibited lower baseline antioxidant levels (Vitamin-C and superoxide dismutase activity) and higher levels of oxidative stress (Thiobarbituic acid reactive species) in comparison to controls. The patients also displayed lower basal flow mediated dilation (p\u3c0.05), which was significantly improved with antioxidant cocktail (3.1±0.5 vs. 4.7±0.6 %, p\u3c0.05, placebo vs. antioxidant cocktail), but not controls (6.7±0.6 vs. 6.9±0.7 %, p\u3e0.05, placebo vs. antioxidant cocktail). The antioxidant cocktail also improved pulse wave velocity in the patients (14±1 vs. 11±1 m·s−1, p\u3c0.05, placebo vs. antioxidant cocktail), while not affecting controls (11±2 vs. 10±1 m·s−1, p\u3e0.05, placebo vs. antioxidant). Patients with chronic obstructive pulmonary disease exhibit vascular dysfunction, likely mediated by an altered redox balance, which can be acutely mitigated by an oral antioxidant. Therefore, free radically-mediated vascular dysfunction may be an important mechanism contributing to this population’s greater risk and incidence of cardiovascular disease

The Mechanoreflex and Hemodynamic Response to Passive Leg Movement in Heart Failure

BACKGROUND: Sensitization of mechanosensitive afferents, which contribute to the exercise pressor reflex, has been recognized as a characteristic of patients with heart failure (HF); however, the hemodynamic implications of this hypersensitivity are unclear. OBJECTIVES: The present study used passive leg movement (PLM) and intrathecal injection of fentanyl to blunt the afferent portion of this reflex arc to better understand the role of the mechanoreflex on central and peripheral hemodynamics in HF. METHODS: Femoral blood flow (FBF), mean arterial pressure, femoral vascular conductance, HR, stroke volume, cardiac output, ventilation, and muscle oxygenation of the vastus lateralis were assessed in 10 patients with New York Heart Association class II HF at baseline and during 3 min of PLM both with fentanyl and without (control). RESULTS: Fentanyl had no effect on baseline measures but increased (control vs fentanyl, P \u3c 0.05) the peak PLM-induced change in FBF (493 ± 155 vs 804 ± 198 ΔmL·min(-1)) and femoral vascular conductance (4.7 ± 2 vs 8.5 ± 3 ΔmL·min(-1)·mm Hg)(-1) while norepinephrine spillover (103% ± 19% vs 58% ± 17%Δ) and retrograde FBF (371 ± 115 vs 260 ± 68 ΔmL·min(-1)) tended to be reduced (P \u3c 0.10). In addition, fentanyl administration resulted in greater PLM-induced increases in muscle oxygenation, suggestive of increased microvascular perfusion. Fentanyl had no effect on the ventilation, mean arterial pressure, HR, stroke volume, or cardiac output response to PLM. CONCLUSIONS: Although movement-induced central hemodynamics were unchanged by afferent blockade, peripheral hemodynamic responses were significantly enhanced. Thus, in patients with HF, a heightened mechanoreflex seems to augment peripheral sympathetic vasoconstriction in response to movement, a phenomenon that may contribute to exercise intolerance in this population

Vascular Function and Multiple Sclerosis

Multiple sclerosis (MS) is a debilitating disease with an assumed autoimmune etiology which may lead to elevated oxidative stress, vascular dysfunction, and subsequent predisposition to cardiovascular disease. Therefore, the primary aim of this study was to evaluate vascular function and the potential role of oxidative stress in patients diagnosed with MS compared to healthy controls (C). Fourteen patients with relapsing-remitting MS (47 ± 3 years) and 13 age- and activity-matched controls (44 ± 5 years) underwent brachial artery flow-mediated dilation (FMD) and reactive hyperemia testing using ultrasound Doppler. Venous blood was analyzed for C-reactive protein (CRP), lipid hydroperoxides (LH), the ferric reducing ability of plasma (FRAP), superoxide dismutase (SOD), and catalase activity. CRP [1.8 ± 0.5 mg/L (MS), 1.0 ± 0.5 mg/L (C)] and LH [1.2 ± 0.2 μmol/L (MS), 1.1 ± 0.1 μmol/L (C)] were not different between MS patients and controls. FMD [8.0 ± 1.2% (MS) and 9.2 ± 1.6% (C)] and reactive hyperemia [380 ± 61 mL (MS) and 402 ± 69 mL (C)] were also not different between groups. Vascular function, as assessed by both FMD and reactive hyperemia, was not impaired in patients with MS compared to controls. Further, there was no evidence of elevated systemic inflammation or oxidative stress in these patients, who were currently all in remission. These findings suggest that impaired vascular function, elevated inflammation and oxidative stress are not an obligatory accompaniment to MS

A Differing Role of Oxidative Stress in the Regulation of Central and Peripheral Hemodynamics during Exercise in Heart Failure

This study sought to characterize the role of free radicals in regulating central and peripheral hemodynamics at rest and during exercise in patients with heart failure (HF). We examined cardiovascular responses to dynamic handgrip exercise (4, 8, and 12 kg at 1 Hz) following consumption of either a placebo or acute oral antioxidant cocktail (AOC) consisting of vitamin C, E, and α-lipoic acid in a balanced, crossover design. Central and peripheral hemodynamics, mean arterial pressure, cardiac index, systemic vascular resistance (SVR), brachial artery blood flow, and peripheral (arm) vascular resistance (PVR) were determined in 10 HF patients and 10 age-matched controls. Blood assays evaluated markers of oxidative stress and efficacy of the AOC. When compared with controls, patients with HF exhibited greater oxidative stress, measured by malondialdehyde (+36%), and evidence of endogenous antioxidant compensation, measured by greater superoxide dismutase activity (+83%). The AOC increased plasma ascorbate (+50%) in both the HF patients and controls, but significant systemic hemodynamic effects were only evident in the patients with HF, both at rest and throughout exercise. Specifically, the AOC reduced mean arterial pressure (-5%) and SVR (-12%) and increased cardiac index (+7%) at each workload. In contrast, peripherally, brachial artery blood flow and PVR (arm) were unchanged by the AOC. In conclusion, these data imply that SVR in patients with HF is, at least in part, mediated by oxidative stress. However, this finding does not appear to be the direct result of muscle-specific changes in PVR

Human Skeletal Muscle Feed Arteries Studied in Vitro: The Effect of Temperature on α(1)-Adrenergic Responsiveness

Heat and cold exposure can decrease and increase total peripheral resistance, respectively, in humans. With unique access to human skeletal muscle feed arteries, we sought both to characterize these vessels and to determine the interaction between temperature and α(1)-adrenergic receptor responsiveness. We hypothesized that α(1)-mediated vasocontraction of human feed arteries would be attenuated in response to 39 or 35°C. Skeletal muscle feed arteries were harvested from thirty-two human volunteers and studied using isometric techniques. Vessel function was assessed using KCl, sodium nitroprusside (SNP), phenylephrine (PE) and ACh dose-response curves to characterize non-receptor- and receptor-mediated vasocontraction and vasorelaxation. Single doses of PE (1 mm) and KCl (100 mm) were administered at 37°C and then, in a balanced design, repeated at both 35 and 39°C. The KCl and PE dose-response curves elicited significant vasocontraction (2009 ± 407 and 1974 ± 508 mg developed tension, respectively), whereas SNP and ACh induced the expected vasorelaxation (102 ± 6 and 73 ± 10% relaxation, respectively). Altering the temperature had no effect on inherent smooth muscle function (KCl response), but both a reduction (35°C) and an increase in temperature (39°C) decreased the vasocontractile response to 1 mm PE (37°C, 1478 ± 338 mg; 35°C, 546 ± 104 mg; and 39°C, 896 ± 202 mg; P \u3c 0.05) or across PE dose (P \u3c 0.05, 35 and 39 versus 37°C). Despite clear heterogeneity between both the human volunteers and the feed arteries themselves, this novel approach to the procurement of human vessels revealed a robust \u27inverted U\u27 response to altered temperature, such that α(1)-mediated vasocontraction was attenuated with either warming or cooling

Contribution of Nitric Oxide to Brachial Artery Vasodilation during Progressive Handgrip Exercise in the Elderly

The reduction in nitric oxide (NO)-mediated vascular function with age has largely been determined by flow-mediated dilation (FMD). However, in light of recent uncertainty surrounding the NO dependency of FMD and the recognition that brachial artery (BA) vasodilation during handgrip exercise is predominantly NO-mediated in the young, we sought to determine the contribution of NO to BA vasodilation in the elderly using the handgrip paradigm. BA vasodilation during progressive dynamic (1 Hz) handgrip exercise performed at 3, 6, 9, and 12 kg was assessed with and without NO synthase (NOS) inhibition [intra-arterial NG-monomethyl-l-arginine (l-NMMA)] in seven healthy older subjects (69 ± 2 yr). Handgrip exercise in the control condition evoked significant BA vasodilation at 6 (4.7 ± 1.4%), 9 (6.5 ± 2.2%), and 12 kg (9.5 ± 2.7%). NOS inhibition attenuated BA vasodilation, as the first measurable increase in BA diameter did not occur until 9 kg (4.0 ± 1.8%), and the change in BA diameter at 12 kg was reduced by ∼30% (5.1 ± 2.2%), with unaltered shear rate (Control: 407 ± 57, l-NMMA: 427 ± 67 s−1). Although shifted downward, the slope of the relationship between BA diameter and shear rate during handgrip exercise was unchanged (Control: 0.0013 ± 0.0004, l-NMMA: 0.0011 ± 0.007, P = 0.6) as a consequence of NOS inhibition. Thus, progressive handgrip exercise in the elderly evokes a robust BA vasodilation, the magnitude of which was only minimally attenuated following NOS inhibition. This modest contribution of NO to BA vasodilation in the elderly supports the use of the handgrip exercise paradigm to assess NO-dependent vasodilation across the life span