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Vasodilatory effects of insulin support the delivery of insulin and glucose to skeletal muscle. Concurrently, insulin exerts central effects that increase sympathetic nervous system activity (SNA), which is required for the acute maintenance of blood pressure (BP). Indeed, in a cohort of young healthy adults, herein we show that intravenous infusion of insulin increases muscle SNA while BP is maintained. We next tested the hypothesis that sympathoexcitation evoked by hyperinsulinemia restrains insulin-stimulated peripheral vasodilation and contributes to sustaining BP. To address this, a separate cohort of participants were subjected to 5-s pulses of neck suction (NS) to simulate carotid hypertension and elicit a reflex-mediated reduction in SNA. NS was conducted before and 60 min following intravenous infusion of insulin. Insulin infusion caused an increase in leg vascular conductance and cardiac output (CO; P < 0.050), with maintenance of BP (P = 0.540). As expected, following NS, decreases in BP were greater in the presence of hyperinsulinemia compared with control (P = 0.045). However, the effect of NS on leg vascular conductance did not differ between insulin and control conditions (P = 0.898). Instead, the greater decreases in BP following NS in the setting of insulin infusion paralleled with greater decreases in CO (P = 0.009). These findings support the idea that during hyperinsulinemia, SNA-mediated increase in CO, rather than restraint of leg vascular conductance, is the principal contributor to the maintenance of BP. Demonstration in isolated arteries that insulin suppresses α-adrenergic vasoconstriction suggests that the observed lack of restraint of leg vascular conductance may be attributed to sympatholytic actions of insulin. NEW & NOTEWORTHY We examined the role of sympathetic activation in restraining vasodilatory responses to hyperinsulinemia and sustaining blood pressure in healthy adults. Data are reported from two separate experimental protocols in humans and one experimental protocol in isolated arteries from mice. Contrary to our hypothesis, the present findings support the idea that during hyperinsulinemia, a sympathetically mediated increase in cardiac output, rather than restraint of peripheral vasodilation, is the principal contributor to the maintenance of systemic blood pressure.

Introduction It remains unclear if naturally occurring respiratory muscle (RM) work influences leg diffusive O2 transport during exercise in heart failure patients with reduced ejection fraction (HFrEF). In this retrospective study, we hypothesized that RM unloading during submaximal exercise will lead to increases in locomotor muscle O2 diffusion capacity (DMO2) contributing to the greater leg VO2. Methods Ten HFrEF patients and 10 healthy control matched participants performed two submaximal exercise bouts (i.e., with and without RM unloading). During exercise, leg blood flow was measured via constant infusion thermodilution. Intrathoracic pressure was measured via esophageal balloon. Radial arterial and femoral venous blood gases were measured and used to calculate leg arterial and venous content (CaO2 and CvO2, respectively), VO2, O2 delivery, and DMO2. Results From CTL to RM unloading, leg VO2, O2 delivery, and DMO2 were not different in healthy participants during submaximal exercise (all, p > .15). In HFrEF, leg VO2 (CTL: 0.7 ± 0.3 vs. RM unloading: 1.0 ± 0.4 L/min, p, Respiratory muscle work negatively influences convective O2 transport in heart failure patients. The present study investigated the impact of respiratory muscle work on leg O2 diffusive capacity during submaximal exercise. We found the degree of respiratory muscle unloading in heart failure patients is related to the improvement in leg O2 diffusive capacity during submaximal exercise.

NEW FINDINGS What is the central question of this study? What is the role of β2 -adrenergic receptor (β2 AR) vasodilatation in older postmenopausal women as compared to premenopausal women and the role of nitric oxide (NO) in β2 AR-mediated vasodilatation in both groups of women? What is the main finding and its importance? β2 AR responsiveness is blunted in postmenopausal women compared to young premenopausal women. Additionally, NO may contribute to β2 AR-mediated vasodilatation in young premenopausal women. ABSTRACT β2 -Adrenergic receptor (β2 AR)-mediated vasodilatation, which is partially dependent on nitric oxide (NO) formation, is blunted in men at risk for developing hypertension. However, the role of β2 AR vasodilatation in hypertension pathophysiology in ageing postmenopausal women is unclear. Therefore, the goals of this study were to determine if forearm vasodilatation to the selective β2 AR agonist terbutaline is blunted in older postmenopausal women (59 ± 4 years) compared to young premenopausal women (27 ± 3 years) and to assess NO contribution to β2 AR-mediated vasodilatation in both groups of women. Forearm blood flow (FBF) and forearm vascular conductance (FVC) were measured using venous occlusion plethysmography at baseline and during intra-arterial infusions of terbutaline at 0.1-2.0 µg (100 ml tissue)-1 min-1 with and without the NO synthase inhibitor l-NG -monomethylarginine (l-NMMA). Mean arterial pressure was significantly greater in postmenopausal women than in young women at baseline (P = 0.01). Baseline FBF and FVC did not differ between young and postmenopausal women (P > 0.05) and rose significantly within each group during terbutaline infusion (P 0.05 for all). These data suggest that β2 AR responsiveness is blunted in postmenopausal women compared to young premenopausal women, and that NO may contribute to β2 AR-mediated vasodilatation in young premenopausal women.

Individuals with high plasma norepinephrine (NE) levels at rest have a smaller reduction in resting energy expenditure (REE) following β ‐adrenergic blockade. If this finding extends to the response to a meal, it could have important implications for the role of the sympathetic nervous system in energy balance and weight gain. We hypothesized high muscle sympathetic nerve activity (MSNA) would be associated with a low sympathetically mediated component of energy expenditure following a meal. Fourteen young, healthy adults completed two visits randomized to continuous saline (control) or intravenous propranolol to achieve systemic β ‐adrenergic blockade. Muscle sympathetic nerve activity and REE were measured (indirect calorimetry) followed by a liquid mixed meal (Ensure). Measures of energy expenditure continued every 30 min for 5 h after the meal and are reported as an area under the curve (AUC). Sympathetic support of energy expenditure was calculated as the difference between the AUC during saline and β ‐blockade (AUC P ropranolol –AUC S aline , β ‐REE) and as a percent (%) of control (AUC P ropranolol ÷AUC S aline × 100). β ‐REE was associated with baseline sympathetic activity, such that individuals with high resting MSNA (bursts/100 heart beats) and plasma NE had the greatest sympathetically mediated component of energy expenditure following a meal (MSNA: β ‐REE R = −0.58, P = 0.03; %REE R = −0.56, P = 0.04; NE: β ‐REE R = −0.55, P = 0.0535; %REE R = −0.54, P = 0.0552). Contrary to our hypothesis, high resting sympathetic activity is associated with a greater sympathetically mediated component of energy expenditure following a liquid meal. These findings may have implications for weight maintenance in individuals with varying resting sympathetic activity.

Heart failure (HF) patients demonstrate impaired pulmonary, circulatory, and nervous system responses to exercise. While HF demonstrates prolonged [time constant (τ)] pulmonary O2 uptake (V̇o2) on-kinetics, contributing to exercise intolerance, it is unknown whether abnormal V̇o2 kinetics couple with ventilatory and circulatory dysfunction secondary to impaired group III/IV afferents in HF. Because lower lumbar intrathecal fentanyl inhibits locomotor muscle afferents, resulting in improved exercise ventilation and hemodynamics, we tested these hypotheses: HF will demonstrate 1) rapid V̇o2 on-kinetics and 2) attenuated steady-state V̇o2 amplitude and O2 deficit (O2def) during exercise with fentanyl versus placebo. On separate visits (randomized), breath-by-breath V̇o2 was measured in HF (ejection fraction: 27 ± 6%, New York Heart Association class I–III) and age- and sex-matched controls (both n = 9, ages: 60 ± 6 vs. 63 ± 8 yr, P = 0.37) during cycling transitions at 65% peak workload (78 ± 24 vs. 115 ± 39 W, P < 0.01) with intrathecal fentanyl or placebo. Regardless of group or condition, optimal phase II (primary component) curve fits reflected a phase I period equal to 35 s (limb-to-lung timing) via single-exponential functions. Condition did not affect steady-state V̇o2, the phase II τ of V̇o2, or O2def within controls ( P > 0.05). Without differences in steady-state V̇o2, reduced O2def in fentanyl versus placebo within HF (13 ± 4 vs. 22 ± 15 ml/W, P = 0.04) was accounted for by a rapid phase II τ of V̇o2 in fentanyl versus placebo within HF (45 ± 11 vs. 57 ± 14 s, P = 0.04), respectively. In an integrative manner, these data demonstrate important effects of abnormal locomotor muscle afferents coupled to pulmonary and circulatory dysfunction in determining impaired exercise V̇o2 in HF. Effects of abnormal muscle afferents on impaired exercise V̇o2 and hence exercise intolerance may not be discernable by independently assessing steady-state V̇o2 in HF. NEW & NOTEWORTHY Inhibition of locomotor muscle afferents results in rapid primary-component O2 uptake (V̇o2) on-kinetics accounting for the decreased O2 deficit in heart failure (HF). This study revealed that abnormal musculoskeletal–neural afferents couple with pulmonary and circulatory dysfunction to provoke impaired exercise V̇o2 in HF. Steady-state V̇o2 cannot properly phenotype abnormal muscle afferent contributions to impaired exercise V̇o2 in HF.

An independent association exists between sleep apnea and diabetes. Animal models suggest exposure to intermittent hypoxia, a consequence of sleep apnea, results in altered glucose metabolism and fasting hyperglycemia. However, it is unknown if acute exposure to intermittent hypoxia increases glucose concentrations in nondiabetic humans. We hypothesized plasma glucose would be increased from baseline following 3 h of intermittent hypoxia in healthy humans independent of any effect on insulin sensitivity. Eight (7M/1F, 21–34 years) healthy subjects completed two study visits randomized to 3 h of intermittent hypoxia or continuous normoxia, followed by an oral glucose tolerance test. Intermittent hypoxia consisted of 25 hypoxic events per hour where oxygen saturation (SpO2) was significantly reduced (Normoxia: 97 ± 1%, Hypoxia: 90 ± 2%, P 0.05). In contrast, circulating glucose concentrations were increased after 3 h of intermittent hypoxia when compared to baseline (5.0 ± 0.2 vs. 5.3 ± 0.2 mmol/L, P = 0.01). There were no detectable changes in insulin sensitivity following intermittent hypoxia when compared to continuous normoxia, as assessed by the oral glucose tolerance test (P > 0.05). Circulating glucose is increased after 3 h of intermittent hypoxia in healthy humans, independent of any lasting changes in insulin sensitivity. These novel findings could explain, in part, the high prevalence of diabetes in patients with sleep apnea and warrant future studies to identify underlying mechanisms.

Patients with type 1 diabetes mellitus exhibit impairments in autonomic and cardiovascular control which are worsened with acute hypoglycemia––thus increasing the risk of adverse cardiovascular events. Hypoxia, as seen with the common comorbidity of sleep apnea, may lead to further autonomic dysfunction and an increased risk of ventricular arrhythmias. Therefore, we hypothesized that heart rate variability (HRV) and baroreflex sensitivity (BRS) would be reduced during hypoglycemia in adults with type 1 diabetes, with a further decline when combined with hypoxia. Subjects with type 1 diabetes (n = 13; HbA1c = 7.5 ± 0.3 %, duration of diabetes = 17 ± 5 yrs) completed two 180 min hyperinsulinemic (2 mU/kg TBW/min), hypoglycemic (~3.3 µmol/mL) clamps separated by a minimum of 1 week and randomized to normoxia (SpO2 ~98 %) or hypoxia (SpO2 ~85 %). Heart rate (electrocardiogram) and blood pressure (finger photoplethysmography) were analyzed at baseline and during the hypoglycemic clamp for measures of HRV and spontaneous cardiac BRS (sCBRS). Hypoglycemia resulted in significant reductions in HRV and sCBRS when compared with baseline levels (main effect of hypoglycemia: p

Beta‐adrenergic vasodilator responses may be blunted in humans who are at an increased risk for hypertension. Because menopause is associated with an increase in blood pressure, we tested the hypothesis that forearm blood flow responses to the β‐adrenergic receptor agonist isoproterenol are blunted in older, postmenopausal women compared to young, premenopausal women. We used venous occlusion plethysmography to measure forearm blood flow in young premenopausal (26 ± 1 years; n = 13) and postmenopausal (61 ± 2 years; n = 12) women. Forearm blood flow and mean arterial pressure were measured at baseline and during isoproterenol infusion at 1.0, 3.0, 6.0, and 12.0 ng/100 mL tissue/min. The two groups did not differ in body mass index or mean arterial pressure. Baseline forearm blood flow was similar between young and postmenopausal women (3.7 ± 0.5 vs. 2.9 ± 0.4 mL/100 mL tissue/min, respectively; P > 0.05). At the lowest dose of isoproterenol, forearm blood flow vasodilator responses were lower in postmenopausal women compared with young women (5.8 ± 0.4 vs. 7.4 ± 0.3 mL/100 mL tissue/min, respectively; P < 0.05). Thereafter, forearm blood flow remained similar between the groups for the remaining isoproterenol doses. In conclusion, β‐adrenergic receptor‐mediated forearm vasodilator responses are blunted in healthy, older postmenopausal women at lower but not higher doses of isoproterenol. This suggests that in aging women, β‐adrenergic receptor‐mediated vasodilator responses may be blunted at a moderate level of stimulation while maximum receptor responses are preserved., This study assessed potential differences in β‐adrenergic receptor responsiveness to forearm isoproterenol infusion in young premenopausal and older postmenopausal women. Our data showed that β‐receptor vasodilator responses to low‐dose isoproterenol are blunted in postmenopausal women in comparison to young women, and responses to higher doses of isoproterenol are similar between the two groups. These results suggest that there is some attenuation of β‐receptor responsiveness in aging women while maximum vasodilator responses remain intact.

The purpose of this study was to compare hemodynamic and blood analyte responses to reduced central venous pressure (CVP) and pulse pressure (PP) elicited during graded lower body negative pressure (LBNP) to those observed during graded blood loss (BL) in conscious humans. We hypothesized that the stimulus-response relationships of CVP and PP to hemodynamic responses during LBNP would mimic those observed during BL. We assessed CVP, PP, heart rate, mean arterial pressure (MAP), and other hemodynamic markers in 12 men during LBNP and BL. Blood samples were obtained for analysis of catecholamines, hematocrit, hemoglobin, arginine vasopressin, and blood gases. LBNP consisted of 5-min stages at 0, 15, 30, and 45 mmHg of suction. BL consisted of 5 min at baseline and following three stages of 333 ml of hemorrhage (1,000 ml total). Individual r2 values and linear regression slopes were calculated to determine whether the stimulus (CVP and PP)-hemodynamic response trajectories were similar between protocols. The CVP-MAP trajectory was the only CVP-response slope that was statistically different during LBNP compared with BL (0.93 ± 0.27 vs. 0.13 ± 0.26; P = 0.037). The PP-heart rate trajectory was the only PP-response slope that was statistically different during LBNP compared with BL (−1.85 ± 0.45 vs. −0.46 ± 0.27; P = 0.024). Norepinephrine, hematocrit, and hemoglobin were all lower at termination in the BL protocol compared with LBNP ( P < 0.05). Consistent with our hypothesis, LBNP mimics the hemodynamic stimulus-response trajectories observed during BL across a significant range of CVP in humans.

An association between insulin resistance and activation of the sympathetic nervous system has been reported in previous studies. However, potential interactions between insulin sensitivity and sympathetic neural mechanisms in healthy people remain poorly understood. We conducted a study to determine the relationship between sympathetic activity and insulin resistance in young, healthy humans.Thirty-seven healthy adults (18-35 years, BMI28 kg m(-2)) were studied. Resting muscle sympathetic nerve activity (MSNA) was measured with microneurography and insulin sensitivity of glucose and free fatty acid metabolism was measured during a hyperinsulinemic-euglycemic clamp with two levels of insulin.During lower doses of insulin, we found a small association between lower insulin sensitivity and higher MSNA (P0.05) but age was a cofactor in this relationship. Overall, we found no difference in insulin sensitivity between groups of low and high MSNA, but when women were analyzed separately, insulin sensitivity was lower in the high MSNA group compared with the low MSNA group of women.These data suggest that MSNA and insulin sensitivity are only weakly associated with young healthy individuals and that age and sex may be important modifiers of this relationship.

The autonomic nervous system plays a central role in both acute and chronic blood pressure regulation in humans. The activity of the sympathetic branch of the autonomic nervous system is positively associated with peripheral resistance, an important determinant of mean arterial pressure in men. In contrast, there is no association between sympathetic nerve activity and peripheral resistance in women before menopause, yet a positive association after menopause. We hypothesized that autonomic support of blood pressure is higher after menopause in women. We examined the effect of ganglionic blockade on arterial blood pressure and how this relates to baseline muscle sympathetic nerve activity in 12 young (25±1 years) and 12 older postmenopausal (61±2 years) women. The women were studied before and during autonomic blockade using trimethaphan camsylate. At baseline, muscle sympathetic nerve activity burst frequency and burst incidence were higher in the older women (33±3 versus 15±1 bursts/min; 57±5 versus 25±2 bursts/100 heartbeats, respectively; P P P r =−0.74; P

Beta-adrenergic–blocking agents have long been prescribed as antihypertensive agents for many high-risk patients with cardiovascular diseases.1 However, beta-blockers, despite producing similar reductions in peripheral blood pressure (BP), may be less effective than other antihypertensive drugs in reducing stroke and cardiovascular mortality.2,3 The less-than-desirable cardiovascular protection provided by beta-blockers may be related to their lack of effectiveness in reducing central aortic BP and wave reflection. In this context, greater central aortic pressures and wave reflection have been observed with traditional nonvasodilating beta-blockers (i.e. atenolol) than with other antihypertensive drugs.4–10 Although the mechanisms responsible for these observations are unclear, they may be related to: (i) prolonged systolic ejection time (as a result of reductions in heart rate (HR)) and a delayed peak of the outgoing aortic pressure wave that allows pressure-wave reflections to augment the central aortic systolic pressure wave10; and/or (ii) a reduction in beta-adrenergically mediated peripheral vasodilation or an unmasking of alpha-adrenergically mediated vasoconstriction.11 The aortic augmentation index (AIx) provides information related to the contribution of wave reflection to the ascending aortic pressure waveform, and is defined as the proportion of central pulse pressure contributed by the late systolic peak, which is in turn attributed to the reflected pulse wave. Importantly, AIx is associated with cardiovascular risk as well as with all-cause and cardiovascular mortality.12,13 We previously demonstrated that acute systemic beta-blockade increased aortic wave reflection (i.e. AIx) in young normotensive adults, and that this effect was more pronounced in women than in men.14 Additionally, the mechanisms responsible for the increased wave reflection appeared to differ in males and females in that the beta-blocker–induced change in aortic wave reflection was associated with changes in HR in men whereas it was related to changes in total peripheral resistance (TPR) in women, in accord with a higher level of tonic beta-adrenergic vasodilator tone in younger women. Interestingly, beta-adrenergic receptor sensitivity in the peripheral vasculature appears to be lower in postmenopausal women than in their younger counterparts.15 With this information as a background, we conducted the present study to examine the effects of acute systemic beta-blockade on aortic wave reflection in older postmenopausal women. We hypothesized that postmenopausal women would have an attenuated change in aortic wave reflection during acute beta-blockade as compared with their younger counterparts.

The magnitude of decrease in blood pressure (BP) during a vasoactive drug bolus may be associated with the calculated baroreflex sensitivity (BRS). The purpose of the present study was to evaluate whether sympathetic and/or cardiac BRS relates to the extent of change in BP and whether this was altered by sex hormones. Fifty-one young women (27 ± 1 years), 14 older women (58 ± 1 years), and 36 young men (27 ± 1 years) were studied. Heart rate, BP, and muscle sympathetic nerve activity (MSNA) were monitored. Sympathetic BRS was analyzed using the slope of the MSNA-diastolic blood pressure (DBP) relationship and cardiac BRS was analyzed using the R–R interval-systolic blood pressure (SBP) relationship. Young women and men had similar mean arterial pressures (MAP, 91 ± 1 vs. 90 ± 1 mmHg), cardiac BRS (19 ± 1 vs. 21 ± 2 ms/mmHg), and sympathetic BRS (−6 ± 1 vs. −7 ± 1 AU/beat/mmHg), respectively. Older women had higher MAP (104 ± 4 mmHg, p

The use of microneurography to measure muscle sympathetic nerve activity has provided important insights in human physiology. However, placing microelectrodes into nerves can be challenging, particularly in certain patient populations. In this paper, we describe the use of real-time ultrasound guidance to assist with microneurography, including advantages, disadvantages, and proper training.

Chemoreceptors in the carotid bodies sense arterial oxygen tension and regulate respiration. Isolated carotid body glomus cells also sense glucose, and animal studies have shown the carotid bodies play a role in the counterregulatory response to hypoglycaemia. Thus, we hypothesized that glucose infusion rate would be augmented and neuro-hormonal counterregulation blunted during hypoglycaemia when the carotid bodies were desensitized by hyperoxia. Seven healthy adults (four male, three female) underwent two 180 min hyperinsulinaemic (2 mU (kg fat-free mass (FFM))(-1) min(-1)), hypoglycaemic (3.33 mmol l(-1)) clamps 1 week apart, randomized to either normoxia (arterial P(O2) (P(aO2)) 111 ± 6.3 mmHg) or hyperoxia (P(aO2) 345 ± 80.6 mmHg) (P0.05). Plasma glucose concentrations were similar during normoxia and hyperoxia at baseline (5.52 ± 0.15 vs. 5.55 ± 0.13 μmol ml(-1)) and during the clamp (3.4 ± 0.05 vs. 3.3 ± 0.05 μmol ml(-1)). The glucose infusion rate was 44.2 ± 3.5% higher (P0.01) during hyperoxia than normoxia at steady state during the clamp (28.2 ± 0.15 vs. 42.7 ± 0.65 μmol (kg FFM)(-1) min(-1); P0.01). Area under the curve values (expressed as percentage normoxia response) for counterregulatory hormones during hypoglycaemia were significantly suppressed by hyperoxia (noradrenaline 50.7 ± 5.2%, adrenaline 62.6 ± 3.3%, cortisol 63.2 ± 2.1%, growth hormone 53.1 ± 2.7%, glucagon 48.6 ± 2.1%, all P0.05 vs. normoxia). These data support the idea that the carotid bodies respond to glucose and play a role in the counterregulatory response to hypoglycaemia in humans.