Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults.

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.

Effect of Combined Grape Seed Extract and L-Citrulline Supplementation on Hemodynamic Responses to Exercise in Young Males.

Grape seed extract (GSE) or L-citrulline supplement has been known to increase nitric oxide (NO) bioavailability and enhance endothelial-mediated vasodilation. Accordingly, to examine the additive benefits of combination of the two supplementations on hemodynamic responses to dynamic exercise, young, healthy males were recruited for this study. Effects of 7 days of 1) GSE + L-citrulline, 2) GSE, 3) L-citrulline, and 4) placebo supplementation on systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), cardiac output, total vascular conductance (TVC), and oxygen (O2) consumption were examined at rest and during cycling exercise. Compared with placebo, GSE, L-citrulline, and combined supplementations did not reduce SBP, DBP, and MAP, while cardiac output (placebo; 23.6 ± 1.3 L/min, GSE; 25.7 ± 1.1 L/min; L-citrulline, 25.2 ± 1.2 L/min; GSE + L-citrulline; 25.3 ± 0.9 L/min) and TVC (placebo; 234.7 ± 11.3 ml/min/mmHg, GSE; 258.3 ± 10.6 ml/min/mmHg; L-citrulline, 255.2 ± 10.6 ml/min/mmHg; GSE + L-citrulline; 260.4 ± 8.9 ml/min/mmHg) were increased at only the 80% workload (p < 0.05). Compared with placebo and L-citrulline, GSE and combined supplementations had a reduction in VO2 across workloads (p < 0.05). However, there was no additive benefits on these variables. We conclude that supplementation with GSE, L-citrulline, and combined supplementations increased cardiac output due partially to decreased vascular resistance. Our findings suggest that GSE may act as an ergogenic aid that can improve O2 delivery to exercising muscles.

Reproducibility and diurnal variation in middle cerebral artery blood velocity in healthy humans.

NEW FINDINGS: What is the central question of this study? We sought to establish between-day reproducibility in estimates of middle cerebral artery blood velocity (MCAv) and cerebrovascular reactivity (CVR) in young, healthy male and female adults in tightly controlled experimental conditions. What is the main finding and its importance? Measures of MCAv assessed during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in CVR, with values being highest during the evening compared with the morning. Greater diurnal variation in CVR is associated with more efficient sleep and greater nocturnal blood pressure dipping. These data enhance our understanding of modulators of MCAv and CVR. ABSTRACT: Transcranial Doppler (TCD) is used to assess cerebral blood velocity (CBV) and cerebrovascular reactivity (CVR). Assessments of TCD reproducibility are limited, and few include multiple within-day measurements. We sought to establish reproducibility of CBV and CVR in healthy adults during three time periods (morning, afternoon and evening). We hypothesized that CBV and CVR measured at the same time of day are reproducible between days. We also hypothesized that CBV and CVR exhibit diurnal variation, with measurements being higher in the evening compared with morning/afternoon hours. Twelve adults [six male and six female, 27 years (95% CI, 22-31 years)] completed three measurements (morning, afternoon and evening) on two separate days in controlled conditions (e.g., meals, activity and sleep). Middle cerebral artery blood velocity (MCAv, TCD) was measured continuously at rest and during two CVR tests (end-expiratory apnoea and carbogen inhalation). Intraclass correlation coefficients for resting MCAv showed moderate to good reproducibility, which did not differ between morning, afternoon and evening (0.87, 0.56 and 0.67, respectively; P > 0.05). Intraclass correlation coefficients for peak MCAv during apnoea (0.80, 0.46 and 0.65, respectively; P > 0.05) and minute 2 of carbogen inhalation (0.81, 0.74 and 0.73, respectively; P > 0.05) were also not different from morning compared with afternoon/evening. Time of day had no effect on resting MCAv (F = 0.69, P = 0.51, ƞp 2  = 0.06) or the peak response to apnoea (F = 1.00, P = 0.39, ƞp 2  = 0.08); however, peak MCAv during carbogen breathing exhibited diurnal variation, with highest values in the evening (F = 3.41, P = 0.05, ƞp 2  = 0.24). Measures of CBV and CVR assessed via TCD during morning, afternoon and evening hours are reproducible between days. There is diurnal variation in the MCAv response to carbogen exposure, with CVR being highest during evening compared with morning hours.

Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans.

Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

Effects of chronic dietary grape seed extract supplementation on aortic stiffness and hemodynamic responses in obese/overweight males during submaximal exercise.

We investigated the effect of chronic grape seed extract (GSE) on blood pressure and aortic stiffness (AoS) among overweight and obese males. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (Q), total vascular conductance (TVC), and AoS were measured during two submaximal cycling exercises (40% and 60% VO2max), after 7 consecutive days of GSE or placebo (PL) ingestion with one week washout period. Compared with PL, GSE supplementation significantly decreased MAP at rest (85 ± 3 mmHg vs. 82 ± 3 mmHg), 40% (102 ± 3 mmHg vs. 99 ± 3 mmHg), and 60% workloads (109 ± 3 mmHg vs. 107 ± 3 mmHg) (P = 0.001, ES = 0.2). AoS was significantly reduced (13.0 ± 1.9 AU vs. 10.2 ± 1.0 AU) at rest (P = 0.002, ES = 0.6). Q was decreased at rest and across all workloads, but there were no significant differences (7.5 ± 0.4 L/min vs. 7.1 ± 0.4 L/min; 20.4 ± 1.2 L/min vs. 19.6 ± 0.9 L/min; 26.3 ± 1.1 L/min vs. 25.5 ± 1.6 L/min, respectively). GSE had no effect on HR, TVC, and SV. Our study indicates that chronic supplementation with GSE reduces arterial pressure at rest and during exercise primarily via the substantial reduction in AoS. Thus, GSE can be a dietary supplement to treat augmented blood pressure responses in obese and overweight males at rest and during exercise.Trial registration: ClinicalTrials.gov identifier: NCT04465110.

Hyperinsulinemia blunts sympathetic vasoconstriction: a possible role of ß-adrenergic activation.

Herein we report in a sample of healthy young men (n = 14) and women (n = 12) that hyperinsulinemia induces time-dependent decreases in total peripheral resistance and its contribution to the maintenance of blood pressure. In the same participants, we observe profound vasodilatory effects of insulin in the lower limb despite concomitant activation of the sympathetic nervous system. We hypothesized that this prominent peripheral vasodilation is possibly due to the ability of the leg vasculature to escape sympathetic vasoconstriction during systemic insulin stimulation. Consistent with this notion, we demonstrate in a subset of healthy men (n = 9) and women (n = 7) that systemic infusion of insulin blunts sympathetically mediated leg vasoconstriction evoked by a cold pressor test, a well-established sympathoexcitatory stimulus. Further substantiating this observation, we show in mouse aortic rings that insulin exposure suppresses epinephrine and norepinephrine-induced vasoconstriction. Notably, we found that such insulin-suppressing effects on catecholamine-induced constriction are diminished following ß-adrenergic receptor blockade. In accordance, we also reveal that insulin augments ß-adrenergic-mediated vasorelaxation in isolated arteries. Collectively, these findings support the idea that sympathetic vasoconstriction can be attenuated during systemic hyperinsulinemia in the leg vasculature of both men and women and that this phenomenon may be in part mediated by potentiation of ß-adrenergic vasodilation neutralizing α-adrenergic vasoconstriction.

Effects of Acute Grape Seed Extract Supplementation on Hemodynamics in Normal Body Weight and Obese Males.

Recently, it has been reported that dietary supplementation with grape seed extract (GSE) ameliorates endothelial function and increase nitric oxide (NO) bioavailability. Thus, we investigated if elevated blood pressure and aortic stiffness (AoS) characterized in obese individuals are attenuated following acute GSE supplementation. Twenty men (obese=10; normal body weight (NBW)=10) participated in this study. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR), and AoS were compared 2 h after ingestion of GSE or placebo (PL) on different days, 1 wk apart. Compared with the PL, GSE supplementation significantly decreased SBP (NBW: 103±4 vs. 99±3 mmHg; obese: 118±3 vs. 112±5 mmHg) and MAP (NBW: 75±2 vs. 72±2 mmHg; obese: 86±3 vs. 84±3 mmHg) in both groups, while there were no differences in HR, SV, DBP, TPR, and AoS. GSE supplementation significantly decreased CO in only obese group. In NBW group, TPR tended to be decreased, but there was no significant difference. Our study suggests that acute supplementation with GSE reduced both SBP and MAP via a reduction in CO in obese individuals and decreased peripheral vasoconstriction in NBW group.

Effects of combined histamine H1 and H2 receptor blockade on hemodynamic responses to dynamic exercise in males with high-normal blood pressure.

While postexercise hypotension is associated with histamine H1 and H2 receptor-mediated postexercise vasodilation, effects of histaminergic vasodilation on blood pressure (BP) in response to dynamic exercise are not known. Thus, in 20 recreationally active male participants (10 normotensive and 10 with high-normal BP) we examined the effects of histamine H1 and H2 receptor blockade on cardiac output (CO), mean atrial pressure (MAP), aortic stiffness (AoStiff), and total vascular conductance (TVC) at rest and during progressive cycling exercise. Compared with the normotensive group, MAP, CO, and AoStiff were higher in the high-normal group before and after the blockade at rest, while TVC was similar. At the 40% workload, the blockade significantly increased MAP in both groups, while no difference was found in the TVC. CO was higher in the high-normal group than the normotensive group in both conditions. At the 60% workload, the blockade substantially increased MAP and decreased TVC in the normotensive group, while there were no changes in the high-normal group. A similar CO response pattern was observed at the 60% workload. These findings suggest that the mechanism eliciting an exaggerated BP response to exercise in the high-normal group may be partially due to the inability of histamine receptors. Novelty Males with high-normal BP had an exaggerated BP response to exercise. The overactive BP response is known due to an increase in peripheral vasoconstriction. Increase in peripheral vasoconstriction is partially due to inability of histamine receptors.