Forearm Blood Flow Research Articles

The forearm vascular response to sympathetic activation is attenuated in female, but not male, participants following acute intermittent hypoxia.

Acute exposure to hypoxia promotes both an increase in sympathetic nervous system activity (SNA) and local vasodilation. In rodents, intermittent hypoxia (IH)-mediated increases in SNA are associated with an increase in blood pressure in males but not females; notably, the protective effect of female sex is lost following ovariectomy. These data suggest the vascular response to hypoxia and/or SNA following IH may be sex- and/or hormone specific-although mechanisms are unclear. We hypothesized that hypoxia-mediated vasodilation and SNA-mediated vasoconstriction would be unchanged following acute IH in male adults. We further hypothesized that hypoxic vasodilation would be augmented and SNA-mediated vasoconstriction would be attenuated in female adults following acute IH, with the greatest effect when endogenous estradiol was high. Twelve male (25 ± 1 yr) and 10 female (25 ± 1 yr) participants underwent 30 min of IH. Females were studied in a low (early follicular) and high (late follicular) estradiol state. Preceding and following IH, participants completed two trials [steady-state hypoxia and cold pressor test (CPT)], where forearm blood flow and blood pressure were measured and used to determine forearm vascular conductance (FVC). The FVC response to hypoxia (P = 0.67) and sympathetic activation (P = 0.73) were unchanged following IH in males. There was no effect of IH on hypoxic vasodilation in females, regardless of estradiol state (P = 0.75). In contrast, the vascular response to sympathetic activation was attenuated in females following IH (P = 0.02), independent of estradiol state (P = 0.65). Present data highlight sex-related differences in neurovascular responsiveness following acute IH.NEW & NOTEWORTHY We examined the effects of acute intermittent hypoxia (AIH) on the vascular response to sympathetic activation and acute hypoxia. Present findings show, despite no effect of AIH on the vascular response to hypoxia, the forearm vasoconstrictor response to acute sympathetic activation is attenuated in females following AIH, independent of estradiol state. These data provide mechanistic understanding of potential benefits of AIH, as well as the impact of biological sex.

Neurovascular and hemodynamic responses to mental stress and exercise in severe COVID-19 survivors.

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m2) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m2) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (P < 0.001), and FBF and FVC responses were attenuated (P < 0.05). MAP was similar between the groups (P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (P > 0.05). MAP was lower in COVID-19 survivors (P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

The Effect of Additional Treatment with Empagliflozin or Semaglutide on Endothelial Function and Arterial Stiffness in Subjects with Type 1 Diabetes Mellitus-ENDIS Study.

We investigated the effect of additional treatment with newer antidiabetic drugs on endothelium function and arterial stiffness in subjects with type 1 diabetes mellitus (T1DM) without cardiovascular diseases. A total of 89 participants, all users of CGMS (continuous monitoring glucose system), were randomized into three comparable groups, receiving empagliflozin (E; n = 30), receiving semaglutide (S; n = 30), and a control group (C; n = 29). At baseline and 12 weeks post treatment, we measured FMD (brachial artery flow-mediated dilation) and FBF (forearm blood flow as reactive hyperemia assessed with strain gauge plethysmography) as parameters of endothelial function, as well as pulse wave velocity (PWV) and peripheral resistance as parameters of arterial stiffness. Improvement in FMD was significant in both intervention groups compared to controls (E group 2.0-fold, p = 0.000 and S group 1.9-fold, p = 0.000), with no changes between those two groups (p = 0.745). During the evaluation of FBF, there were statistically insignificant improvements in both therapeutic groups compared to controls (E group 1.39-fold, p = 0.074 and S group 1.22-fold, p = 0.701). In arterial stiffness parameters, improvements were seen only in the semaglutide group, with a decline in peripheral resistance by 5.1% (p = 0.046). We can conclude that, for arterial stiffness, semaglutide seems better, but both drugs positively impact endothelial function and, thus, could also have a protective role in T1DM.

Acute effect of various dosages of sugar ingestion on vascular function in offspring of hypertensive and normotensive parents.

We aimed to study vascular function in healthy men with a parental history of hypertension compared to those without. Acute effect of various dosages of sugar ingestion on vascular function was also investigated in both groups. Thirty-two healthy men were recruited and divided into two groups, offspring of hypertensive parents (OHT) and offspring of normotensive parents (ONT). Participants were orally given 15, 30, and 60 g of sucrose solution compared to water. Peak forearm blood flow (FBF), forearm vascular resistance (FVR), pulse wave velocity (PWV), and oxidative stress markers were measured at baseline and after sucrose intake at 30, 60, 90, and 120 min. At baseline, peak FBF was significantly lower (22.40 ± 1.18 vs. 25.24 ± 0.63 ml × dl -1 × min -1 , P < 0.001), FVR was significantly higher (3.73 ± 0.42 vs. 3.30 ± 0.26 mmHg × ml -1 × dl × min, P = 0.002), and PWV was significantly faster (6.31 ± 0.59 vs. 5.78 ± 0.61 m/s, P = 0.017) in OHT than ONT. After each sucrose intake, peak FBF significantly declined and was lowest at 30 min in both groups. The reduction in peak FBF was seen in all doses of sucrose and the higher dose of sucrose intervened, the longer reduction in peak FBF observed. Vascular function was attenuated in healthy men with a family history of hypertension and became worse after sucrose ingestion even at the low dose. Our findings suggest that the ones, especially those with a parental history of hypertension, should reduce sugar consumption as low as possible.

#6650 SGLT2-INHIBITION IMPROVES VASCULAR FUNCTION IN TYPE 2 DIABETES: A DOUBLE BLIND, RANDOMIZED, PLACEBO CONTROLLED CROSSOVER TRIAL

Abstract Background and Aims Sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce cardiovascular events and protects kidney function in type 2 diabetes (DM2) patients. These benefits may partly be related to improvement of vascular function. In this study we examined the effects of SGLT2i treatment on vasodilatory capacity in patients with DM2. Method Using a double-blind, randomized, placebo-controlled cross-over study design, we included 15 patients with DM2 and preserved kidney function (eGFR &amp;gt; 60 ml/min/1.73 m2). Each participant received four weeks of SGLT2i treatment (empagliflozin 10 mg once daily) or matching placebo. After a two-week wash-out period, each participant was crossed over to four weeks of the opposite treatment. At the end of each treatment period, vascular function was evaluated by venous occlusion plethysmography. Forearm blood flow (FBF) was measured during intra-arterial infusion of increasing concentrations of acetylcholine (ACh) and sodium nitroprusside (SNP), assessing endothelium-dependent and independent vasodilation, respectively. Repeated measures two-way ANOVA was performed to compare absolute FBF between groups. Results 11/15 (73%) of participants were male. Mean age was 68±9 (SD) years (range 49-82), eGFR was 81±10 ml/min/1.73 m2 and duration of diabetes was 15.8±9 years. 11/15 (73%) had hypertension and 9/15 (60%) received treatment with an ACE-inhibitor or Angiotensin-II blocker. 4/15 (27%) had cardiovascular disease. The median albumin-to-creatinine ratio was 29 mg/g (range: 4-1293). Both ACh and SNP dose-dependently increased FBF (Figure 1 and 2). FBF during SNP infusion was significantly higher during empagliflozin treatment as compared to placebo (p = 0.004), whereas there was no difference between empagliflozin and placebo in FBF during ACh infusion (P = 0.399). Conclusion Empagliflozin improves endothelium-independent vasodilatation in patients with DM2, whereas no changes could be observed in endothelium-dependent vasodilation. These results suggest that SGLT2i positively affects vascular function and that the effect is not related to nitric oxide from the endothelium.

#4063 APELIN INCREASES FOREARM BLOOD FLOW IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) affects 1 in 10 people and cardiovascular disease is its commonest complication. Despite current standard of care, many patients continue to progress to kidney failure and/or die of cardiovascular disease. Thus, there is an urgent unmet need for new treatments that slow kidney function decline and offer broad cardiovascular protection. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is an attractive therapeutic target for CKD. Apelin is an endothelium-dependent vasodilator and a potent inotrope. Clinical studies show that apelin improves endothelial function in health and heart failure, and pre-clinical studies in models of kidney disease find apelin offers renoprotection. At present, apelin has not been studied in patients with CKD. The aims of this study were to examine the local vascular actions of apelin in CKD. Method Participants with stable, non-diabetic CKD and age- and sex-matched healthy volunteers were recruited to a prospective, randomised, placebo-controlled study. Blood pressure and arterial stiffness (measured using pulse wave velocity) were assessed at baseline. Endothelial function was examined using gold-standard venous occlusion plethysmography. Forearm vasodilatation was measured in response to incremental intra-arterial doses of acetylcholine (7.5, 15 and 30 μg/min, used to assess endothelium-dependent vasodilatation), sodium nitroprusside (1, 2 and 4 μg/min, used to assess endothelium-independent vasodilatation), and pyroglutamated apelin-13 ([Pyr1]apelin-13; 0.3, 1, 3, 10, 30 and 100 nmol/min). Circulating tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) were assessed as measures of endogenous fibrinolysis. Results Fifteen patients with CKD (mean age 55±4 years; 53% male) and 15 healthy volunteers (mean age 51±3 years; 67% male) completed the study. In comparison to healthy volunteers, patients with CKD had a higher blood pressure (mean arterial pressure: 102 mmHg versus 93 mmHg, p&amp;lt;0.05) and increased pulse wave velocity (7.5±2.2 m/s versus 6.0±0.9 m/s, p&amp;lt;0.01). Similar dose-dependent vasodilatation to acetylcholine and sodium nitroprusside was seen in both groups. [Pyr1]apelin-13 increased forearm blood flow by a maximum of ∼30% in both health and CKD (p&amp;lt;0.01 compared to baseline for both) (Figure 1). This response appeared to be dose-dependent. Net tPA antigen release increased 20-70 fold in response to [Pyr1]apelin-13 in both health and CKD, with a trend to a greater release in CKD. There was no change in PAI-1. No relationship was seen between the response to [Pyr1]apelin-13 and kidney function. Conclusion Apelin promotes vasodilatation in optimally managed patients with CKD and may regulate endogenous fibrinolysis. If this effect were maintained in the long-term with systemic apelin treatment, it would be expected to reduce cardiovascular risk. Systemic studies are now justified to investigate the haemodynamic and renal effects of apelin in these patients.

A HYPERADRENERGIC STATE IN HYPERTENSION IS ASSOCIATED WITH MOOD DISTURBANCE AND IMPAIRED STRESS-MODULATED VASOMOTOR RESPONSES

Objective: Increasing evidence suggests a high prevalence of affective disorders in hypertension, however, the physiological associations remain unclear. Noradrenergic activation in the central and peripheral nervous systems is a putative mechanism that may explain the link between both conditions. Here, we investigate whether these stress-sensitive co-morbidities may be dependent on basal noradrenergic activity and whether vascular responses to centrally acting stimuli vary according to noradrenergic activity. Design and method: We examined the relation of affective disorders and stress-mediated vascular responses to plasma concentrations of normetanephrine (NMN), a measure of noradrenergic activity, in subjects with primary hypertension. Subjects on antidepressant medication, alpha- and beta-blockers were excluded. The Patient Health Questionnaire (PHQ-9), the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR-16), and Generalised Anxiety Disorder-7 (GAD-7) questionnaires were used for the evaluation of symptoms of depression and anxiety. Forearm blood flow (strain gauge plethysmography) was used to assess vascular responses to mental stress (Stroop colour-word test) and slow breathing (by biofeedback), interventions that respectively increase or decrease noradrenergic activity in the pre-frontal cortex and locus coeruleus. Results: 100 subjects (53% male) with (mean ± SD) age 43.4 ± 10.9 years were recruited. 88% of subjects were treated with anti-hypertensive medications and 4% had type 2 diabetes. 31% and 34% of the study population scored moderate to severe depression for PHQ-9 and QIDSSR-16 respectively indicating significant mood disturbance. Scores representing low mood and high anxiety were 2-3-fold higher for hypertensive subjects in the highest compared to lowest NMN tertiles (PHQ-9: 9.2 ± 5.8 vs 3.8 ± 2.7, P &lt; 0.001; QIDSSR-16: 12.3 ± 4.9 vs 4.5 ± 3.5, P = 0.003; GAD-7: 9.0 ± 5.5 vs 4.6 ± 3.8, P = 0.003). Forearm vasodilator responses to mental stress and vasoconstrictor responses to slow breathing were attenuated in those with high compared to low NMN (28.3 ± 21% vs. 47.1 ± 30% increases for mental stress and 3.7 ± 21% vs. 18.6 ± 15% decreases for slow breathing for highest vs. lowest tertiles of NMN, both P &lt; 0.01). Conclusions: A hyperadrenergic state in hypertension is associated with mood disturbance and impaired stress-modulated vasomotor responses. This association may be mediated by chronic stress impinging on pathways regulating central arousal and peripheral sympathetic nerve activity.

FACTORS RELATED TO SKIN MICROVASCULAR DYSFUNCTION IN INDIVIDUALS WITH DIFFERENT RANGE OF GLUCOSE LEVELS

Objective: Existing data confirm the presence of microvascular dysfunction in hypertension and diabetes mellitus (DM). Prediabetes is recognized as a significant metabolic status, being a key factor in the occurrence of DM and there is increasing evidence concerning microvascular complications in prediabetes. Laser speckle contrast analysis (LASCA) is a non-invasive technique that can be used to evaluate skin microvascular function. The aim of our study was to assess cardiovascular factors that are possibly associated with microvascular reactivity in a population from normoglycaemia to DM. Design and method: Individuals with normoglycemia, prediabetes and diabetes without established cardiovascular disease were included in the study. In all participants, forearm skin blood flow was recorded under standardized conditions using a laser speckle contrast imager (PeriCam PSI NR System, Perimed). Post-occlusive reactive hyperaemia (PORH) was assessed following a standardized protocol and data were analyzed with a signal processing software (PIMSoft, Perimed). Skin microvascular reactivity was expressed as a percentage increase between baseline and peak perfusion (%). Office BP was measured in each participant according to a standard methodology and aortic blood pressure was assessed using the Sphygmocor device. Results: Fifty individuals (18 patients with prediabetes, 16 patients with DM and 16 controls) were included in the study. In the univariate model both glucose levels and aortic systolic blood pressure (aSBP) correlated inversely with microvascular reactivity (r = -0.382 and r = -0.349, p&lt;0.01 for both comparisons) However, in the multivariate model only the association with aSBP remained statistically significant (beta = -0.363, p&lt;0.05). Conclusions: Only central SBP, but not glucose predicted skin microvascular dysfunction in individuals with normoglycemia, prediabetes and diabetes and without established cardiovascular disease.

The effect of vitamin C on nitroglycerin-mediated vasodilation in individuals with and without the aldehyde dehydrogenase 2 polymorphism.

To mediate its pharmacodynamic effects, glyceryl trinitrate (GTN) requires bioactivation, by which it releases nitric oxide or a nitric oxide moiety. The exact mechanism of GTN bioactivation remains uncertain. Mitochondrial aldehyde dehydrogenase (ALDH-2) has been proposed as the primary enzyme responsible for this bioactivation process. Evidence for the importance of ALDH-2 in GTN bioactivation has been inconsistent, particularly in human models. An alternative hypothesis suggests that decreased ALDH-2 activity leads to accumulation of reactive cytotoxic aldehydes, which either inhibit the vasoactive product(s) of GTN or impair other enzymatic pathways involved in the bioactivation of GTN. We investigated the effect of supplemental vitamin C on vascular responses to GTN in healthy volunteers of East Asian descent, of whom 12 with and 12 without the ALDH-2 polymorphism participated. Subjects underwent 2 sequential brachial artery infusions of GTN at rates of 5, 11 and 22 nmol/min, separated by a 30-min washout period. The GTN infusions were carried out in the presence and absence of vitamin C using a randomized, crossover design. Venous occlusion plethysmography was used to measure forearm blood flow responses to GTN. Compared to subjects with functional ALDH-2, the variant group exhibited blunted hemodynamic responses to intra-arterial GTN infusions, although this reduction in response was not statically significant. Contrary to our hypothesis, vitamin C had an inhibitory effect on GTN mediated vasodilation as compared to GTN during saline in both groups. We conclude that vitamin C did not augment the acute vascular response to GTN in those with the ALDH-2 polymorphism.

Rapid onset vasodilation in response to forearm muscle contraction in Hispanic American and Caucasian American Adults

Hispanic Americans (HA) are the fastest growing ethnic populations in the U.S., estimated to double in the next four decades. According to NHANES 2013-2016 data, prevalence of type 2 diabetes (T2D) is 15.1% in HA men and 14.1% in HA women, compared to 9.4 and 7.3% in non-Hispanic Caucasian American (CA) men and women, respectively. Even HA children have a 5-fold higher rate of T2D compared to their age-matched CA counterparts. Impaired vascular function is a hallmark of T2D however, limited number of studies have investigated the effect of ethnicity on vascular function at rest and during exercise. To our knowledge, only one study has reported a higher flow-mediated dilation at rest in healthy HA compared to CA adults. Hence, the purpose of this study was to investigate the rapid onset vasodilation in response to a single muscle contraction of the forearm at progressively increasing intensity (20, 40, and 60% of maximum voluntary contraction (MVC)) in young, healthy HA compared to age- and weight-matched CA individuals. A single muscle contraction model was chosen to isolate the robust local vasodilatory responsiveness of the vasculature without increases in sympathetic nerve activity or large hemodynamic changes. We hypothesized that HA would demonstrate an attenuated forearm vascular conductance (FVC) and forearm blood flow (FBF) in response to skeletal muscle contractions, compared to CA group. Young, healthy HA (n=4) and CA (n=4) adults performed skeletal muscle contractions at 20%, 40 % and 60% of their maximum voluntary contraction (MVC). To isolate the effect of mechanical compression during muscle contractions, FBF and FVC responses to a brachial cuff inflation were also measured. Heart rate (ECG), mean arterial pressure (MAP; finger photoplethysmography) and forearm blood flow (FBF; duplex Doppler ultrasound) were measured. FVC was calculated as FBF/MAP. Baseline FBF (CA: 115.21 ± 48.9 and HA: 68.89 ± 21.9 ml/min; p=0.27), MAP (CA: 82 ± 7.48 and HA: 81 ± 2.87 mmHg; p=0.77), FVC (p=0.15), and MVCs (CA: 67 ± 26.8 and HA: 70 ± 7.4 kg; p=0.82) were similar between the groups. Following single muscle contractions, both groups exhibited an intensity dependent increase in FVC and FBF, however, there was no difference between HA and CA groups. For instance, following muscle contraction at 40% MVC, peak FVC (%Δ) was 251% ± 46.35 in HA and 189% ± 34.98 in CA (race effect p = 0.23, time effect = 0.01, interaction p = 0.029). Similarly, peak %Δ FBF or %Δ FVC following 60% contractions were similar between the groups (FVC: 327% ± 84.36 in HA vs. 286% ± 74.45 in CA (race effect p=0.62, time effect p&lt;0.01, interaction effect p=0.01)). Both groups exhibited a similar response to brachial cuff inflation for peak FVC (p=0.21) and peak FBF (p=0.30). Our preliminary findings indicate that HA have a preserved rapid onset vasodilation in response to a single forearm contraction when compared to CA adults. Supported by Kinesiology and Health Education UT Austin Start-up Account 19-2635-91 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Forearm vascular conductance responses to rhythmic handgrip in young African American compared with Caucasian American women

Non-Hispanic African American (AA) individuals have a disproportionately high prevalence, and mortality rate of cardiovascular disease (CVD) compared to other populations. Previous studies have demonstrated that even young, healthy AA individuals have blunted flow-mediated dilation, attenuated vasodilatory responses to pharmacological infusions and rhythmic handgrip exercise (RHG), as well as higher arterial stiffness and exaggerated peripheral vasoconstriction to isometric handgrip exercise and other non-exercise-stimuli compared to Caucasian-American (CA) individuals. These studies indicate that vascular alterations occur early on in life of AA individuals, potentially contributing to elevated risk of CVD in this racial group. However, these racial disparities in vascular function have almost exclusively been studied in men. Herein, we tested the hypothesis that, similar to young AA men, young AA women will exhibit an attenuated increase in forearm blood flow (FBF) and forearm vascular conductance (FVC) during rhythmic handgrip exercise (RHG) compared to age-matched CA women. Forearm blood flow (FBF; duplex Doppler ultrasound) and mean arterial pressure (MAP; finger photoplethysmography) were measured in young CA (n = 5) and AA (n = 5) women during rhythmic handgrip exercise performed at three workloads (15%, 30%, and 45% of maximal voluntary contraction (MVC)). FVC was calculated as FBF/MAP. Baseline FBF (CA: 66.0 ± 12.8 and AA: 61.6 ± 12.2 ml/min; mean ± SD, p = 0.30); FVC (CA: 0.8 ± 0.2 and AA: 0.7 ± 0.2 ml/min/mmHg; p = 0.16), MAP (CA: 82 ± 11 and AA: 88 ± 4 mmHg; p = 0.28), and MVCs (CA: 50 ± 4 and AA: 52 ± 5 kg; p = 0.35) were similar between the groups. Both groups exhibited intensity-dependent increases in FBF and FVC; however, contrary to our hypothesis, there were no race difference (mixed-model two-way ANOVA; FVC: race effect p = 0.18, intensity effect p &lt; 0.0001, interaction p = 0.48). For instance, in response to RHG at 45%, CA had 384 ± 112% increase in FBF from baseline and AA had 499 ± 153% increase. Increase in FVC from baseline was 198 ± 76% for CA women and 314 ± 151% for AA women. MAP did not differ between the groups (e.g., ΔMAP at 45%; CA: 13 ± 11 vs AA: 9 ± 5, p = 0.41). These preliminary data suggest that the hyperemic response to rhythmic handgrip exercise in young African American women are similar to age-matched Caucasian-American women. Supported byKinesiology and Health Education UT Austin Start-up Account 19-2635-91. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Enhanced protection with ischemic preconditioning against endothelial ischemia-reperfusion injury during the luteal phase of the menstrual cycle in premenopausal women

PURPOSE: In premenopausal women, we have previously shown that the capacity of remote ischemic preconditioning (IPC) to protect against endothelial ischemia/reperfusion (I/R) injury is diminished during the early follicular phase of the menstrual cycle compared with the late follicular phase. The aim of this research was to extend our initial findings by determining how the luteal phase of the menstrual cycle influences remote IPC to alleviate endothelial I/R injury in a second sample of women. It was hypothesized that the capacity of remote IPC to alleviate endothelial I/R injury will be greater during the luteal phase of the menstrual cycle compared with the early follicular phase. METHODS: Eleven premenopausal eumenorrheic women (age 24±3 yr.) not taking any contraceptive medications were studied. Primary outcomes were the assessment of vascular endothelial function measured during the early follicular (after onset of menses; days 1-6) and at the peak luteal phase (days 21-24 after positive urine progesterone test). Endothelium-dependent vasodilation was assessed by the forearm blood flow (FBF) response to reactive hyperemia using venous occlusion plethysmography with and without endothelial I/R injury (20 min brachial artery ischemia, 15 min reperfusion) when preceded by remote IPC (3×5 min cycles of arm ischemia). RESULTS: Without endothelial I/R injury, peak FBF was similar (P=0.25) between the early follicular (26.6±5.0 ml/100 ml tissue/min) and luteal phases (25.1±3.9 ml/100 ml tissue/min). In contrast, there was a significant main effect (P&lt;0.001) of cycle phase on the capacity of IPC to protect against endothelial I/R injury. During the early follicular phase, peak FBF was significantly (P&lt;0.001) diminished 18% with endothelial I/R injury (from: 26.6±5.0 to 21.8±4.6 ml/100 ml tissue/min) despite remote IPC. As a result, total FBF during reactive hyperemia (area under the curve) was decreased ~25% (P=0.006) after (45.1±10.0) compared with before (59.8±14.1 ml/100 ml tissue) endothelial I/R injury. However, during the luteal phase endothelial I/R injury was prevented with remote IPC. Indeed, in the presence of endothelial I/R injury, peak FBF was well preserved (from: 25.1±3.9 to 27.2±5.7 ml/100 ml tissue/min; P=0.267). As a result, total FBF was similar (P=0.774) after (55.9±13.3) compared with before (51.7±13.8 ml/100 ml tissue) endothelial I/R injury. The level of endothelial protection from I/R injury with remote IPC during the luteal phase was similar (P=0.34) to the late follicular phase in our previous study. CONCLUSIONS: IPC-mediated vascular endothelial protection is robust during the luteal phase of the menstrual cycle but wanes in the early follicular phase. Greater circulating estrogens and perhaps progesterone during the luteal phase may contribute to the protective benefits of IPC in women, and sheds light about how cardioprotection may change with ovarian hormone deficiency with the menopause transition. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Nitric oxide contribution to endothelium-mediated vasodilation is attenuated in postmenopausal compared to premenopausal females

Background: Hypertension prevalence increases in females following menopause. Poor endothelial microvascular function increases risk of hypertension. Endothelial-mediated vasodilation is dependent on nitric oxide (NO). Estrogen enhances NO production; therefore, reduced estrogen levels in postmenopausal females may result in a reduced contribution of NO to endothelial-mediated vasodilation, although studies are limited. Herein, we aimed to investigate the contribution of NO to endothelial-mediated vasodilation in premenopausal and postmenopausal females. We hypothesized that postmenopausal females would have attenuated endothelium-mediated vasodilation and reduced contribution of NO compared to premenopausal females. Methods: Ten premenopausal (27±3 yrs) and eleven postmenopausal (59±4 yrs) normotensive females were studied. Resting brachial blood pressures were measured using a standard arm cuff. Brachial arterial catheters were placed for continuous blood pressure measurement and pharmacologic infusions. Forearm blood flow (FBF) was measured using venous occlusion plethysmography at baseline (saline) and during infusion of an endothelium-dependent vasodilator (acetylcholine; 1.0, 2.0, 4.0, and 8.0 μg/100mL tissue/min) with and without a NO synthase inhibitor (L-NG-monomethylarginine [L-NMMA]; 1.0 mg/min) co-infusion. Forearm vascular conductance (FVC) was calculated as FBF/mean arterial pressure✕100. Data were analyzed using a two-way repeated-measures ANOVA. Results: Resting systolic blood pressure (SBP) but not diastolic blood pressure (DBP) was greater in postmenopausal compared to premenopausal females (SBP: 121±15 vs. 103±9 mmHg, respectively; P&lt;0.01; DBP: 72±11 vs. 65±5 mmHg, respectively; P=0.07). FBF responses to acetylcholine did not differ between premenopausal and postmenopausal females (Group Main Effect: P=0.11). When correcting for blood pressure, premenopausal females exhibited greater FVC responses to acetylcholine compared to postmenopausal females (Group Main Effect: P=0.04). In premenopausal females, FBF and FVC responses to acetylcholine were reduced with co-infusion of L-NMMA compared to acetylcholine infusion only (L-NMMA Main Effect: P=0.02 and P=0.01, respectively). In postmenopausal females, the FBF and FVC responses to acetylcholine were unaffected by L-NMMA (L-NMMA Main Effect: P=0.79 and P=0.76, respectively). Conclusion: Compared to premenopausal females, postmenopausal females have impaired endothelial microvascular function. Attenuated NO contribution during endothelium-mediated vasodilation in postmenopausal women may partially contribute to the increased hypertension risk in this population. AHA 14PRE18040000, AHA 898649, NIH HL083947, NIH HL148144, NCATS UL1 TR000135 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A single high-fat meal impairs functional sympatholysis in young healthy adults

Introduction: A high-fat diet increases the risk of cardiovascular disease and mortality, but the underlying mechanisms remain incompletely understood. During exercise, sympathetically mediated vasoconstriction is dampened in active skeletal muscle due to the counteracting vasodilatory effects of metabolic by-products from muscle contraction. This phenomenon, termed functional sympatholysis, plays a critical role in the redistribution of cardiac output to contracting skeletal muscles to meet the metabolic demands of exercise. Whether a high-fat meal modulates the magnitude of sympatholysis is currently unknown. Herein, we tested the hypothesis that a high-fat meal would acutely impair functional sympatholysis in young healthy adults. Methods: In a randomized, controlled, and cross-over design, 14 healthy adults (8 women, 26±4 years), consumed either a high- (1030kcals, 91g fat) or a low-fat (1006kcals, 1g fat) meal on two separate days. Forearm blood flow (FBF; Doppler ultrasound) and beat-to-beat mean arterial pressure (MAP; finger photoplethysmography) were measured during sympathetic activation induced by -20 mmHg lower-body negative pressure (LBNP) applied at rest and simultaneously during rhythmic handgrip exercise at 15% and 30% maximum voluntary contraction (MVC). Measurements were taken pre-meal and at 1-, 2-, and 3-hours post-prandial. Forearm vascular conductance (FVC) was calculated as FBF/MAP and the magnitude of sympatholysis as the difference of LBNP-induced changes in FVC between handgrip and rest. Results: Prior to the high-fat meal, LBNP decreased resting FVC (Δ-57±10%), and this response was attenuated during exercise at 15% (Δ-18±8%) and 30% MVC (Δ-9±7%). After the high-fat meal, LBNP induced smaller decreases in resting FVC (1h: Δ-43±12%, 2h: Δ-45±12%, 3h: Δ-49±8%, all P≤0.01 vs. pre), but during exercise greater decreases in FVC were observed at both 15% (1h: Δ-22±10%, 2h: Δ-23±8%, 3h: Δ-25±8%, all P≤0.04 vs. pre) and 30% MVC (1h: Δ-15±8%, 2h: Δ-15±6%, 3h: Δ-16±6%, all P≤0.04 vs. pre). As a result, the high-fat meal decreased the magnitude of sympatholysis during rhythmic handgrip exercise at 15% (pre-prandial: 39±8%, 1h: 20±10%, 2h: 21±8%, 3h: 24±7%, all P≤0.001) and 30% MVC (pre-prandial: 48±11%, 1h: 28±10%, 2h: 30±11%, 3h: 33±8%, all P≤0.001). The low-fat meal did not change the magnitude of sympatholysis at either 15% (pre-prandial: 37±6%, 1h: 39±6%, 2h: 38±7%, 3h: 37±8%, all P≥0.07) or 30% MVC (pre-prandial: 45±10%, 1h: 47±8%, 2h: 47±9%, 3h: 46±7%, all P≥0.39). Conclusion: These findings demonstrate the capacity of a high-fat meal to acutely impair the ability of contracting skeletal muscle to offset the vascular responsiveness to α1-adrenoreceptor activation during low- and moderate-intensity rhythmic handgrip exercise. Natural Science and Engineering Research Council (NSERC) of Canada Discovery Grant (P.J.M) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of obesity on the vascular response to sympathetic activation during hypoxia in female participants

Background: Activation of the sympathetic nervous system causes vasoconstriction and an acute reduction in peripheral blood flow. However, during hypoxia, sympathetically-mediated vasoconstriction is attenuated in young females without obesity. Given sustained increases in sympathetic activity associated with obesity may create a greater propensity to vasoconstrict in response to sympathetic activation, we sought to examine the effect of obesity on the vascular response to sympathetic activation during hypoxia. We hypothesized sympathetically-mediated vasoconstriction during hypoxia would be greater in premenopausal female adults with obesity when compared to females without obesity. Methods: Blood pressure (BP, finger photoplethysmography) and forearm blood flow (FBF, venous occlusion plethysmography) were assessed in premenopausal female adults with obesity (n=5, 25±3 yrs, 37±1 kg/m2, 48±1% body fat) and without obesity [n=19, 23±1 yrs, 23±1 kg/m2, (33±2% body fat, n=8)]. Data were combined from two cohorts (IRB #2022525, 2011312) to test present hypotheses. Participants completed two trials consisting of a 2-min cold pressor test (CPT) during baseline normoxia (98±1% SpO2) and following 3-5 min of steady-state hypoxia (0.10±0.01 FiO2, 82±1% SpO2). FBF was normalized for BP (forearm vascular conductance, FVC) and a change in FVC during the last 1-min of CPT was calculated (ΔFVC). The main effect of group (obese, non-obese), condition (normoxia, hypoxia) and the interaction of group and condition were compared using a two-way repeated measures ANOVA. Results: In female participants without obesity, ΔFVC during normoxia was attenuated during hypoxia (-0.57±0.19 vs +0.36±0.34 mL/dL/100mmHg/min; p=0.009). Conversely, in female participants with obesity, ΔFVC during normoxia did not differ from the response during hypoxia (-0.31±0.46 vs -0.87±0.34 mL/dL/100mmHg/min; p=0.382). Group differences in ΔFVC were not observed during normoxia (p=0.657), but were present during hypoxia (p=0.039). Conclusion: Sympathetically-mediated vasoconstriction is attenuated during steady-state hypoxia in premenopausal females without obesity, whereas this response is not observed in female adults with obesity. These preliminary data advance our understanding of the impact of obesity on hypoxic vascular control in premenopausal female participants and have implications for conditions in which hypoxia and sympathetic activation are observed ( e.g., sleep apnea, heart failure, COVID-19). NIH HL130339 (JKL), NIH HL153523 (JKL), AHA 909014 (DWJ) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impaired Endothelial Vasomotor Function with Borderline-High Triglycerides

Approximately 1 in 3 adults in the United States have a triglyceride (TG) concentration above 150 mg/dL and 1 in 5 adults have TG levels 200 mg/dL or higher. Moreover, the prevalence of suboptimal TGs (&gt;150 mg/dL) has increased 5-fold in middle-aged and older adults over the last 3 decades. While much attention has focused on the cardiovascular effects of high and very high TG levels, where other lipid and metabolic abnormalities are often present, there are currently little data on the influence of borderline-high TG concentrations on vascular health. This represents a critical void in our understanding of the pathogenesis of cardiovascular disease (CVD) with TGs. Impaired endothelial vasomotor function is a central etiologic feature in the development of CVD and associated thrombotic events. We tested the hypothesis that endothelium-dependent vasomotor function is impaired in adults with borderline-high TG concentrations. Thirty-two sedentary, adults were studied: 15 (7M/8F, age: 56±1 yr; BMI: 26.8±0.6 kg/m2) with normal TG (35-140 mg/dL) and 17 (9M/8F, age: 57±1 yr; BMI: 28.7±0.8 kg/m2) with borderline-high TG (150-199 mg/dL) levels. Forearm blood flow (FBF; plethysmography) was determined in response to the intra-arterial infusion: acetylcholine (ACh) (4.0, 8.0, and 16.0 mg/100 mL tissue/min), sodium nitroprusside (1.0, 2.0, and 4.0 mg/100 mL tissue/min) and selective ETa receptor blocker (BQ-123, 100 nmol/min for 60 min). FBF response to ACh was significantly lower (~20%) in the borderline-high TG (from 4.7±0.3 to 11.6+0.6 mL/100 mL tissue/min) vs normal TG (from 4.3±0.3 to 14.6±0.5 mL/100 mL tissue/min) group. There were no significant group differences in the FBF responses to sodium nitroprusside. BQ-123 elicited a significant vasodilator response (~20%) in the borderline-high TG adults but did not alter FBF in the normal TG adults. Co-infusion of BQ-123 did not affect FBF responses to ACh in normal TG group but resulted in an ~30% increase in Ach-induced vasodilation (from 4.3±0.4 to 15.1±0.7 mL/100 mL tissue/min; P&lt;0.05) in borderline-high TG group. Triglyceride levels were significantly and inversely associated with total FBF response to ACh (r=-0.63) and positively associated with the peak FBF response to BQ-123 (r=0.53; P&lt;0.05). These results indicate that borderline-high TG concentrations are associated with diminished endothelium-dependent vasodilation and enhanced ET-1-mediated vasoconstrictor tone. Impaired endothelial vasomotor function may underlie the increased risk of CVD in adults with borderline-high TG levels. Nothing to disclose This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inspiratory resistance training transiently improves endothelium-dependent dilation in young adults

Introduction: Inspiratory resistance training (IRT) is a resisted breathing exercise originally devised to improve diaphragmatic strength. We have shown IRT to be a potent non-pharmacological therapy that yields significant reductions in resting blood pressure. When performed daily for 6 weeks, systolic blood pressure is reduced by ~9 mmHg, secondary to reductions in systemic vascular resistance. Whereas the effects of IRT on the vasculature have been described over the intermediate term, the acute responses that mediate these longer-term adaptations have not been fully characterized. Purpose: Our primary aim was to quantify the acute effects of a single bout of IRT on (endothelium-dependent dilation) EDD in healthy men and women. Secondarily, our goal was to determine the acute effects of IRT on arterial stiffness. Methods: Nitric oxide-mediated EDD and ischemia-induced maximal shear rate were assessed with brachial artery flow-mediated dilation (FMD), and arterial stiffness was assessed via carotid-femoral pulse wave velocity (PWV). Twenty healthy young adults (22.9 ± 3.4 years; 10 males, 10 females) were randomized to the experimental (IRT; 5 sets of 6 breaths at 50% of maximal inspiratory pressure with 1-minute rest intervals) and control (time-matched supine rest) conditions in a crossover design, with at least 48 hours between visits. FMD and PWV were performed before, 10 minutes after, and 40 minutes after the assigned intervention. Statistical analysis included repeated measures ANOVA with Sidak post hoc analyses. Results: All values are mean difference ± SD. There were no between-day differences in EDD at baseline (mean difference: 0.08 ± 3.03%; p=0.908). EDD was significantly increased from baseline at 10 minutes post-IRT (+1.86 ± 2.75%; p=0.025), but returned to baseline levels at 40 minutes post-IRT (-0.10 ± 3.00%; p=0.998). During the control condition, EDD was unchanged from baseline at 10 minutes post-rest and 40 minutes post-rest ( p=0.136). Lastly, maximal shear rate following 5 minutes of forearm blood flow occlusion was not different from baseline at any time point following IRT ( p=0.749) and thus, the change in EDD is not a result of a modified hyperemic response. However, in the control condition maximal shear rate was significantly lower at 40 minutes post-rest, relative to baseline (mean difference -9.94 ± 2.64 per second; p=0.005), although the reduced shear rate did not impact EDD at 40 minutes post-rest. Arterial stiffness was unchanged from baseline in response to IRT ( p=0.217) or the rest intervention ( p=0.150). Conclusions: In healthy young adult men and women, a single bout of IRT elicits a transient enhancement in EDD. The effect endures for at least 10 minutes but is extinguished at 40 minutes post IRT. Repeated acute enhancements in EDD may contribute to sustained IRT-related reductions in vascular resistance after 6 weeks of traini This work was supported by NIA/NIH Grant Number: 1R01AG065346-01A1 (EFB), NIH Training Grant Number: 5T32HL007249-44 (DT), and NIH/NHLBI Grant Number: 1K01HL153326-01 (DHC) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Aging increases metabolic capacity and reduces work efficiency during handgrip exercise in males.

Maximal oxygen uptake and exercise performance typically decline with age. However, there are indications of preserved vascular function and blood flow regulation during arm exercise. Yet, it is unknown if this potential physiological preservation with age is mirrored in peripheral metabolic capacity and V̇o2/W ratio. Thus, to investigate the effects of aging in the arms, we measured metabolic and vascular responses to 6-min bouts of dynamic handgrip exercise at 40% and 80% of maximal work rate (WRmax) in 11 young (26 ± 2 yr) and 12 old (80 ± 6 yr) males, applying Doppler-ultrasound combined with blood samples from a deep forearm vein. At baseline, the old had a larger arterial diameter compared with young (P < 0.001). During exercise, the two groups reached the same WRmax. V̇o2, blood flow, and oxygen supply were higher (40%WRmax; 80%WRmax, all P < 0.01), and arteriovenous oxygen difference was lower (80%WRmax, P < 0.02), in old compared with young. Old also had a higher oxygen excess at 80%WRmax (P < 0.01) than young, whereas no difference in muscle diffusion or oxygen extraction was detected. Only young exhibited an increase in intensity-induced arterial dilation (P < 0.05), and they had a lower mean arterial pressure than old at 80%WRmax (P < 0.001). V̇o2/W (40%WRmax; 80%WRmax) was reduced in old compared with young (both P < 0.05). In conclusion, in old and young males with a similar handgrip WRmax, old had a higher V̇o2 during 80%WRmax intensity, achieved by an increased blood flow. This may be a result of the available cardiac output reserve, compensating for reduced work efficiency and attenuated vascular response observed in old.NEW & NOTEWORTHY Contrasting the typically observed decline in V̇o2max with age, the current study reveals an age-related increase in forearm metabolic capacity during handgrip exercise in old, mediated by an increased forearm blood flow. Exercise with a small muscle mass in arms, where central components of the oxygen transport are not limiting, allows old to attain a similar maximal work rate as young despite their increased V̇o2/W ratio.

Flowmotion imaging analysis of spatiotemporal variations in skin microcirculatory perfusion.

Flowmotion is the rhythmical variations in measured skin blood flow that arise due to global and local regulation of the vessels and can be studied using frequency analysis of time-resolved blood flow signals. It has the potential to reveal clinically useful information about microvascular diseases, but the spatial heterogeneous nature of the microvasculature makes interpretation difficult. However, recent technological advances in multi-exposure laser speckle contrast imaging (MELSCI) enable new possibilities for simultaneously studying spatial and temporal variations in flowmotion. To develop a method for flowmotion analysis of MELSCI perfusion images. Furthermore, to investigate the spatial and temporal variations in flowmotion in forearm baseline skin perfusion. In four healthy subjects, forearm skin perfusion was imaged at 15.6 fps for 10 min in baseline. The time-trace signal in each pixel was analyzed using the wavelet transform and summarized in five physiologically relevant frequency intervals, resulting in images of flowmotion. Furthermore, a method for reducing the effect of motion artifacts in the flowmotion analysis was developed. The flowmotion images displayed patterns of high spatial heterogeneity that differed between the frequency intervals. The spatial variations in flowmotion, quantified as the coefficient of variation, was between 11 % and 31 % in four subjects. Furthermore, significant temporal variations in flowmotion were also observed, indicating the importance of a spatiotemporal analysis. The new imaging technique reveals significant spatial differences in flowmotion that cannot be obtained with single-point measurements. The results indicate that global statistics of flowmotion, such as the mean value in a large region of interest, is more representative of the microcirculation than data measured only in a single point. Therefore, imaging techniques have potential to increase the clinical usefulness of flowmotion analysis. • Flowmotion imaging displays significant spatiotemporal variations in forearm skin blood flow. • Flowmotion imaging has potential to be more accurate than single-point techniques. • A simple and effective method for motion artifact removal is presented.

Ischemic Preconditioning Acutely Improves Functional Sympatholysis during Handgrip Exercise in Healthy Males but not Females.

Ischemic preconditioning (IPC), a procedure that involves the cyclic induction of limb ischemia and reperfusion via tourniquet inflation, has been reported to improve exercise capacity and performance, but the underlying mechanisms remain unclear. During exercise, sympathetically mediated vasoconstriction is dampened in active skeletal muscle. This phenomenon, termed functional sympatholysis, plays a critical role in maintaining oxygen delivery to working skeletal muscle and may contribute to determining exercise capacity. Herein, we investigate the effects of IPC on functional sympatholysis in humans. In 20 (10M/10F) healthy young adults, forearm blood flow (Doppler ultrasound) and beat-to-beat arterial pressure (finger photoplethysmography) were measured during lower body negative pressure (LBNP; -20 mm Hg) applied at rest and simultaneously during rhythmic handgrip exercise (30% maximum contraction) before and after local IPC (4 × 5-min 220 mm Hg) or sham (4 × 5-min 20 mm Hg). Forearm vascular conductance (FVC) was calculated as forearm blood flow/mean arterial pressure and the magnitude of sympatholysis as the difference of LBNP-induced changes in FVC between handgrip and rest. At baseline, LBNP decreased FVC (females [F] = ∆-41% ± 19%; males [M] = ∆-44% ± 10%), and these responses were attenuated during handgrip (F = ∆-8% ± 9%; M = ∆-8% ± 7%). After IPC, LBNP induced similar decreases in resting FVC (F = ∆-37% ± 19%; M = ∆-44% ± 13%). However, during handgrip, this response was further attenuated in males (∆-3% ± 9%, P = 0.02 vs pre) but not females (∆-5% ± 10%, P = 0.13 vs pre), which aligned with an IPC-mediated increase in sympatholysis (M-pre = 36% ± 10% vs post = 40% ± 9%, P = 0.01; F-pre = 32% ± 15% vs post = 32% ± 14%, P = 0.82). Sham IPC had no effect on any variables. These findings highlight a sex-specific effect of IPC on functional sympatholysis and provide evidence of a potential mechanism underlying the beneficial effects of IPC on human exercise performance.