Ranadive, Sushant M.

AbstractMenopause is associated with vascular dysfunction. During the menopausal transition, endogenous oestradiol concentrations diminish. Oestradiol is vasoprotective because it has direct and indirect effects on the vasculature. The present study aimed to determine the effect of acute exogenous oestradiol on endothelium‐dependent, endothelium independent and β2‐adrenergic receptor‐induced vasodilatation in females. Forearm blood flow (venous occlusion plethysmography) was measured during brachial intraarterial infusions of ACh (endothelium‐dependent agonist), sodium nitroprusside (endothelium independent agonist) and terbutaline (β2‐adrenergic receptor agonist) with and without concurrent infusion of 17β‐oestradiol. Nine young premenopausal (age: 26 ± 4 years) and nine postmenopausal (PM, age: 58 ± 4 years, 8 ± 1 years post‐menopause) females completed the study. Concurrent oestradiol infusion augmented the vasodilatory response to ACh, sodium nitroprusside and terbutaline in young premenopausal (all P < 0.05) but not older postmenopausal (all P > 0.05), females. Local infusion of exogenous 17β‐oestradiol augmented endothelial and smooth muscle microvascular vasodilatation in premenopausal but not postmenopausal, females. imageKey points Menopause is associated with vascular dysfunction. Because oestradiol has vasoprotective effects, the menopause‐associated drop in oestradiol concentrations is hypothesized to contribute to vascular dysfunction during the menopause transition. The present study shows that local infusion of exogenous oestradiol augmented microvascular vasodilatation in premenopausal but not postmenopausal females.

The purpose of this study was to explore dose dependent vasodilation responses of the individual compounds of Shakuyakukanzoto (SKT), a 1:1 combination of extracts from Paeony and Licorice roots: glycyrrhetic acid (GA), paeoniflorin (PF), and isoliquiritigenin (ISO). 20 young, healthy participants (13M/7W) had four intradermal microdialysis fibers placed in the forearm skin for local delivery of: 1) control (diluent), 2) GA, 3) PF, or 4) ISO at doses of 1, 10, 50, or 100 μm. Cutaneous red cell flux, an index of skin blood flow, was measured by laser‐Doppler flowmetry. Blood pressure (BP) was monitored continuously during fixed measurement periods via finger photo‐plethsmography (Finapres). Cutaneous vascular conductance (CVC) was derived as red cell flux divided by BP and was normalized as a percentage of baseline (%CVCbl, saline at 4 μl/min) and the maximum CVC (%CVCmax, 28mM sodium nitroprusside at 4 μl/min, local temperature 43°C). Mean CVC did not statistically differ between baseline and individual compound plateau (average of last 5 minutes of infusion) at any dose. The peak flux was significantly higher from baseline at doses 50 and 100 μm for control (56.17±13.32 vs. 96.73±20.32 and 44.64±5.68 vs. 80.21±9.54), PF (62.70±10.09 vs. 115.72±16.16 and 62.37±16.2 vs. 150.21±34.26), GA (48.37±4.41 vs. 71.76±7.16 and 58.36±13.68 vs. 91.51±3.41), and ISO (96.50±23.20 vs. 128.57±27.90 and 44.95±8.78 vs. 91.18±20.37) (p<0.05). However, peak CVC was significantly higher only for GA at dose 50 μm, as well as for control and PF at dose 100 μm compared to their respected baselines (GA: 0.60±0.06 vs. 1.01±0.11, control: 0.61±0.09 vs.1.55±0.61, PF: 0.81±0.20 vs. 1.30±0.30, p<0.05). There were no other significant differences between the control and the compounds for change in CVC from baseline to peak (ΔCVC), %CVCbl, or %CVCmax. There were no significant differences between doses 1, 10, or 50 as compared to 100 μm for other variables. These results suggest that the doses may be lower or below the threshold to cause a vasodilatory effect. Future studies that investigate higher doses of these compounds may be needed. Support or Funding Information The University of Oxford Systems Biology Project sponsored by Tsumura.

AbstractWe tested the hypothesis that post‐COVID‐19 adults (PC) would have impaired cutaneous nitric oxide (NO)‐mediated vasodilation compared to controls (CON). We performed a cross‐sectional study including 10 (10 F/0 M, 69 ± 7 years) CON and 7 (2 F/5 M, 66 ± 8 years) PC (223 ± 154 days post‐diagnosis). COVID‐19 symptoms severity (survey) was assessed (0–100 scale for 18 common symptoms). NO‐dependent cutaneous vasodilation was induced by a standardized 42°C local heating protocol and quantified via perfusion of 15 mM NG‐nitro‐L‐arginine methyl ester during the plateau of the heating response (intradermal microdialysis). Red blood cell flux was measured with laser‐Doppler flowmetry. Cutaneous vascular conductance (CVC = flux/mm Hg) was presented as a percentage of maximum (28 mM sodium nitroprusside +43°C). All data are means ± SD. The local heating plateau (CON: 71 ± 23% CVCmax vs. PC: 81 ± 16% CVCmax, p = 0.77) and NO‐dependent vasodilation (CON: 56 ± 23% vs. PC: 60 ± 22%, p = 0.77) were not different between groups. In the PC group neither time since diagnosis nor peak symptom severity (46 ± 18 AU) correlated with NO‐dependent vasodilation (r < 0.01, p = 0.99 and r = 0.42, p = 0.35, respectively). In conclusion, middle‐aged and older adults who have had COVID‐19 did not have impaired NO‐dependent cutaneous vasodilation. Additionally, in this cohort of PC, neither time since diagnosis nor symptomology were related to microvascular function.

A history of preeclampsia (PE) places women at higher risk for future cardiovascular disease and cognitive decline. We have previously shown that postmenopausal women with a history of PE demonstrated a reduced cerebral blood flow response to hypercapnia compared with postmenopausal women with a history of a normotensive pregnancy (NP). These findings suggest cerebrovascular effects of PE 30+ years postpartum. In addition, we have reported that women with a history of PE did not have an exaggerated pressor response to a sympathoexcitatory stimulus. However, it is possible that women with a history of PE may have an altered cerebral blood flow response to a sympathoexcitatory stimulus. In this study, middle cerebral artery blood velocity (MCAv) and beat‐to‐beat mean arterial blood pressure (MAP) were measured during isometric handgrip to fatigue (IHG) at 30% of maximal voluntary contraction followed by post‐exercise ischemia (PEI) for 90 seconds and a two minute recovery period (REC). Participants were postmenopausal women with a history of PE (n = 21; age at study = 58±5 y; years since last pregnancy = 35±3 y) and NP (n = 27; age at study = 58±5 y; years since last pregnancy = 35±3 y). Baseline MAP and MAP responses to IHG and PEI were similar between groups (p>0.05). PE women demonstrated lower MCAv at baseline (NP: 72±3 cm/s vs. PE: 57±4 cm/s), IHG (NP: 78±4 cm/s vs. PE: 63±4 cm/s), PEI (NP: 74±4 cm/s vs. PE: 60±4 cm/s), and REC (NP: 70±3 cm/s vs. PE: 58±4 cm/s) compared with NP women (p<0.05 for all). MCAv, when calculated as a percent change from baseline, was elevated during IHG in both PE and NP women as expected (p<0.05); however, PE women had an augmented MCAv response during the last third of IHG compared with NP women (NP: 9±2 % vs. PE: 13±2 %; p<0.05). PE women also had a higher MCAv response during REC compared with NP women (NP:−2±2% vs. PE: 3±2%; p<0.05). Importantly, these elevated MCAv responses occurred despite the fact that MAP was not different between groups. In summary, PE women demonstrated a lower basal cerebral blood velocity but an elevated cerebrovascular response to a sympathoexcitatory stimulus compared with NP women. This suggests that in postmenopausal women, there is an effect of pregnancy history on the sensitivity of the cerebral blood flow response to a sympathoexcitatory stimulus. Support or Funding Information NIH: AG 044170. This investigation was supported by the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32 HL 007936 from the National Heart Lung and Blood Institute to the University of Wisconsin‐Madison Cardiovascular Research Center. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Introduction Acute estrogen infusion augments β 2 ‐adrenergic receptor responsiveness in premenopausal women. This suggests an influential role of estrogen in controlling the vasodilator responsiveness via β 2 ‐adrenergic receptors in premenopausal women. Postmenopausal women present with a reduced β 2 ‐adrenergic receptor responsiveness as compared to premenopausal women. This divergent finding in β 2 ‐adrenergic receptor responsiveness could be due to loss of endogenous estrogen postmenopause. Objective Hence, the objective of the study was to compare the β 2 ‐adrenergic vasodilator responses with and without estrogen in postmenopausal women. We hypothesized that the vasodilator effects during endothelial dependent, independent and during β 2 ‐adrenergic agonist infusion would be significantly greater with acute, local estrogen administration. Methods Venous occlusion plethysmography was used to measure forearm blood flow (FBF) in 8 older (age = 59 ± 1 years) healthy, non‐obese (BMI = 23 ± 1 kg/m 2 ) women. FBF was measured at baseline and during an intra‐arterial infusion of acetylecholine (ACH) at 1.0, 2.0, 4.0, and 8.0 μg/100 ml tissue/min, sodium nitroprusside (NTP) at 0.25, 0.5, 1.0 and 2.0 ug/100 ml tissue/min and terbutaline (β 2 agonist) at 0.1, 0.5, 1.0, 2.0 μg/100 ml tissue/min before (with dextrose co‐infusion) and during acute, local intra‐arterial infusion of estrogen (20 ηg/mL at 1 mL/min). Forearm vascular conductance (FVC) was calculated as FBF divided by mean arterial pressure. Area under the curve (AUC) was calculated for the absolute FVC and percent baseline FVC of ACH, NTP and terbutaline. Results There were no significant differences in FVC with estrogen infusion as compared to control during ACH, NTP and all terbutaline doses except dose 2 of ACH (Table 1). The AUC are not significantly different during estrogen (p>0.05) as compared to control for ACH, NTP and terbutaline (figure 1). Conclusions These data suggest that acute administration of estrogen, which corresponds to the endogenous levels of estrogen seen in premenopausal women during mid‐cycle, does not augment the β 2 ‐adrenergic vasodilator responses in postmenopausal women. Additionally, these data suggest that estrogen infusion does not increase the endothelial dependent and independent vasodilatory capacity in postmenopausal women. Support or Funding Information HL83947 (MJJ) and Mayo Clinic Women's Health Scholarship (K12 HD065987). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Common carotid artery (CA) and middle cerebral artery (MCA) blood flow are controlled by multiple factors to ensure that the brain receives adequate blood supply. Additionally, CA arterial stiffness may affect blood flow regulation. The purpose of this study was to investigate the effect of cyclooxygenase (COX) inhibition on arterial stiffness and the relationship between CA and MCA blood flow in young (26±5y) and older (66±7y) adults to determine if aging modifies this relationship. While baseline CA flow and flow velocity were similar between groups, baseline MCA flow velocity was greater in young (59±6 cm/s) compared to older (40±4 cm/s) adults (p<0.05). During COX inhibition, CA flow, CA flow velocity and MCA flow velocity decreased from baseline in young (∆: ‐116±35 mL/min, ‐6±1 cm/s, ‐23±5 cm/s; respectively) and older adults (∆: ‐153±40 mL/min, ‐5±1 cm/s, ‐11±2 cm/s; respectively). The association between CA flow velocity and MCA flow velocity was altered by COX inhibition (r=0.60 vs. r=0.15). β‐stiffness was higher in older compared to young adults (13±2 vs. 5±1 AU; p<0.05). Among older adults, there was a trend for COX inhibition to increase β‐stiffness. Our results suggest that CA and MCA blood flow are regulated differently and that COX inhibition alters the correlation between CA and MCA blood flow. Therefore, it may be incorrect to assume that CA flow is a surrogate measurement for cerebral blood flow.

New Findings What is the central question of this study? What is the role of β2‐adrenergic receptor (β2AR) vasodilatation in older postmenopausal women as compared to premenopausal women and the role of nitric oxide (NO) in β2AR‐mediated vasodilatation in both groups of women? What is the main finding and its importance? β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women. Additionally, NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women. Abstractβ2‐Adrenergic receptor (β2AR)‐mediated vasodilatation, which is partially dependent on nitric oxide (NO) formation, is blunted in men at risk for developing hypertension. However, the role of β2AR 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 β2AR 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 β2AR‐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). There were significant group × dose interactions for FBF (P = 0.01) and FVC (P = 0.001), indicating vasodilator responses were lower in postmenopausal women. In young women, FVC response to the highest dose of terbutaline tended to be lower with l‐NMMA co‐infusion vs. without l‐NMMA (P = 0.05). There were no significant decreases in FBF or FVC responses to terbutaline in postmenopausal women with l‐NMMA co‐infusion (P > 0.05 for all). These data suggest that β2AR responsiveness is blunted in postmenopausal women compared to young premenopausal women, and that NO may contribute to β2AR‐mediated vasodilatation in young premenopausal women.

New Findings What is the central question of this study? What is the effect of an elevated baseline blood flow, induced by high‐dose intra‐arterial infusion of either adenosine or ATP, on the rapid‐onset vasodilatory response to a single forearm muscle contraction? What is the main finding and its importance? The peak response to a single contraction is unaffected by augmented baseline blood flow, and thus, is likely to be attributable to a feedforward vasodilatory mechanism. AbstractThe hyperaemic responses to single muscle contractions are proportional to exercise intensity, which, in turn, is proportional to tissue metabolic demand. Hence, we tested the hypothesis that the rapid‐onset vasodilatory response after a single muscle contraction would be unaffected when baseline blood flow was increased via high‐dose intra‐arterial infusion of either adenosine (ADO) or ATP. Twenty‐four healthy young participants (28 ± 1 years) performed a single forearm contraction (20% maximal voluntary contraction) 75 min after commencement of a continuous infusion of ADO (n = 6), ATP (n = 8) or saline (control; n = 10). Brachial artery diameter and blood velocity were measured using Doppler ultrasound. Resting forearm vascular conductance (FVC; in millilitres per minute per 100 mmHg per decilitre of forearm volume) was significantly higher during ADO (33 ± 17) and ATP infusion (33 ± 17) compared with the control infusion (8 ± 3; P < 0.05). The peak FVCs post‐contraction during ADO and ATP infusions were significantly greater than during the control infusion (P < 0.05), but not different from one another. The peak change in FVC from baseline was similar in all three conditions (control, 14 ± 1; ADO, 24 ± 2; and ATP, 23 ± 6; P = 0.15). Total FVC (area under the curve) did not differ significantly between ADO and ATP (333 ± 69 and 440 ± 125); however, total FVC during ATP infusion was significantly greater compared with the control value (150 ± 19; P < 0.05). We conclude that the peak response to a single contraction is unaffected by augmented baseline blood flow and is therefore likely to be attributable to a feedforward vasodilatory mechanism.

Preeclampsia (PE) is a hypertensive disorder of pregnancy described as a condition of excessive sympathoexcitation. PE places a woman at increased risk for lifelong hypertension and cognitive impairment. Cerebral blood velocity is blunted in response to a vasoactive stimulus in women with a history of PE. This study investigated how a sympathoexcitatory stimulus affects cerebral blood velocity in women with a history of PE. Middle cerebral artery blood velocity (MCAv) and beat-to-beat mean arterial blood pressure (MAP) were measured in postmenopausal women with a history of PE ( n = 21; age = 59 ± 5 yr) and a history of a normotensive pregnancy (NP; n = 27; age = 58 ± 4 yr), at baseline, during isometric handgrip to fatigue (IHG) followed by postexercise ischemia (PEI), and a recovery period (REC). Baseline MAP and MAP responses to IHG and PEI did not differ between groups. MCAv at baseline and throughout the stimulus was lower in PE women compared with NP women ( P < 0.05 for all). MCAv increased during IHG in both groups ( P < 0.05). This increase in MCAv was greater in PE compared with NP women during IHG and REC (IHG: PE 13 ± 2% vs. NP 9 ± 2%; REC: PE 3 ± 2% vs. NP −2 ± 2%; P < 0.05 for both). Thus, a history of PE is associated with low baseline cerebral blood velocity but an augmented response to a sympathoexcitatory stimulus. These changes in cerebral blood flow regulation may lead to an increased risk for cognitive impairment in women with a history of PE.