Barnes, Jill N.

Women with uterine fibroids (UF), benign tumors of the myometrium, have a greater prevalence of hypertension than women without UF. The mechanism of this predisposition is unclear. Individuals with borderline hypertension have endothelial dysfunction in the form of decreased endothelium‐dependent vasodilation in response to intra‐arterial acetylcholine infusion. It is possible that women with UF also demonstrate impaired endothelium‐dependent vasodilation prior to overt clinical hypertension. We measured forearm blood flow (FBF) using venous occlusion plethysmography at baseline and during intra‐arterial acetylcholine (ACH; 1.0‐4.0 μg/100 ml tissue/min) and sodium nitroprusside (SNP; 0.25‐2.00 μg/100 ml tissue/min) infusions in 4 normotensive women with UF (41±3 y) and 4 age‐matched normotensive women without UF. These women did not differ in body mass index or mean arterial pressure (97±4 vs. 103±6 mmHg, Control vs. UF; p>0.05). Baseline FBF was not different between the two groups (1.6±0.4 vs. 3.0±1.3 ml/100 ml tissue/min; Control vs. UF; p>0.05). FBF increased significantly from baseline in both groups at the highest doses of ACH and SNP; however, the change in FBF was not significantly different between groups (ACH: Δ8.6±1.6 vs. 9.5±4.1 ml/100 ml tissue/min; SNP: Δ9.8±3.0 vs. 13.1±4.6 ml/100 ml tissue/min; Control vs. UF; p>0.05). Our preliminary results suggest that FBF responses to ACH and SNP do not differ between women with and without UF; thus, impairments in endothelium‐dependent and ‐independent vasodilation do not appear to contribute to hypertension risk in normotensive women with UF. Funded by AHA and NIH.

Cerebrovascular reactivity to hypercapnia declines with age and low reactivity may be a biomarker of cognitive decline. Central elastic arteries that perfuse the brain stiffen with age, increasing their transmission of pulsatile mechanical forces into the cerebral microvasculature and impairing cerebral microvessel function. Habitual physical activity, however, has been shown to reduce central arterial stiffness and is associated with better cognitive function. Therefore, the purpose of this study was to evaluate cerebrovascular reactivity in young and older healthy adults who habitually exercise. We hypothesized that older adults who habitually exercised would have similar cerebrovascular reactivity when compared with young adults. However, because the underlying mechanisms of cerebral blood flow regulation may differ with age, we also evaluated blood pressure and central hemodynamic measures. We recruited 25 young (YA: age = 27 ± 1 y) and 20 older (OA: age = 59 ± 1 y) habitual exercisers. Middle cerebral artery velocity (MCAv) was recorded using transcranial Doppler ultrasound. In order to assess cerebrovascular reactivity, mean arterial pressure (MAP), end‐tidal carbon dioxide (ETCO 2 ), and MCAv were continuously recorded at rest and during stepwise elevations of inhaled CO 2 . Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. Reactivity was calculated as the linear relationship between the change in ETCO 2 and the change in each variable of interest (MCAv, CVCi and MAP). Central arterial stiffness (carotid‐femoral pulse wave velocity, PWV) and central hemodynamics (augmentation index, AIx) were assessed by applanation tonometry. Older adults had higher MAP (YA: 85 ± 2 mmHg; OA: 90 ± 3 mmHg; p<0.05) and AIx (YA: 0 ± 3 %; OA: 20 ± 2 %; p<0.05) at rest compared with young adults. PWV was not statistically different between groups (YA: 4.9 ± 0.3 cm/s; OA: 5.7 ± 0.5 cm/s; p=0.18). MCAv and CVCi reactivity to hypercapnia were similar between young and older adults (MCAv reactivity, YA: 2.0 ± 0.2 cm/s/mmHg; OA: 2.2 ± 0.1 cm/s/mmHg; p=0.46, CVCi reactivity, YA: 0.018 ± 0.002 cm/s/mmHg 2 ; OA: 0.016 ± 0.001 cm/s/mmHg 2 ; p=0.42); however, older adults demonstrated higher MAP reactivity to hypercapnia (YA: 0.3 ± 0.1 a.u.; OA: 0.8 ± 0.1 a.u.; p<0.05). PWV and AIx were not associated with MCAv, CVCi, or MAP reactivity to hypercapnia (p>0.05). Our results suggest that habitual exercise preserves cerebrovascular reactivity; however, MAP reactivity is augmented with aging allowing older adults to sufficiently increase cerebral blood flow during hypercapnia. Support or Funding Information Supported by National Institute of Health grant HL118154 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Cerebrovascular reactivity to hypercapnia, an estimate of microvascular responses in the brain, is increased during menopausal hormone treatment (MHT) in postmenopausal women. It is unclear whether this effect of MHT continues beyond the treatment period. We hypothesized that prior MHT use would not affect cerebrovascular reactivity 3 years after treatment. In addition, we have previously shown that cerebrovascular reactivity is associated with vascular activation in postmenopausal women with elevated cardiovascular risk. We hypothesized that cerebrovascular reactivity is not associated with markers of intravascular cellular activation in postmenopausal women with low cardiovascular risk who are within 10 years of menopause. Cerebrovascular reactivity to hypercapnia was measured in 58 postmenopausal women from the Kronos Early Estrogen Prevention Study at Mayo Clinic 3 years after the cessation of MHT [oral conjugated equine estrogen (oCEE), n=15; transdermal 17β‐estradiol (tE2, n=22); or placebo (PLA, n=23)]. Cerebrovascular reactivity was estimated from the middle cerebral artery flow velocity (MCAv) response to hypercapnia. Mean arterial blood pressure (MAP) was measured continuously throughout the protocol. Fasting blood was analyzed for a set of 14 activation markers of platelet and endothelial cells, inflammation and thrombogenicity. Principal components (PC) analysis was used to reduce these measures to fewer dimensions on which the associations of intravascular cellular activation with cerebrovascular reactivity could be based. Women were 60±3 years of age with a body mass index of 28±4 Kg/m 2 . MAP (99±14 mmHg in PLA, 97±7 mmHg in tE2, 98±9 mmHg in oCEE; p>0.90) and MCAv (60±14 cm/s in PLA, 68±20 cm/s in tE2, 71±18cm/s in oCEE; p>0.16) did not differ among groups. Cerebrovascular reactivity did not differ among women based on previous MHT randomization (1.2±0.7 cm/s/mmHg in PLA, 1.4±1.0 cm/s/mmHg in tE2 and 1.7±1.0 cm/s/mmHg in oCEE; p>0.17). The 14 markers of intravascular cellular activation were reduced to five PC that did not differ based on prior MHT assignment. There was no overall association of cellular activation PC with cerebrovascular reactivity. Effects of MHT on cerebral microvascular reactivity do not extend beyond the time of menopausal hormone treatment. Intravascular cellular activation does not alter cerebrovascular reactivity to hypercapnia in postmenopausal women with low cardiovascular risk profiles 3 years after the cessation of MHT. Support or Funding Information NIH grant P50 AG44170 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Reduced cerebral blood flow and reactivity may explain age‐related changes in cognitive function. We examined cerebrovascular reactivity, and the potential role of prostaglandins, in young and old healthy humans. Middle cerebral artery velocity (MCAv) responses to stepped hypercapnia were measured in young (26±2y; 6M/5F) and old (66±2y, 3M/4F) adults before (PRE) and 90 min after (POST) oral indomethacin (1.2mg/kg). To account for any changes in blood pressure, cerebrovascular conductance index (CVCi) was calculated as the MCAv divided by mean arterial pressure. Cerebrovascular reactivity slopes were calculated using linear regression between either MCA velocity or CVCi and end‐tidal CO 2 . There were no differences between young and old adults in height, weight, BMI, or brachial blood pressures. Young adults demonstrated greater MCAv (53.7±6.7 vs. 32.0±3.3), MCAv reactivity (1.62±0.21 vs. 0.94±0.10), and CVCi (0.66±0.08 vs. 0.39±0.04) compared with old adults at PRE (P<0.05 for all). In both young and old adults, MCAv, MCAv reactivity, CVCi, and CVCi reactivity decreased between PRE and POST measurements. Furthermore, any age‐related differences in these cerebrovascular variables were abolished by indomethacin. These results suggest that cerebral blood flow and cerebrovascular reactivity is attenuated in aging adults and that this reduction may be mediated by prostaglandins. NIH: AG16574‐11PP2

Baroreflex sensitivity is calculated from the slope of the relationship between blood pressure and muscle sympathetic nerve activity (MSNA) or cardiac R‐R interval. The magnitude of decrease in blood pressure during a vasoactive drug bolus (i.e. modified Oxford) to test the baroreflex may be associated with the calculated baroreflex sensitivity (BRS) slope. We investigated whether the cardiac or sympathetic BRS are associated with the acute decrease in blood pressure during a modified Oxford in young healthy men and women. Forty‐five women (27 ± 1 yrs, BMI 22.9 ± 0.3 kg/m2) and 30 men (27 ± 1 yrs, 24.2 ± 0.4 kg/m2) were studied. MSNA was measured via peroneal microneurography and blood pressure was measured with a brachial intraarterial catheter. Women and men had similar mean arterial pressures (91 ± 1 vs. 90 ± 1 mmHg), cardiac BRS (19 ± 1 vs. 21 ± 2 ms/mmHg), and sympathetic BRS (−6 ± 0.4 vs. −7 ± 0.6 AU/beat/mmHg), respectively. The decrease in systolic blood pressure (SBP) and pulse pressure (PP) was positively related to cardiac BRS in men (r=.47; p<0.01; r=.49; p<0.01). However, there was no relationship between the decrease in blood pressure and sympathetic BRS in men. In addition, there was no association between any blood pressure transients with either cardiac or sympathetic BRS in women. Our results suggest the magnitude of decrease in blood pressure is associated with cardiac BRS in men, but not women. Funded by NIH

Pulse wave velocity (PWV) and sympathetic nerve activity increase with age. However, it is unknown if the age‐related increase in sympathetic activity influences PWV. We determined the effect of autonomic blockade on peripheral and central arterial stiffness in young (23 ± 4 yr) and older, postmenopausal (57 ± 3 yr) women before and during administration of trimethaphan camsylate. Arterial tonometry was used to measure carotid‐radial (peripheral) and carotid‐femoral (central) PWV. The groups did not differ in height, weight, BMI, or mean arterial pressure (MAP). At baseline, peripheral PWV did not differ between the groups. However, central PWV was significantly greater in older women compared with young women (8.2 vs. 6.1 m/s, respectively; p<0.05). Trimethaphan infusion caused a substantial drop in MAP; therefore, we corrected PWV for the change in MAP. Peripheral PWV was greater in older women compared with young women (0.12 vs. 0.08 m/s·mmHg −1 ; p<0.05). In addition, central PWV remained higher in older women during trimethaphan infusion (0.11 vs. 0.08 m/s·mmHg −1 in young; p<0.05). In conclusion, central PWV was greater in older women before and during autonomic blockade, whereas peripheral PWV was only higher in the older women after autonomic blockade. This suggests that peripheral PWV is influenced by sympathetic activity to a greater extent in young vs. older women. Funded by NIH

Acute ß‐adrenergic blockade (BB) increases aortic wave reflection in young women, however, it is unknown if this effect extends to post‐menopausal women. Thus, we examined systemic BB on aortic wave reflection in 14 post‐menopausal women (58 ± 2 yr). Non‐invasive aortic pressure waveforms were synthesized from high‐fidelity radial pressure waveforms obtained from applanation tonometry before and during systemic BB (0.25mg/kg bolus, with 0.004 mg/kg/min continuous infusion of propranolol). Aortic blood pressure, augmentation index (AIx), AIx adjusted for heart rate (AIx@75), aortic augmented pressure (AP), and wasted left ventricular energy (Ew) were calculated from the aortic pressure waveform. Heart rate (60 ± 2 vs. 51 ± 2 bpm) and mean arterial pressure (95 ± 3 vs. 91 ± 3 mmHg) were reduced with BB (P < 0.05 for both). AIx increased during BB (32 ± 2 vs. 35 ± 2%, P < 0.01), however, AIx@75 was unchanged (25 ± 2 vs. 24 ± 2%, ns). Additionally, AP (20 ± 2 vs. 20 ± 2 mmHg, ns) and Ew (4313 ± 538 vs. 4277 ± 537 dyne*cm2/sec, ns) remained unchanged during BB. When compared to our previously published study in young women, indices of aortic wave reflection were significantly less affected in post‐menopausal women in response to acute systemic BB. Taken together, our data suggest that the negative effects (i.e. increased aortic wave reflection) of non‐selective BB are less pronounced in post‐menopausal women.

In young women, tonic autonomic nervous system activity contributes less to resting blood pressure than that in men. It is unknown whether the autonomic support of blood pressure increases in postmenopausal women, therefore we examined the effect of autonomic blockade on blood pressure and how this relates to baseline muscle sympathetic nerve activity (MSNA) in women. Five young (23±4 yr) and 6 older (57±3 yr) women were examined before and during autonomic blockade using trimethaphan camsylate (TM). MSNA burst frequency and burst incidence were higher in older women (24±2 vs. 14±3 bursts/min; 41±3 vs. 23±5 bursts/100hb, respectively; p<0.05). Older women had a greater drop in mean arterial pressure (MAP; −25±2 vs. −8±3 mmHg; p<0.01) and total peripheral resistance (−0.7±0.1 vs. −0.2±0.1 AU; p<0.01) during autonomic blockade. MSNA bursts were abolished by TM within minutes. Baseline burst frequency and burst incidence were associated with the decrease in MAP during autonomic blockade (r=−0.64, r=−0.63; respectively; p<0.05). In conclusion, autonomic blockade reduces MAP to a greater extent in older women, and this decrease in blood pressure is associated with resting levels of MSNA. Our results suggest that autonomic support of blood pressure is greater in older women compared to young women. Elevated sympathetic nerve activity may explain the increased incidence of hypertension after menopause.

Aortic wave reflection increases with age, and is influenced by numerous factors, including sympathetic nerve activity. The purpose of this study was to examine the effect of autonomic blockade using trimethaphan camsylate on indices of aortic wave reflection in young (23±4 yr) and older postmenopausal (57±3 yr) women and determine if aging alters these interactions. Arterial tonometry was used to non‐invasively measure arterial waveforms from the radial artery before and during trimethaphan infusion. Aortic augmentation index (AI x ), augmented pressure, and left ventricular wasted energy (E w ) were higher in older women compared to young women at baseline (p<0.05). Mean arterial pressure was similar between young (93±5 mmHg) and older women (91±2 mmHg) at baseline. AI x (Δ −12±5%), augmented pressure (Δ −11±4 mmHg), and E w (Δ −2364±1020 dyne·cm 2 ·sec) decreased after autonomic blockade in older women (p<0.05 for all). In addition, the age‐related differences in AI x and aortic wave reflection persisted during autonomic blockade (p<0.05). In conclusion, autonomic blockade reduces augmentation index and aortic wave reflection in older women. Our results suggest that sympathetic activity contributes to the higher aortic wave reflection observed in older women.

Cerebral vasodilator responses to hypercapnia decrease with aging, and recent data suggests sex differences in cerebrovascular regulation exist. Yet, it is unknown how sex and age interact in response to the stress of cyclooxygenase inhibition. We examined cerebral vasodilator responses to hypercapnia in 7 young men (YM), 8 young women (YW), 7 older men (OM), and 6 older women (OW) before (CON) and during cyclooxygenase (COX) inhibition via indomethacin (INDO). There was no age by sex interaction in middle cerebral artery velocity responses to hypercapnia (MCAv Slope). However, when accounting for mean arterial pressure during hypercapnia, there was an age by sex interaction in cerebrovascular conductance index (CVCi Slope). YM demonstrated higher CVCi Slope (1.27 ± 0.21 AU) compared with YW (0.65 ± 0.10 AU) and older adults (0.58 ± 0.10 AU in OM; 0.66 ± 0.06 AU in OW; p<0.05 for all). There was no difference in CVCi Slope between YW and OW, indicating that the age‐associated reduction in CVCi Slope only pertains to men. During INDO, there was an age by sex interaction for the ΔCVCi Slope (from CON to INDO) with YM having a greater slope compared with both YW (0.72 ± 0.15 vs. 0.27 ± 0.13 AU; p<0.01) and OM (0.26 ± 0.18 AU; p<0.01). Taken together, our results suggest that sex differences exist in the cerebrovascular response to hypercapnia with and without COX inhibition and that the effect of age is different in women compared to men.