Barnes, Jill N.

Vascular function in older women versus young women may differ based on the β‐adrenergic receptor‐mediated contribution to basal vascular tone. Thus, we tested the hypothesis that forearm blood flow (FBF) responses to the β‐receptor agonist isoproterenol (ISO) are blunted in older, postmenopausal women compared to young, premenopausal women. We used venous occlusion plethysmography to measure FBF in young (26 ± 3 yr; n = 13) and older (61 ± 6 yr; n = 12) women. FBF and mean arterial pressure (MAP) were measured at baseline and during ISO infusion at 1.0, 3.0, 6.0, and 12.0 ng/100 ml tissue/min. The two groups did not differ in body mass index or MAP. Baseline FBF (3.7 ± 1.7 vs. 2.9 ± 1.3 ml/100 ml/min, respectively) and forearm vascular conductance (FVC) (0.04 ± 0.02 vs. 0.03 ± 0.01 AU, respectively) were similar between young and older women. FBF and FVC remained similar between the groups for all ISO doses, including the 12.0 ng/100 ml tissue/min dose of ISO, for which the greatest difference between the groups would be expected; FBF was 10.7 ± 2.3 vs. 9.4 ± 2.1 ml/100 ml/min (young vs. older, respectively) and FVC was 0.11 ± 0.02 vs. 0.10 ± 0.02 AU (young vs. older, respectively). In conclusion, β‐adrenergic receptor‐mediated forearm responses to stimulation are similar between young and older women, suggesting that β‐adrenergic receptor response and contribution to vascular tone are preserved with aging in women. Funded by NIH

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.

Lower body negative pressure (LBNP) is often used to simulate blood loss in humans. However, it is unknown if the effects of actual blood loss (BL) on cerebral blood flow regulation is analogous to simulated blood loss during LBNP. Nine healthy men (32±6 y) were studied at baseline, during 3 levels of LBNP (5 min each at ‐15, ‐30, ‐45 mmHg), and during 3 levels of blood loss (5 min each at 333, 667, 1000 mL). LBNP and BL conditions were randomized. Intra‐arterial mean arterial pressure (MAP) was similar during LBNP compared with BL (p>0.20). Central venous pressure (CVP; 2.8±0.7 vs. 4.0±0.8, 1.2±0.6 vs. 3.5±0.8, 0.2±0.9 vs. 2.1±0.9 mmHg for level 1, 2, and 3; p<0.01) and stroke volume (71±4 vs. 80±3, 60±3 vs. 74±3, 51±2 vs. 68±4 mL for level 1, 2, and 3; p<0.01) were lower during LBNP compared with BL. Despite differences in CVP, middle cerebral artery velocity (MCAv) and cerebrovascular conductance index (CVCi) were similar between LBNP and BL at each level (MCAv at level 3: 62±6 vs. 66±5 cm/s; p=0.37; CVCi at level 3: 0.72±0.05 vs. 0.73±0.05 cm/s/mmHg; p=0.29). Furthermore, the slope of the relationship between MAP and MCAv was not different between LBNP and BL (1.06 vs. 1.07 cm/s/mmHg). Our results suggest that the cerebral hemodynamic responses to LBNP are similar to actual blood loss. Grant Funding Source : Supported by U.S. Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823

The relationship between mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and total peripheral resistance (TPR) is altered in young women versus men and postmenopausal women due to endogenous sex hormone differences. Exogenous sex hormones in the form of oral contraceptive pills (OCPs) may further affect this relationship. We performed a retrospective review of 136 premenopausal women in whom MSNA and arterial pressure were measured, including 78 women with natural menstrual cycles in the early follicular phase (26±1 yr) and 58 women in the placebo phase of OCPs (24±1 yr). TPR and cardiac output (CO) were measured in a subset of women in whom continuous intra‐arterial blood pressure was recorded. Compared to those with natural menstrual cycles, women on OCPs had greater MAP (89±1 vs. 84±1 mmHg, p<0.01) and tended to have lower MSNA (15±1 vs. 18±1 bursts/100 heart beats, p=0.06). MAP and MSNA were positively correlated (r=0.22, p<0.05), TPR and MSNA were positively associated (r=0.41, p<0.05) and CO and MSNA (r=‐0.44, p<0.05) were inversely associated in naturally cycling women (n=26) but not in women on OCPs (r=0.15, r=0.11, r=‐0.01, respectively; p>0.05; n=38). In contrast to naturally cycling women, there appears to be no relationship between MSNA and hemodynamics in women on OCPs, suggesting that these women may regulate their blood pressure differently than women. Grant Funding Source : Supported by NIH

Abstract BACKGROUND Studies demonstrate an association between aortic hemodynamics and cognitive function. The impact of pregnancy history on this association is unknown. METHODS Postmenopausal women (age 59 ± 5 years; years since last pregnancy 35 ± 3) with either a history of preeclampsia (PE; n = 34) or a history of a normotensive pregnancy (NP; n = 30) underwent cognitive testing: Letter-Number Sequencing, Digit Span, Trail Making Test, and letter and category fluency. Applanation tonometry was used to derive aortic systolic and diastolic blood pressure and augmentation index. RESULTS Distribution of cognitive scores and aortic hemodynamic measures was similar between the PE and NP groups. Principal component (PC) analysis was used to reduce the 3 aortic hemodynamic measures and the 5 cognitive variables to single summary indices, each representing a weighted average of their respective constituent variables. Using a multivariable linear model based on these PCs that adjusted for pregnancy history and body mass index, the composite index of aortic hemodynamics was associated with the summary cognitive index, whether taking into account a potential interaction with pregnancy history (P = 0.035) or not (P = 0.026) (interaction P = 0.178). Multivariable modeling of individual cognitive tests revealed a differential association for letter fluency by pregnancy history (test for interaction P = 0.023); this score correlated with the aortic hemodynamic index in the PE (partial R2 = 0.20), but not the NP (partial R2 = 0.00) group. CONCLUSIONS Elevated aortic hemodynamics may negatively impact cognitive function in postmenopausal women with specific executive functions, such as letter fluency, being impacted more by a pregnancy history of PE.

Aging increases autonomic support of blood pressure; however, the impact of aerobic fitness on autonomic support of blood pressure has not been addressed in women. As such, we hypothesized that aerobic fitness would be related to the change in blood pressure during ganglionic blockade such that women with greater aerobic fitness would have a blunted fall in blood pressure during ganglionic blockade due to increased vagal tone. Thirteen young premenopausal and 13 older postmenopausal women completed a screening visit where aerobic fitness (maximal oxygen consumption, VO 2max ) was measured. On a separate study day, participants were instrumented for assessment of muscle sympathetic nerve activity, heart rate (electrocardiography), and beat by beat blood pressure (arterial catheter and pressure transducer) and underwent pharmacological blockade of the autonomic ganglia using trimethaphan camyslate. Heart rate, blood pressure, and muscle sympathetic nerve activity were analyzed before and during ganglionic blockade. In young women, there was a significant relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =0.761, P =0.003). In older women, there was no relationship between aerobic fitness and the change in blood pressure during ganglionic blockade ( r =−0.106, P =0.73). Measures of heart rate variability were related to fitness in young women, but not older women (root mean square of successive differences between normal heartbeats, r =0.713, P =0.006 versus r =−0.172, P =0.575). Our data suggest that in young women, autonomic support of blood pressure is attenuated in those that are highly fit; however, this relationship is not significant in older women.

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.

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.

AbstractBiological sex and changes in sex hormones throughout life influence all aspects of health and disease. In women, changes in sex hormonal status reflect ovarian function, pregnancy and the use of exogenous hormonal treatments. Longitudinal data from defined cohorts of women will help to identify mechanisms by which the hormonal milieu contributes to cerebrovascular ageing, brain structure and ultimately cognition. This review summarises the phenotypes of three cohorts of women identified through the medical records‐linkage system of the Rochester Epidemiology Project and the Mayo Clinic Specialized Center of Research Excellence (SCORE) on Sex Differences: (i) menopausal women with histories of normotensive or hypertensive pregnancies; (ii) women who had bilateral oophorectomy ≤45 years of age; and (iii) women who experienced natural menopause and used menopausal hormone treatments for 4 years. Data from these cohorts will influence the design of follow‐up studies concerning how sex hormonal status affects neurovascular ageing in women.