Joyner, Michael J.

<a name=“OLE_LINK2”></a><a name=“OLE_LINK1”>Hypertensive pregnancy (HP) disorders have been linked to a four‐fold increased risk for development of future cardiovascular diseases. We examined whether history of HP in postmenopausal women (N=20, 59±5 yr) influenced the risk factors for cardiovascular disease as assessed by aortic pulse wave characteristics, compared to age and parity matched controls (N=18, 60±4 yr). Non‐invasive aortic pressure waveforms were synthesized from high‐fidelity pressure waveforms obtained from SphygmoCor applanation tonometry using the radial artery. Aortic systolic and diastolic blood pressure (ASBP, ADBP), aortic augmentation index (AI x ), augmented pressure (AP), aortic pulse pressure (APP), and left ventricular wasted energy (E w ) were calculated from the generated aortic pressure waveform. There were no differences in ASBP (125±4 vs. 129±4 mmHg), ADBP (79±2 vs. 81±2 mmHg), AP (17±2 vs. 17±2 mmHg), AI x (35±2 vs. 29±1%), AI x @75BPM (31±2 vs. 29±1%), E w (3313±338 vs. 3364±432 dynes/cm 2 /s), between women with a history of HP vs. matched controls, respectively (P>0.05 for all). Body mass index was significantly higher in women with a history of HP (30.6±1 vs. 26.7±1 kg/m 2 , P<0.05), however it did not statistically influence any of the indices (P>0.05 for all). Our results suggest that postmenopausal women with a history of HP do not demonstrate elevated aortic blood pressure or altered aortic pulse wave characteristics in comparison to matched controls. </a> Supported by: National Institute of Aging 1P50AG044170‐01 and CTSA UL1 TR000135 and HL 118154

The forearm blood flow response to mental stress (MS) is due to circulating epinephrine (Epi), release of nitric oxide, and forearm sympathetic withdrawal. We recently demonstrated that forearm venous Epi predicts the vascular conductance (FVC) and HR response to MS. In a large, ongoing phenotyping study of sympathoexcitation and adrenergic receptor gene variation, we hypothesized that arterial Epi would predict the forearm vasodilator response to MS, while norepinephrine (NE) would predict the pressor response. In 54 healthy, normotensive young adults, FVC (plethysmography), HR (ECG), and blood pressure (brachial artery) were measured in a recumbent chair at rest and during 3 min of a computerized Stroop colored‐word test. During the final 30 sec of stress, arterial Epi and NE were assayed (HPLC). MS increased HR, BP, FVC, Epi, and NE (p < 0.05 for all). Unexpectedly, during MS the arterial Epi levels did not correlate with HR or FVC. However, a robust correlation existed for HR and FVC (r = 0.73, p < 0.001). Further, systolic pressure correlated with FVC (r = 0.36, p < 0.01) and NE (r = 0.46, p < 0.001). We conclude that the HR response to MS is a major contributor to FVC, independent of arterial Epi, suggestive of mechanical effects and potentially flow‐mediated dilation. This also confirms previous work that catecholamine spillover assays are more indicative of sympathoadrenal activation and hemodynamic responses. Support: K23 RR17520, HL 46493.

Hypercapnic cerebrovascular reactivity is decreased in obstructive sleep apnea and congestive heart disease patients. Ventilatory response to hypercapnia and/or hypoxia is blunted in apnea divers, whereas cerebrovascular reactivity to hypercapnia is presently unknown. We hypothesized that cerebrovascular reactivity to hypercapnia is increased in elite apnea divers, compared to control subjects, as a part of the O 2 conserving mechanism to maintain adequate brain O 2 supply. In the present study we determined cerebrovascular reactivity by measuring change in middle cerebral artery velocity per mmHg change in P ET CO 2 in response to two hyperoxic hypercapnia rebreathing maneuvers in seven elite apnea divers and seven control subjects. Ventilatory response to hypercapnia was blunted in divers compared to controls. Hypercapnia‐induced ventilation increase was significantly lower in divers due to lower respiratory frequency. Cerebrovascular reactivity was unchanged in both groups (3.7±1.4 vs 3.4±1.3 %/mmHg P ET CO 2 in divers and controls) and the same was found for cerebral vascular resistance and a time for middle cerebral artery velocity recovery to baseline value. Results indicate that the regulation of the cerebral circulation in response to hypercapnia shows no difference between divers and controls serving as protective mechanism against chronic intermittent cerebral hypoxia/hypercapnia. This study was supported by Croatian Ministry of Science, Education and Sports.

Cerebrovascular reactivity to hypercapnia is higher in women receiving menopausal hormone therapy (MHT) compared with controls, and this may persist after cessation of MHT. We hypothesized that the effect of MHT may be influenced by mean arterial pressure (MAP). Therefore, we examined both middle cerebral artery velocity (MCAv) and MAP responses to stepped hypercapnia in 60 postmenopausal women who were previously randomized to receive oral conjugated equine estrogen (oCEE, n=15), transdermal 17β estradiol (tE2, n=22), or placebo (PLA, n=23) for 4 years. After a 3 year washout period, reactivity was calculated from the slope of the relationship between MCAv or MAP and end‐tidal CO 2 . MCAv reactivity was higher in the oCEE group compared with the PLA group (1.6±0.2 vs. 1.1±0.1 cm/s/mmHg; oCEE vs. PLA, respectively, p<0.05), but similar between the tE2 and PLA group (1.3±0.2 vs. 1.1±0.1 cm/s/mmHg; tE2 vs. PLA, respectively, p>0.05). There were no significant differences in MAP reactivity (1.0±0.2, 0.6±0.1, 0.7±0.2 mmHg/mmHg of CO 2 , oCEE vs. tE2 vs. PLA, respectively, p>0.05) among the groups. However, in the combined MHT group, MAP reactivity was positively correlated with MCAv reactivity (r=0.58, p<0.001), such that women with higher MAP responses demonstrate greater MCAv responses to hypercapnia. In conclusion, there were no differences in MAP reactivity 3 years after cessation of MHT. In addition, our results suggest that greater cerebrovascular reactivity in postmenopausal women who received MHT may be driven by augmented blood pressure responses to hypercapnia. Funding: K99 HL 118164, AG 044170 and HL 83947.

Cerebral blood flow velocity responses to hypercapnia are blunted by the cyclooxygenase inhibitor indomethacin (INDO). We hypothesized that INDO would also attenuate middle cerebral artery blood flow velocity (MCAv) responses to an acute cognitive challenge. We evaluated the MCAv responses to an acute cognitive challenge in 20 healthy young (20‐35 yrs) and older (56‐76 yrs) healthy adults, including 10 men and 10 women before and 90 minutes after INDO administration. The cognitive challenge consisted of 2 blocks of the Stroop color word test: easy (3 colors) and difficult (8 colors). Mean arterial pressure (MAP), end‐tidal CO 2 , and MCAv were monitored throughout the protocol. There were no differences in MAP or end tidal CO 2 between trials. Indeed, MCAv was lower during INDO than baseline for both the easy (50±4 vs. 68±4 cm/s; p<0.01) and difficult (49±3 vs. 66±3 cm/s; p<0.001) cognitive challenges. Additionally, there was an Age x Sex interaction for the increase in MCAv during the easy cognitive task, with older men having a greater increase than older women (15±5 vs. ‐1±5%, respectively; p<0.05). This interaction was not statistically significant for the difficult cognitive task or during the INDO trial. In conclusion, similar to hypercapnia, the cyclooxygenase inhibitor INDO blunts cerebral blood flow velocity responses to an acute cognitive challenge. Funded by NIH grant HL 118154

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.

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 .

Introduction Baroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of patients with arterial hypertension not sufficiently responding to pharmacological therapy. Previous studies suggested that peripheral chemoreflex afferents located in proximity to carotid baroreceptors are tonically active in hypertensive patients and may inhibit baroreflex responses. Therefore, we hypothesized that peripheral chemoreflex activation attenuates the efficacy of electrical carotid sinus stimulation. Methods We screened 35 patients with an implanted electrical carotid sinus stimulator. Of those, 11 patients exhibited a consistent acute depressor response and were included in the study (7 men/4 women, age: 67±8 years, BMI: 31.6±5.2 kg/m 2 , 6±2 antihypertensive drug classes). We assessed responses to electrical baroreflex stimulation during normoxia, isocapnic hypoxia (SpO2: 79.0±1.5%), and hyperoxia (40% end‐tidal O2 fraction) by recording ECG, blood pressure (SBP), ventilation, SpO2, end‐tidal CO2 and O2 fractions, and muscle sympathetic nerve activity (MSNA). Results During normoxia, baroreflex activation reduced SBP from 164±27 to 151±25 mmHg (means±SD, p<0.001), HR from 64±13 to 61±13 bpm (p=0.002), and MSNA from 42±12 to 36±12 bursts/min (p=0.004). Hypoxia increased SBP 8±12 mmHg (p=0.057), HR 10±6 bpm (p<0.001), MSNA 7±7 bursts/min (p=0.031), and ventilation 10±7 l/min (p=0. 002). However, responses to electrical carotid sinus stimulation did not differ between hypoxic and hyperoxic conditions; SBP: −15±7 vs −14±8 mmHg (p=0.938), HR: −2±3 vs −2±2 bpm (p=0.701), and MSNA: −6±4 vs −4±3 bursts/min (p=0.531). Conclusion The main finding of our study is that moderate peripheral chemoreflex activation does not attenuate acute responses to electrical baroreflex activation therapy (BAT) in patients with resistant hypertension. These patients provide insight in human baroreflex physiology and baroreflex‐chemoreflex interactions that could not be gained otherwise. Support or Funding Information Financial support by Boston Scientific Corporation (St. Paul, MN, U.S.A.) 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 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 .

Background Central hypovolemia elicited by hemorrhage triggers sympathetically‐mediated baroreflex responses to maintain organ perfusion through peripheral vasoconstriction; humans with low tolerance (LT) to central hypovolemia have a diminished vasoconstrictor response during progressive reductions in central volume. Using the lower body negative pressure (LBNP) hemorrhage model, we tested the hypothesis that humans with LT to central hypovolemia would display attenuated resting beat‐to‐beat neuro‐hemodynamic transduction of muscle sympathetic nerve activity (MSNA) compared to those with high tolerance (HT). Methods MSNA (microneurography, peroneal nerve) and diastolic arterial pressure (DAP; finger photoplethysmography) were recorded in 33 human subjects (23 men, 10 women, age: 31 ± 9 years, BMI: 26 ± 4 kg/m 2 ) who subsequently underwent LBNP to tolerance (onset of pre‐syncopal symptoms) – Figure 1. Consistent with previous studies, subjects were classified as LT if they experienced pre‐syncopal symptoms prior to completing LBNP of −60 mm Hg, or as HT if they experienced pre‐syncopal symptoms after completing LBNP of −60 mm Hg. We performed linear regression analysis on data of binned MSNA burst areas against DAP; the slope of this regression represents transduction. Results Of the 33 subjects, 8 exhibited LT (time to pre‐syncope for LT: 17 ± 2 min and HT: 27 ± 5 min) Contrary to our hypothesis, resting beat‐to‐beat neuro‐hemodynamic transduction was not different between LT and HT subjects (median 0.09 IQR 0.03 – 0.16 mmHg (%s) − 1 vs. median 0.12 IQR 0.06 – 0.16 mmHg (%s) − 1 , respectively, p = 0.44) and was not related to time to pre‐syncope ( p = 0.70). Conclusion Tolerance to simulated blood loss is not related to resting sympathetic neuro‐hemodynamic transduction. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .