Greater cerebral artery vasodilation mediated by cyclooxygenase (COX) in female animals is unexplored in humans. We hypothesized that young, healthy women would exhibit greater basal cerebral blood flow (CBF) and greater vasodilation during hypoxia or hypercapnia compared to men, mediated by a larger contribution of COX. We measured middle cerebral artery velocity (MCAv, transcranial Doppler ultrasound) in 42 adults (24 women, 18 men; 24 ± 1 years) during two visits, in a double-blind, placebo-controlled design (COX inhibition, 100 mg oral indomethacin, Indo). Women were studied early in the follicular phase of the menstrual cycle (days 1–5). Two levels of isocapnic hypoxia (SPO2 = 90% and 80%) were induced for 5-min each. Separately, hypercapnia was induced by increasing end-tidal carbon dioxide (PETCO2) 10 mmHg above baseline. A positive change in MCAv (ΔMCAv) reflected vasodilation. Basal MCAv was greater in women compared to men (P < 0.01) across all conditions. Indo decreased baseline MCAv (P < 0.01) similarly between sexes. Hypoxia increased MCAv (P < 0.01), but ΔMCAv was not different between sexes. Indo did not alter hypoxic vasodilation in either sex. Hypercapnia increased MCAv (P < 0.01), but ΔMCAv was not different between sexes. Indo elicited a large decrease in hypercapnic vasodilation (P < 0.01) that was similar between sexes. During the early follicular phase, women exhibit greater basal CBF than men, but similar vasodilatory responses to hypoxia and hypercapnia. Moreover, COX is not obligatory for hypoxic vasodilation, but plays a vital and similar role in the regulation of basal CBF (∼30%) and hypercapnic response (∼55%) between sexes.

Animal data suggest females rely more on cyclooxygenase (COX) than males to achieve increases in cerebral blood flow. Our aim was to determine the contribution of COX to hypoxia‐mediated increases in cerebral blood flow in young, healthy female and male humans. We hypothesized females would exhibit greater hypoxia‐mediated increases in cerebral blood flow due to increased COX signaling. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound in young (24±1 yr) females (n=12) and males (n=17). Females were studied during early follicular phase (cycle day 1 ‐ 5) to minimize the effects of female hormones. Inspired air was titrated to lower arterial O2 saturation to 80% for 5 minutes while end‐tidal CO2 was maintained at basal levels. MCAv was normalized for blood pressure as cerebrovascular conductance index (CVCi). Hypoxia was conducted on twice after ingestion of placebo or COX inhibitor (100mg indomethacin). Hypoxia increased CVCi (ΔCVCi) but ΔCVCi was not different between groups (females: 13±2 vs. males: 10±2 cm/s/mmHg, p=0.55). Indomethacin reduced ΔCVCi 4±3 cm/s/mmHg in females and increased ΔCVCi 0.5±2 cm/s/mmHg in males; however, the indomethacin‐mediated change in ΔCVCi was not statistically significant (p=0.15). Our data indicate males and females respond similarly to hypoxia, but COX may play a relatively larger role in females to mediate cerebral vasodilation. Grant Funding Source: AHA PRE7390038 & NIH HL105820

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The pathophysiological basis of autonomic symptoms in Parkinson's disease remains incompletely understood. The hypothalamus plays a key regulatory role in autonomic function and has been shown to be affected in Parkinson's disease. Here, using diffusion magnetic resonance imaging, we investigated whether microstructural properties of the hypothalamus differ in Parkinson's disease patients with high compared to low autonomic symptom burden.Parkinson's disease patients with low (n=25) and high (n=25) autonomic symptom burden were identified from a larger pool, based on scores from a questionnaire assessing autonomic symptoms in Parkinson's disease (SCOPA-AUT). In each patient, we first segmented the hypothalamus manually, based on anatomical landmarks. Diffusivity measures were then extracted from the hypothalamus. Diffusivity measures calculated in the brainstem and the putamen were used to assess the specificity of the results.Relative to patients with low autonomic symptom burden, patients with high burden showed increased mean, axial, and radial diffusivity in the hypothalamus. In contrast, we did not find significant group differences in any of these measures extracted from the brainstem or the putamen.These results reveal consistent differences in the microstructural properties of the hypothalamus between patients with low and high autonomic symptom burden. Hypothalamic diffusivity properties can thus potentially be used as an imaging marker to assist in the identification of therapeutic targets for autonomic dysfunction in Parkinson's disease.

Nitric oxide (NO) and prostaglandins (PGs) play important roles in exercise hyperemia in healthy humans, but the role of NO & PGs in young obese (OB) adults is currently unknown. We hypothesized the relative contribution of NO and PGs to exercise hyperemia would be lower in young OB adults when compared to lean adults. 11 healthy lean (27±2yrs, BMI=23±1) and 7 OB adults (23±2yrs, BMI=38±4) performed two 10‐minute trials of dynamic forearm exercise (20 contractions/minute) at 15% of maximal voluntary contraction. A brachial artery catheter was used for local infusion of the NO synthase inhibitor, L‐NMMA, alone or in combination with the cycloxygenase inhibitor, ketorolac. L‐NMMA or ketoroloac was infused during the last 5 minutes of each exercise trial to achieve single and double blockade respectively. Forearm blood flow (FBF) was measured using Doppler ultrasound, and forearm vascular conductance (FVC) was calculated (FBF÷BP=FVC). From steady state exercise, the relative change in FVC with L‐NMMA was similar between groups (Lean−34±10 vs. OB−35±15%). With the addition of ketorolac, the relative change in FVC was opposite between groups (Lean−7±8 vs. OB+30±17%, p=0.02). We conclude the contribution of NO to exercise hyperemia appears intact in young OB adults, although they may produce more vasoconstrictor PGs that alter blood flow regulation. Support: NIH R01 HL105820.