Pearson, Andrew G.

Background Prostaglandins, such as cyclooxygenase (COX), may play an important role in regulating the cerebral blood flow response to a stimulus. We have previously shown that the vasodilatory response to a chemical stimulus decreases with age, and this difference is abolished by COX inhibition. However, the effects of COX inhibition on the cerebrovascular response to an increase in metabolic demand during a cognitive challenge is unknown. This information is important due to the frequent use of COX inhibitors for pain management. Thus, the purpose of this study was to determine the effect of COX inhibition on the cerebrovascular response to a metabolic stimulus in young and older adults. Methods Seventy‐six participants, including 42 young adults (YA; 26 ± 5 y) and 34 older adults (OA; 64 ± 6 y) completed the Stroop Color Word Test, which is a test of executive function. A subset of 42 participants (n = 22 YA, n = 20 OA) also completed the N‐back Test, which is a test of working memory. Beat‐to‐beat middle cerebral artery velocity (MCAv) and mean arterial pressure (MAP) were measured at baseline and in response to each cognitive test. Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. The response to each cognitive test was calculated as the peak percent change (%Δ) from baseline. Oral administration of the COX inhibitor Indomethacin (Indo) was given at 1.2mg/kg. Cognitive tests were then repeated after a 120‐minute wash‐in period. Results At baseline, YA had higher MCAv, CVCi, and lower MAP (p<0.01 for all) compared to OA. There were no significant differences between groups in the %Δ from baseline during the Stroop or N‐back test (p>0.05). During Indo, YA had higher MCAv (p<0.01), CVCi (p<0.01), and lower MAP (p<0.05) compared to OA. Indo decreased baseline MCAv and CVCi in both groups (p<0.01 for all) but had no effect on MAP (p>0.05). During Indo, the %Δ in MCAv during Stroop and N‐back was lower in YA (p<0.01) compared to baseline in YA. During Indo, the %Δ in MCAv was lower during Stroop in OA (p<0.01), with a trend for significance in OA during N‐back (p=0.06) compared to baseline. In YA during Indo, the %Δ in MAP was lower during Stroop (p<0.01) with a trend for significance during Nback (p=0.08) compared to baseline. In OA, the %Δ in MAP during N‐back was lower during Indo compared to baseline (p<0.05). Indo had no effect on the %Δ in CVCi (p>0.05). Importantly, there were group differences in the %Δ in MAP during Indo, such that the change was greater in OA compared with YA during Stroop (14.1 ± 1.3% vs. 10.6 ± 1.0%; p<0.05). Conclusion After administration of Indo, OA increased MAP to a greater extent during the Stroop test when compared to YA. These results suggest that OA required a larger increase in blood pressure to complete a test of executive function during COX inhibition. Because some COX inhibitors attenuate cerebral blood flow, OA may need to augment blood pressure to complete this metabolically‐challenging task. Support or Funding Information This research was funded by NIH grant HL118154. This abstract is from the Experimental Biology 2019 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 .