Hines, Casey N.

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

New Findings What is the central question of this study? We aimed to investigate the effects of the cyclo‐oxygenase (COX) inhibitor indomethacin on resistance vessel function in young and older adults and to test the hypothesis that indomethacin will attenuate forearm vascular conductance during reactive hyperaemia. What is the main finding and its importance? Older adults demonstrated an attenuated vasodilator response to ischaemia after COX inhibition compared with their younger counterparts. This suggests that older adults do not compensate for the vascular changes induced by an acute dose of indomethacin. Long‐term use of indomethacin may increase vascular resistance and reduce the response to acute haemodynamic stress in older adults. The risk for potential adverse cardiovascular consequences of COX inhibition should be considered. We have previously shown that non‐selective cyclo‐oxygenase inhibition, via indomethacin, unfavourably increased central blood pressure in older adults, with little effect in young adults. In addition, the vasoactive prostaglandins have been shown to contribute to both peripheral vasodilator responses and large artery function; however, there is little information available in older adults and conflicting reports in young adults on the extent to which resistance vessel function is influenced by indomethacin. Thus, we tested the hypothesis that cyclo‐oxygenase inhibition using indomethacin would attenuate forearm vascular conductance during reactive hyperaemia in older adults compared with young adults. Forearm blood flow responses to 5 min of forearm ischaemia were measured in 26 healthy adults (13 young, 25 ± 5 years old; and 13 older, 65 ± 6 years old), using venous occlusion plethysmography before and after indomethacin. Baseline forearm blood flow and vascular conductance were not different between groups during either trial, and there were no age‐related differences prior to cyclo‐oxygenase inhibition. Peak forearm vascular conductance and blood flow were similar between groups before indomethacin, but lower in older adults after indomethacin compared with young adults (27 ± 4 versus 41 ± 4 ml (100 ml)−1 min−1 (100 mmHg)−1, P = 0.02; and 23 ± 3 versus 33 ± 3 ml (100 ml)−1 min−1, P = 0.02, respectively). These results, in conjunction with our previous findings in large arteries, suggest that ageing alters the effect of cyclo‐oxygenase inhibition on vascular responses, and specifically, the resistance vessel responses underlying reactive hyperaemia.

The augmentation index and central blood pressure increase with normal aging. Recently, cyclooxygenase (COX) inhibitors, commonly used for the treatment of pain, have been associated with transient increases in the risk of cardiovascular events. We examined the effects of the COX inhibitor indomethacin (Indo) on central arterial hemodynamics and wave reflection characteristics in young and old healthy adults. High-fidelity radial arterial pressure waveforms were measured noninvasively by applanation tonometry before (control) and after Indo treatment in young (25 ± 5 yr, 7 men and 6 women) and old (64 ± 6 yr, 5 men and 6 women) subjects. Aortic systolic (control: 115 ± 3 mmHg vs. Indo: 125 ± 5 mmHg, P < 0.05) and diastolic (control: 74 ± 2 mmHg vs. Indo: 79 ± 3 mmHg, P < 0.05) pressures were elevated after Indo treatment in older subjects, whereas only diastolic pressure was elevated in young subjects (control: 71 ± 2 mmHg vs. Indo: 76 ± 1 mmHg, P < 0.05). Mean arterial pressure increased in both young and old adults after Indo treatment ( P < 0.05). The aortic augmentation index and augmented pressure were elevated after Indo treatment in older subjects (control: 30 ± 5% vs. Indo 36 ± 6% and control 12 ± 1 mmHg vs. Indo: 18 ± 2 mmHg, respectively, P < 0.05), whereas pulse pressure amplification decreased (change: 8 ± 3%, P < 0.05). In addition, older subjects had a 61 ± 11% increase in wasted left ventricular energy after Indo treatment ( P < 0.05). In contrast, young subjects showed no significant changes in any of the variables of interest. Taken together, these results demonstrate that COX inhibition with Indo unfavorably increases central wave reflection and augments aortic pressure in old but not young subjects. Our results suggest that aging individuals have a limited ability to compensate for the acute hemodynamic changes caused by systemic COX inhibition.