Hypoxic Cerebral Vasodilation in Healthy and Metabolic Syndrome Adults: Distinct Interactions between Cyclooxygenase and Reactive Oxygen Species Signaling

Abstract

Excess reactive oxygen species (ROS) limit hypoxia‐mediated cerebral vasodilation in animal models of metabolic syndrome (MetSyn). Cyclooxygenase (COX) may be a source of ROS, but data are lacking in humans. We hypothesized ROS limit hypoxic cerebral vasodilation in human MetSyn, but COX is not the source. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound in 12 MetSyn adults (34±2 yr) and 12 healthy adults (28±1 yr) during baseline and steady‐state hypoxia (SPo2=80%). Intravenous ascorbic acid suppressed ROS during the first steady‐state hypoxia. Oral indomethacin was administered to inhibit COX prior to a second hypoxia trial to investigate the combined roles of ROS and COX during hypoxia. MCAv was normalized for MABP as cerebrovascular conductance index [CVCi = (MCAv ÷ MABP) * 100], and a change in CVCi from baseline (ΔCVCi) indicated hypoxic dilation. ΔCVCi was ~50% lower in adults with MetSyn during control hypoxia (p<0.05). Ascorbic acid infusion increased ΔCVCi in MetSyn adults (p<0.05), but not healthy adults. Combined ascorbic acid and indomethacin increased ΔCVCi in MetSyn adults (p<0.05) similar to ascorbic acid alone. Surprisingly in healthy adults, combined ascorbic acid and indomethacin reduced ΔCVCi by ~75% (p<0.05). This contrasts previous data in healthy adults that indicated no effect of indomethacin alone. In summary, healthy adults express a ROS‐COX redundancy, whereby ROS suppression increased reliance on COX products to achieve hypoxic cerebral vasodilation. MetSyn disrupts this complementary role of ROS, such that COX‐derived ROS restrain hypoxic cerebral vasodilation.