Cyclooxygenase-derived vasoconstriction restrains hypoxia-mediated cerebral vasodilation in young adults with metabolic syndrome

Abstract

Poor cerebrovascular function in metabolic syndrome (MetSyn) likely contributes to elevated risk of cerebrovascular disease in this growing clinical population. Younger MetSyn adults without clinical evidence of cerebrovascular disease exhibit preserved hypercapnic vasodilation yet markedly impaired hypoxic vasodilation, but the mechanisms behind reduced hypoxic vasodilation are unknown. Based on data from rats, we tested the hypothesis that younger adults with MetSyn exhibit reduced cerebral hypoxic vasodilation due to loss of vasodilating prostaglandins. Middle cerebral artery velocity (MCAv) was measured with transcranial Doppler ultrasound in adults with MetSyn (n = 13, 33 ± 3 yr) and healthy controls (n = 15, 31 ± 2 yr). Isocapnic hypoxia was induced by titrating inspired oxygen to lower arterial saturation to 90% and 80% for 5 min each. Separately, hypercapnia was induced by increasing end-tidal CO2 10 mmHg above baseline levels. Cyclooxygenase inhibition (100 mg indomethacin) was conducted in a randomized double-blind, placebo controlled design. MCAv was normalized for group differences in blood pressure (healthy: 89 ± 2 mmHg vs. MetSyn: 102 ± 2 mmHg) as cerebrovascular conductance index (CVCi), and used to assess cerebral vasodilation. Hypoxia increased CVCi in both groups; however, vasodilation was ∼55% lower in MetSyn at SpO2 = 80% (P < 0.05). Indomethacin tended to decrease hypoxic vasodilation in healthy controls, and unexpectedly increased dilation in MetSyn (P < 0.05). In contrast to hypoxia, hypercapnia-mediated vasodilation was similar between groups, as was the decrease in vasodilation with indomethacin. These data indicate increased production of vasoconstrictor prostaglandins restrains hypoxic cerebral vasodilation in MetSyn, preventing them from responding appropriately to this important physiological stressor.

Reactive oxygen species and cyclooxygenase products explain the majority of hypoxic cerebral vasodilation in healthy humans

“…The majority of studies investigating the role of COX metabolites dispute a significant role of COX during hypoxia in healthy participants. Data from our lab and others have demonstrated COX inhibition does not decrease hypoxic cerebral vasodilation in healthy adults . On the contrary, 1 study demonstrated a significant decrease in hypoxic MCA reactivity following indomethacin administration; however, internal carotid artery reactivity to hypoxia was unaffected .…”

“…Current findings indicate an interplay between ROS and COX products towards increasing CBF during hypoxia. Several prior studies report no effect or a modest decrease in hypoxic cerebral vasodilation with COX inhibition alone . Additionally, single inhibition of other potential mechanisms have failed to decrease CBF responses to hypoxia, including adenosine receptors, α 1 ‐adrenergic receptors and nitric oxide synthase .…”

“…We did not administer ascorbic acid and indomethacin in a reverse drug order with the current study design. Numerous studies report non‐significant effects of indomethacin alone on hypoxic vasodilation measured at the MCA; therefore, we felt it burdensome to subjects and unnecessary to give indomethacin prior to ascorbic acid.…”

“…Human studies provide strong evidence for COX contributing to basal CBF; however, there is little evidence of COX products significantly contributing to increases in CBF during hypoxia . Two studies reported no decrement in hypoxic CBF responses with COX inhibition, while 1 reported a ~28% reduction in middle cerebral artery reactivity . Given the modest outcomes, the simplest explanation is that COX metabolites, presumably vasodilating prostaglandins, play a non‐compulsory role in increasing CBF during hypoxia.…”

To decipher the hypoxic pulmonary hypertension: Vascular heterogeneity and the hypothesis of hypoxic responsive threshold

“…There scarcely exist the progressively increased peripheral vascular resistance and vascular remodeling; instead, such vessels will dilate to supply ample blood perfusion in anoxic organs [26,27]. Complicated elements participate the nascency and development of HPH, while, based on our preliminary experiment, we are prone to account pulmonary vascular heterogeneity as the primary pathogenesis, which has been expressed in another way before [5].…”