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.

Keywords: cerebral blood flow; cyclooxygenase; metabolic syndrome.

Fig. 1.

Experimental timeline of study visits. Placebo and indomethacin were administered in a double-blind, randomized order. Hypoxia and hypercapnia were performed in randomized order each visit. Indo, Indomethacin; SpO₂, pulse oximeter arterial saturation; Fi_CO2, fraction of inspired CO₂; HR, heart rate; BP, blood pressure; MCAv, middle cerebral artery velocity; Pet_CO2, end-tidal partial pressure of carbon dioxide.

Fig. 2.

A: indomethacin (Indo) decreased baseline cerebrovascular conductance index (CVCi) in healthy subjects 30 min following administration. B: Indo also decreased baseline CVCi in metabolic syndrome (MetSyn) subjects 30 min following administration. C: Indo caused a greater absolute decrease of CVCi in healthy subjects. D: Indo caused a similar relative decrease in CVCi between groups. *P < 0.05 vs. 0 min; †P < 0.05 vs. placebo; ‡P < 0.05, main effect of group.

Fig. 3.

CVCi vs. oxygen saturation (SpO₂) with and without Indo in healthy (A) and MetSyn (B) adults. C: Indo tended to decrease dilation in healthy subjects at SpO₂ = 80% (P = 0.13). D: Indo increased cerebral vasodilation in MetSyn adults. E: with placebo, ΔCVCi was lower in adults with MetSyn. F: Indo influenced cerebral vasodilation differently in healthy and MetSyn adults. *Main effect of group (P < 0.05), †main effect of Hypoxia, ‡main effect of Indo, §group × Indo interaction (P < 0.05).

Fig. 4.

CVCi vs. Pet_CO2 with and without Indo in healthy (A) and MetSyn adults (B). C: ΔCVCi was similar between groups with and without Indo. *Main effect of Indo (P < 0.05).