Similar Effects of an Orexin Receptor Antagonistand Benzodiazepine Receptor Agonist on Cerebral Blood Flow Regulation

Abstract

Orexin receptor antagonists have a different sleep-inducing mechanism from common hypnotic benzodiazepinereceptor agonists. Thus, orexin receptor antagonists may affect cerebral circulation differently, although theireffects have rarely been investigated. In this study, the effects of an orexin receptor antagonist on cerebral bloodflow regulation were compared with those of a benzodiazepine, including dynamic cerebral autoregulation. Fifteenhealthy males received suvorexant (1 tablet, 20 mg), an orexin receptor antagonist, and brotizolam (1 tablet, 0.25mg), a benzodiazepine receptor agonist, in a randomized order at least 7 days apart. Before and 1.5 h after drugadministration, arterial blood pressure and cerebral blood flow velocity were measured by transcranial Doppler ina supine position. Dynamic cerebral autoregulation was evaluated by transfer function analysis between mean arterial blood pressure variability and mean cerebral blood flow velocity variability. The steady-state mean cerebralblood flow velocity decreased significantly with both suvorexant and brotizolam (significant main effect of time,P = 0.003) and was associated with unchanged steady-state mean arterial blood pressure. Moreover, transfer function gain in the low- and high-frequency ranges were decreased significantly by both suvorexant and brotizolam(significant main effect of time, P < 0.001), suggesting a decrease in the magnitude of transfer from arterial bloodpressure oscillations to cerebral blood flow fluctuations. These changes were not significantly different betweensuvorexant and brotizolam (no significant interaction effect). The present results indicate that suvorexant andbrotizolam, two different types of hypnotic drug, have similar effects on cerebral blood flow regulation, includingpossible improvements in dynamic cerebral autoregulation with decreased steady-state cerebral blood flow.