Intranasally administered orexin A does not activate sympathetic baroreflex function in healthy humans

Background: Orexin A (OreA) is a hypothalamic hormone crucially involved in the regulation of sleep/wake states. Orexinergic neurons project to blood pressure (BP) regulating brain networks, and OreA was previously reported to induce BP-relevant sympathetic activation in animals (1). In humans, intranasal (i.n.) administration effectively delivers neuropeptides directly to the central nervous system, as evidenced by functional effects of i.n. OreA on sleep architecture in orexin-deficient narcoleptic patients (2). However, in humans sympathetic BP effects of OreA remain to be elucidated. Using highly specific microneurographic techniques, we therefore investigated whether i.n. OreA alters sympathetic baroreflex function in healthy humans. Methods: In a balanced, double-blind cross-over study OreA (500 nmol) and placebo (sterile water), respectively, was administered i.n. to 12 awake normotensive male subjects. Muscle sympathetic nerve activity (MSNA) was assessed microneurographically and correlated with oscillometric BP and heart rate during supine rest and at pharmacologic baroreceptor challenge before (pre-substance) and from 30-60 minutes after OreA administration (post-substance). Results: OreA did not induce any changes of BP or heart rate with regard to pre- vs. post-substance period as well as at OreA vs. placebo comparisons. Moreover, resting MSNA was not increased and sympathetic baroreflex sensitivity was not altered during baroreceptor testing with vasoactive drugs at the respective periods. Conclusion: In this pilot study we found that i.n. OreA at doses previously shown to induce central nervous effects in humans (2) does not alter sympathetic baroreflex function in healthy male subjects. Protocols with higher doses of OreA warrant further investigation.