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Meusel, M.* ; Voß, J.* ; Krapalis, A.* ; Machleidt, F.* ; Vonthein, R.* ; Hallschmid, M. ; Sayk, F.*

Intranasal orexin A modulates sympathetic vascular tone - a pilot study in healthy male humans.

J. Neurophysiol. 127, 548-558 (2022)

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INTRODUCTION: Previous research suggests that the neuropeptide orexin A contributes to sympathetic blood pressure (BP) control inasmuch as hypothalamic injection of orexin A increases sympathetic vasomotor tone and arterial BP in rodents. In humans with narcolepsy, a disorder associated with loss of orexin-producing neurons, vasoconstrictive muscle sympathetic nerve activity (MSNA) is reduced. Since intranasally administered oligopeptides like orexin are known to modulate brain function, we investigated the effect of intranasal orexin A on vascular sympathetic baroreflex function in healthy humans. METHODS: In a balanced, double-blind cross-over study, orexin A (500 nmol) and placebo, respectively, were intranasally administered to 10 lean healthy males (age, 25.8±4.6 years). MSNA was assessed microneurographically before and 30-45 minutes after either substance administration. Additionally, baroreflex was challenged via graded infusions of vasoactive drugs before and after substance administration. Baroreflex function was defined as the correlation of BP with MSNA and heart rate. RESULTS: Intranasal orexin A compared to placebo induced a significant increase in resting MSNA from prior to post administration (Δ-burst rate, orexin A vs. placebo: +5.8±0.8 vs. +2.1±0.6; p=0.007; total activity (169±11.5% vs. 115±5.0%; p=0.002). BP, heart rate and sympathovagal balance to the heart, as represented by HRV, as well as baroreflex sensitivity during the vasoactive challenge were not altered. CONCLUSION: Intranasally administered orexin A acutely induced vasoconstrictory sympathoactivation in healthy male humans. This result suggests that orexin A mediates upward resetting of the vascular baroreflex setpoint at centers superordinate to the mere baroreflex-feedback-loop.

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