Article Figures & Data
Figures
- Fig. 1.
Effect of intrathecal orexin-A at (A) subthreshold bolus (100 pmol)/intermittent (10 pmol × 10) and (B) suprathreshold bolus (20 nmol)/intermittent (2 nmol × 10) doses in a urethane-anesthetized rat on (from the top) HR (beats per minute), MAP (mm Hg), and sSNA (µV). Time of administration of intrathecal orexin-A (both single and intermittent) are indicated by the arrow(s). Note that intermittent subthreshold (10 pmol) orexin-A causes the generation of sympathetic long-term facilitation.
- Fig. 2.
A comparison of the sympathoexcitatory response elicited by bolus versus intermittent orexin-A at both (A) suprathreshold and (B) subthreshold doses. Single administration of orexin-A (100 pmol; n = 4) and orexin-A (100 pmol) + Almorexant (AXT) at 75 mg⋅kg−1 (n = 5) did not elevate sympathetic activity. (C) No significant changes were observed compared with PBS control (n = 5) when sSNA is measured as % range. Grouped data for the % range from every treatment group are compared. AXT at 75 mg⋅kg−1 (n = 4) produced no effect on baseline sympathetic activity. (D) AXT at 30 mg⋅kg−1 (n = 5) and 75 mg⋅kg−1 (n = 5) attenuated the effect of intermittent orexin-A (10 pmol × 10; n = 5) on sSNA. Statistical significance was determined using one-way analysis of variance followed by Holm-Sidak correction to compare the effects with the control. Data are expressed as mean ± S.E.M. ****P < 0.0001; ***P < 0.001; *P < 0.05. #P < 0.05 compared with intermittent orexin-A (10 pmol × 10).
- Fig. 3.
In vivo effects of acute intermittent hypoxia (AIH, 10 bouts of 10% oxygen interspersed by 5-minute intervals) and intraperitoneal injection of Almorexant (AXT). (A) Experimental trace displaying the effect of AXT 30 mg⋅kg−1 (n = 5) in AIH, recording the changes in electrocardiogram (ECG), HR, MAP, phrenic nerve activity (PNA), and sSNA. Blood gas was analyzed at 30 and 60 minutes after AIH as indicated by the arrows. A 10-minute recording of pre-AIH sSNA and post-AIH sSNA is referred by the expanded period as indicated. (B) Comparison between the change in sSNA between PBS-treated AIH (n = 6) and DMSO-treated AIH (n = 5). All AXT-treated groups are compared with the DMSO-treated AIH group, where both AXT 30 mg⋅kg−1 and 75 mg⋅kg−1 (n = 5) AXT injections were made 10 minutes before AIH. (C) Change in sSNA shown as % range. Statistical significance was determined using one-way analysis of variance followed by Holm-Sidak correction. Data are expressed as mean ± S.E.M.
- Fig. 4.
Difference in the AUC between the initial and final sympathetic responses to hypoxia-induced chemoreceptor activation. The net AUC difference in the sympathetic response to hypoxia was identified for the baseline activity and the response at 60 minutes after treatment: intermittent orexin-A or acute intermittent hypoxia (AIH). (A) The value for the net difference in AUC (final minus initial hypoxia) compared for the treatments groups involving PBS (n = 5), intermittent orexin-A 10 pmol × 10 (n = 5), and Almorexant (AXT) at 30 (n = 5) and 75 mg⋅kg−1 (n = 5). (B) Similarly, net difference in AUC between the baseline and final sympathetic response to hypoxia after AIH + PBS (n = 6), AIH + DMSO (n = 5), AIH + AXT 30 mg⋅kg−1 (n = 5), and AIH + AXT 75 mg⋅kg−1 (n = 5). For grouped data, statistical significance was determined using one-way analysis of variance followed by multiple comparisons with a Holm-Sidak correction to compare the effects with the control. All values are expressed as mean ± S.E.M. ***P < 0.005 for significance. ##P < 0.01 and ####P < 0.0001 compared with intermittent orexin-A (10 pmol × 10).
- Fig. 5.
Sympathetic outflow from hypoxia-induced peripheral chemoreceptor activation requires a contribution from hypothalamic orexin neurons. Hypoxia directly activates the peripheral chemoreceptors of the carotid body, which sends afferent excitatory signals to the brainstem medulla. The nerves synapse to the nucleus tractus solitarii (NTS), which excite the rostral ventrolateral medulla (RVLM) nerves and further relay these signals to the intermediolateral (IML) of the spinal T5/6 level. Simultaneously, orexin neurons are excited by repetitive hypoxia. Both orexin receptor subtypes (OX1R and OX2R) are found on SPNs in the intermediolateral and are necessary to sensitize the sympathetic chemoreflex response to hypoxia.
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Prolonged Sympathoexcitation by Repetitive Orexin-A
