PACAP causes long-term increases in sympathetic nerve activity and is necessary for the sympathetic response to acute intermittent hypoxia

Overall objective: To determine if the sustained elevation of splanchnic sympathetic nerve activity (sSNA), termed long-term facilitation (LTF), following acute intermittent hypoxia (AIH) is due to intermittent, release of sympathoexcitatory peptides, such as pituitary adenylate cyclase activating polypeptide (PACAP). Methods: In urethane-anaesthetized, artificially ventilated, male rats (n=18 Sprague–Dawley), we investigated the effect of 10, 45s, episodes of 10%O2–90%N2 every 5 min (AIH) on sSNA after intrathecal infusion of 10μl of vehicle, PACAP (300μM) or the PAC1/VPAC2 receptor antagonist, PACAP(6–38) (1mM). In a separate group of rats (n=6) without AIH, 10 doses of PACAP (10μL of 10μM) were given intrathecally every 5 min. Results: Vehicle-treated rats showed a 31.0±8.1% increase in sSNA 60min after AIH, which doubled to 67.7±14.1% in PACAP treated rats. Infusing the PACAP antagonist PACAP(6–38) prior to AIH abolished sympathetic LTF (0.1±2.7%). The responses were significantly different (P<0.0001; 2-way ANOVA). Intermittent, sub-threshold, infusion of PACAP (10x10μM) was as effective as AIH in causing LTF (sSNA increase of 38.±8.0%). Conclusion: PACAP, acting via spinal PAC1/VPAC2 receptors, is sufficient to cause sympathetic LTF in the absence of AIH and necessary for the elaboration of sympathetic LTF following AIH.