Spinal adenosine A2A receptor inhibition enhances phrenic long term facilitation following acute intermittent hypoxia

• Published in: The Journal of physiology 2010-01, Vol.588 (1), p.255-266
• Main Authors: Hoffman, M. S., Golder, F. J., Mahamed, S., Mitchell, G. S.
• Format: Article
• Language: English
• Subjects: Respiratory
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2009.180075

Phrenic long term facilitation (pLTF) is a form of respiratory plasticity induced by acute intermittent hypoxia. pLTF requires spinal serotonin receptor activation, new BDNF synthesis and TrkB receptor activation. Spinal adenosine 2A (A 2A ) receptor activation also elicits phrenic motor facilitation, but by a distinct mechanism involving new TrkB synthesis. Because extracellular adenosine increases during hypoxia, we hypothesized that A 2A receptor activation contributes to acute intermittent hypoxia (AIH)-induced pLTF. A selective A 2A receptor antagonist (MSX-3, 8 μg kg −1 , 12 μl) was administered intrathecally (C4) to anaesthetized, vagotomized and ventilated male Sprague–Dawley rats before AIH (three 5 min episodes, 11% O 2 ). Contrary to our hypothesis, pLTF was greater in MSX-3 versus vehicle (aCSF) treated rats (97 ± 6% vs. 49 ± 4% at 60 min post-AIH, respectively; P < 0.05). MSX-3 and aCSF treated rats did not exhibit facilitation without AIH (time controls; 7 ± 5% and 9 ± 9%, respectively; P > 0.05). A second A 2A receptor antagonist (ZM2412385, 7 μg kg −1 , 7 μl) enhanced pLTF (85 ± 11%, P < 0.05), but an adenosine A 1 receptor antagonist (DPCPX, 3 μg kg −1 , 10 μl) had no effect (51% ± 8%, P > 0.05), indicating specific A 2A receptor effects. Intrathecal methysergide (306 μg kg −1 , 15μl) blocked AIH-induced pLTF in both MSX-3 and aCSF treated rats, confirming that enhanced pLTF is serotonin dependent. Intravenous MSX-3 (140 μg kg −1 , 1 ml) enhanced both phrenic (104 ± 7% vs. 57 ± 5%, P < 0.05) and hypoglossal LTF (46 ± 13% vs. 28 ± 10%; P < 0.05). In conclusion, A 2A receptors constrain the expression of serotonin-dependent phrenic and hypoglossal LTF following AIH. A 2A receptor antagonists (such as caffeine) may exert beneficial therapeutic effects by enhancing the capacity for AIH-induced respiratory plasticity.