• P M MacFarlane, S Vinit, and G S Mitchell.
• Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA. Electronic address: pmm71@case.edu.
• Neuroscience. 2014 Jun 6;269:67-78.

AbstractAcute intermittent hypoxia (AIH) induces phrenic long-term facilitation (pLTF) by a mechanism that requires spinal serotonin (5-HT) receptor activation and NADPH oxidase (NOX) activity. Here, we investigated whether: (1) spinal nitric oxide synthase (NOS) activity is necessary for AIH-induced pLTF; (2) episodic exogenous nitric oxide (NO) is sufficient to elicit phrenic motor facilitation (pMF) without AIH (i.e. pharmacologically); and (3) NO-induced pMF requires spinal 5-HT2B receptor and NOX activation. In anesthetized, mechanically ventilated adult male rats, AIH (3 × 5-min episodes; 10% O2; 5 min) elicited a progressive increase in the amplitude of integrated phrenic nerve bursts (i.e. pLTF), which lasted 60 min post-AIH (45.1 ± 8.6% baseline). Pre-treatment with intrathecal (i.t.) injections of a neuronal NOS inhibitor (nNOS-inhibitor-1) near the phrenic motor nucleus attenuated pLTF (14.7 ± 2.5%), whereas an inducible NOS (iNOS) inhibitor (1400 W) had no effect (56.3 ± 8.0%). Episodic i.t. injections (3 × 5μl volume; 5 min) of a NO donor (sodium nitroprusside; SNP) elicited pMF similar in time-course and magnitude (40.4 ± 6.0%, 60 min post-injection) to AIH-induced pLTF. SNP-induced pMF was blocked by a 5-HT2B receptor antagonist (SB206553), a superoxide dismutase mimetic (MnTMPyP), and two NOX inhibitors (apocynin and DPI). Neither pLTF nor pMF was affected by pre-treatment with a protein kinase G (PKG) inhibitor (KT-5823). Thus, spinal nNOS activity is necessary for AIH-induced pLTF, and episodic spinal NO is sufficient to elicit pMF by a mechanism that requires 5-HT2B receptor activation and NOX-derived ROS formation, which indicates AIH (and NO) elicits spinal respiratory plasticity by a nitrergic-serotonergic mechanism.Published by Elsevier Ltd.

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