Spinal nitric oxide synthase activity is necessary for phrenic long‐term facilitation following intermittent hypoxia

Abstract

Acute intermittent hypoxia (AIH) elicits a serotonin‐dependent form of respiratory plasticity known as phrenic long‐term facilitation (pLTF). Although reactive oxygen species (ROS) from spinal NADPH oxidase activity are necessary for AIH‐induced pLTF, little is known about the role of reactive nitrogen species (RNS). Since RNS, and specifically nitric oxide (NO), are necessary for other forms of neuroplasticity, including ventilatory LTF in unanesthetized mice (Kline et al., 2002), we hypothesized that spinal nitric oxide synthase (NOS) activity and NO are required for pLTF. To test this hypothesis, the NOS inhibitor, L‐NAME, was injected intrathecally over the cervical spinal cord (C4) prior to AIH (3, 5‐min episodes, 10% O2) in anesthetized, paralyzed and ventilated rats. In control, vehicle treated rats (aCSF, 12µl volume), AIH elicited a progressive increase in integrated phrenic nerve burst amplitude (ie. pLTF) lasting 60 min post‐AIH. However, pLTF was attenuated in rats pre‐treated with L‐NAME (10mM; 12µl volume; p<0.05), suggesting spinal NOS activity/NO is necessary for AIH‐induced pLTF. The specific role of NO is not yet known.Supported by NIH HL‐80209 and the Francis Family Foundation (PMM)