Respiratory long term facilitation evoked by acute intermittent hypoxia is impaired following intravenous injection of a superoxide dismutase mimetic

Abstract

Acute intermittent hypoxia (AIH) elicits a serotonin-dependent form of respiratory plasticity known as long-term facilitation (LTF). LTF is commonly expressed as a prolonged augmentation in phrenic and hypoglossal (XII) motoneuron output after the final hypoxic episode. Although considerable recent progress has revealed important aspects of the mechanisms underlying LTF, a potential role for reactive oxygen species (ROS) has not been explored, despite evidence suggesting a prominent role for ROS in the response to chronic intermittent hypoxia (Peng et al., 2003). Thus, we investigated whether ROS are necessary for phrenic and XII LTF following AIH. Phrenic and XII nerve activity were recorded in anaesthetized, paralysed, vagotomized and ventilated Sprague Dawley rats before, during and 60 mins after 3, 5-minute episodes of isocapnic hypoxia (FIO2 = 0.11). In control animals (N=8), at 60 mins post-AIH, integrated phrenic and XII nerve amplitudes were increased (93 ± 23% and 70 ± 12%, respectively, P<0.05) from pre-AIH levels, thus confirming significant LTF. Intravenous injection of 5 (N=7) or 10 mg/kg (N=8) of the superoxide dismutase mimetic (Manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride; Mn TMPyP) significantly decreased phrenic LTF in a dose dependent manner (35 ± 12% and 16% ± 10%, at the respective doses, P<0.05). A similar effect of Mn TMPyP was observed in hypoglossal LTF (14 ± 6% and 11% ± 13%, respectively, P<0.05). These results indicate that ROS formation (specifically O2-·) during AIH is necessary for the expression of LTF in both phrenic and XII nerve activity. Supported by NIH HL65383 and HL89209. Peng YJ, Overholt JL, Kline D, Kumar GK, Prabhakar NR. (2003). Proc. Natl. Acad. Sci. 100(17): 10073-8