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An important functional role of persistent Na⁺ current in carotid body hypoxia transduction

Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut

Submitted 24 January 2006 ; accepted in final form 6 June 2006

Systemic hypoxia in mammals is sensed and transduced by the carotid body into increased action potential (AP) frequency on the sinus nerve, resulting in increased ventilation. The mechanism of hypoxia transduction is not resolved, but previous work suggested that fast Na⁺ channels play an important role in determining the rate and timing of APs (Donnelly, DF, Panisello JM, and Boggs D. J Physiol. 511: 301–311, 1998). We speculated that Na⁺ channel activity between APs, termed persistent Na⁺ current (I_NaP), is responsible for AP generation that and riluzole and phenytoin, which inhibit this current, would impair organ function. Using whole cell patch clamp recording of intact petrosal neurons with projections to the carotid body, we demonstrated that I_NaP is present in chemoreceptor afferent neurons and is inhibited by riluzole. Furthermore, discharge frequencies of single-unit, chemoreceptor activity, in vitro, during normoxia (PO₂ 150 Torr) and during acute hypoxia (PO₂ 90 Torr) were significantly reduced by riluzole concentrations at or above 5 µM, and by phenytoin at 100 µM, without significant affect on nerve conduction time, AP magnitude (inferred from extracellular field), and AP duration. The effect of both drugs appeared solely postsynaptic because hypoxia-induced catecholamine release in the carotid body was not altered by either drug. The respiratory response of unanesthetized, unrestrained 2-wk-old rats to acute hypoxia (12% inspired O₂ fraction), which was measured with whole body plethysmography, was significantly reduced after treatment with riluzole (2 mg/kg ip) and phenytoin (20 mg/kg ip). We conclude that I_NaP is present in chemoreceptor afferent neurons and serves an important role in peripheral chemoreceptor function and, hence, in the ventilatory response to hypoxia.

riluzole; phenytoin; hypoxic ventilatory response; chemoreceptor; petrosal neuron

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