A Neuronal Mechanism of Propofol-Induced Central Respiratory Depression in Newborn Rats

Abstract

The neural mechanisms of propofol-induced central respiratory depression remain poorly understood. In the present study, we studied these mechanisms and the involvement of gamma-aminobutyric acid (GABA)A receptors in propofol-induced central respiratory depression. The brainstem and the cervical spinal cord of 1- to 4-day-old rats were isolated, and preparations were maintained in vitro with oxygenated artificial cerebrospinal fluid. Rhythmic inspiratory burst activity was recorded from the C4 spinal ventral root. The activity of respiratory neurons in the ventrolateral medulla was recorded using a perforated patch-clamp technique. We found that bath-applied propofol decreased C4 inspiratory burst rate, which could be reversed by the administration of a GABAA antagonist, bicuculline. Propofol caused resting membrane potentials to hyperpolarize and suppressed the firing of action potentials in preinspiratory and expiratory neurons. In contrast, propofol had little effect on resting membrane potentials and action potential firing in inspiratory neurons. Our findings suggest that the depressive effects of propofol are, at least in part, mediated by the agonistic action of propofol on GABAA receptors. It is likely that the GABAA receptor-mediated hyperpolarization of preinspiratory neurons serves as the neuronal basis of propofol-induced respiratory depression in the newborn rat.

Coadministration of the AMPAKINE CX717 with Propofol Reduces Respiratory Depression and Fatal Apneas

“…Note that the propofol-induced respiratory depression in this study was much severe than that in previous report. 5 This is likely due to the higher extracellular K + ([K + ] o , 6.2 mM) used in that study compared with the more physiologically relevant 3 mM K + concentration used in the current study. The [K + ] o influences the function of co-transporters that determine transmembrane Cl − gradients and thus the reversal potential for chloride-mediated conductances.…”

“…21 This in turn modulates the amplitude of inhibitory actions via GABA A receptors through which propofol is acting. 5,6 In vitro, we have shown that GABA A receptor-mediated enhancement of chloride conductance suppresses respiratory frequency by acting within the putative inspiratory rhythm generator located in the ventrolateral medulla, the preBötC. 21,25 AMPAKINEs, including CX717, increase AMPAR-mediated neurotransmission in preBötC neurons 12 and hypoglossal motoneurons.…”

“…The dose of propofol added to the bathing medium is within the range present in brain tissue after an anesthetic dose of propofol administered to a rat in vivo. 5 Subsequent administration of CX717 to the bathing medium reverses the propofolinduced depression of respiratory frequency. Note that the propofol-induced respiratory depression in this study was much severe than that in previous report.…”

“…These data are consistent with the effect reported for a similar propofol dose and infusion rate on respiratory rate in adult rats. 5 The maximal depression was observed during second minute of propofol administration (n = 7; fig. 4A) with …”

“…3,4 Part of the propofol-induced respiratory depression is due to the activation of γ-aminobutyric acid (GABA) receptors in respiratory brainstem neuronal networks. 5,6 Here, we performed a study toward the development of pharmacological means for minimizing propofol-induced depression of respiration. Specifically, we used in vitro, in situ, and in vivo rat models to show that the pre-or coadministration of the AMPAKINE CX717 can reduce respiratory depression induced by propofol.…”