Background: Propofol (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's disadvantages include the induction of respiratory depression and apnea. Here, the authors report a clinically feasible pharmacological solution for reducing propofol-induced respiratory depression via a mechanism that does not interfere with anesthesia. Specifically, they test the hypothesis that the AMPAKINE CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from propofol-induced severe apnea. Methods: The actions of propofol and the AMPAKINE CX717 were measured via (1) ventral root recordings from newborn rat brainstem-spinal cord preparations, (2) phrenic nerve recordings from an adult mouse in situ working heartbrainstem preparation, and (3) plethysmographic recordings from unrestrained newborn and adult rats. Results:In vitro, respiratory depression caused by propofol (2 μM, n = 11, mean ± SEM, 41 ± 5% of control frequency, 63 ± 5% of control duration) was alleviated by CX717 (n = 4, 50-150 μM). In situ, a decrease in respiratory frequency (44 ± 9% of control), phrenic burst duration (66 ± 7% of control), and amplitude (78 ± 5% of control) caused by propofol (2 μM, n = 5) was alleviated by coadministration of CX717 (50 μM, n = 5). In vivo, pre-or coadministration of CX717 (20-25 mg/kg) with propofol markedly reduced propofol-induced respiratory depression (n = 7; 20 mg/kg) and propofol-induced lethal apnea (n = 6; 30 mg/kg). Conclusions: Administration of CX717 before or in conjunction with propofol provides an increased safety margin against profound apnea and death. P ROPOFOL (2,6-diisopropylphenol) is used for the induction and maintenance of anesthesia in human and veterinary medicine. Propofol's favorable attributes are its pharmacokinetic properties that result in a rapid, clear emergence. Its disadvantages include the induction of respiratory depression, apnea, and blood pressure reductions.1,2 Furthermore, there are increasing reports What We Already Know about This Topic• Propofol depresses respiration partly due to the activation of γ-aminobutyric acid receptors within brainstem respiratory center AMPAKINEs effectively alleviates opioid-induced respiratory depression without interfering with analgesia in rodentsWhat This Article Tells Us That Is New Address correspondence to Dr. Greer: University of Alberta, Department of Physiology, Centre for Neuroscience, Women and Children's Health Research Institute, 3-020M Katz Building, Edmonton, Alberta, Canada T6G 2S2. john.greer@ualberta.ca. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology's articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Despite the enormous diversity of glutamate (Glu) receptors and advances in understanding recombinant receptors, native Glu receptors underlying functionally identified inputs in active systems are poorly defined in comparison. In the present study we use UBP-302, which antagonizes GluR5 subunit-containing kainate (KA) receptors at ≤ 10 μM, but other KA and AMPA receptors at ≥ 100 μM, and rhythmically active in vitro preparations of neonatal rat to explore the contribution of non-NMDA receptor signalling in rhythm-generating and motor output compartments of the inspiratory network. At 10 μM, UBP-302 had no effect on inspiratory burst frequency or amplitude. At 100 μM, burst amplitude recorded from XII, C1 and C4 nerve roots was significantly reduced, but frequency was unaffected. The lack of a frequency effect was confirmed when local application of UBP-302 (100 μM) into the pre-Bötzinger complex (preBötC) did not affect frequency but substance P evoked a 2-fold increase. A UBP-302-sensitive (10 μM), ATPA-evoked frequency increase, however, established that preBötC networks are sensitive to GluR5 activation. Whole-cell recordings demonstrated that XII motoneurons also express functional GluR5-containing KA receptors that do not contribute to inspiratory drive, and confirmed the dose dependence of UBP-302 actions on KA and AMPA receptors. Our data provide the first evidence that the non-NMDA (most probably AMPA) receptors mediating glutamatergic transmission within preBötC inspiratory rhythm-generating networks are pharmacologically distinct from those transmitting drive to inspiratory motoneurons. This differential expression may ultimately be exploited pharmacologically to separately counteract depression of central respiratory rhythmogenesis or manipulate the drive to motoneurons controlling airway and pump musculature.
Kainate (KA) receptors (Rs) are glutamate Rs assembled from GluR5‐7 and KA1‐2 subunits. They are widely expressed in the CNS, but their functional significance is largely unknown, due in part to a lack of selective antagonists. UBP302 is a GluR5 antagonist that is selective at concentrations 10 μM. To assess the role of GluR5 Rs in respiratory activity, UBP302 was bath‐applied to rhythmic brainstem‐spinal cord (BSSC) or medullary slice preparations. At 10 μM, it had no effect on frequency (f) of XII or C4 nerve burst amplitude. At 100 μM UB302, C4 and XII burst amplitudes fell to 0.7 ± 0.1 (BSSC; n=5) or 0.5 ± 0.1 of control, (slice; n=6). f was also unaffected by local injection of UBP302 (100 μM) into the PBC (n = 4). To confirm concentration dependence of UBP302 selectivity for KA vs AMPA Rs, we used whole‐cell voltage‐clamp recordings of XII MNs in (1 μM TTX) to assess the effects on membrane current of combinations of ATPA (KAR agonist), UBP302, AMPA, and SYM2206 (AMPAR antagonist). We defined a SYM2206‐insensitive, ATPA current (−23±5pA) that was maximally blocked by 10 μM UBP302. Also, AMPA currents were inhibited by UBP302, but only when UBP302 was >100 μM. These data indicate that XII MNs express GluR5‐containing KARs that do not contribute to inspiratory drive. Data also suggest differential involvement of AMPAR subtypes in inspiratory rhythm generation and transmission of the drive to MNs. Funding: AHFMR, CIHR, CFI, AHFMR
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