Browsing by Author "Hubbard, Dallin"

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    Erythrocytic Metabolism of ATLX-0199: An Agent that Increases Minute Ventilation
    (Elsevier, 2023) Krasinkiewicz, Jonathan M.; Hubbard, Dallin; de Guzman, Nicholas Perez; Masters, Andi; Zhao, Yi; Gaston, Herbert; Gaston, Benjamin; Pediatrics, School of Medicine
    Both L- and D-isomers of S-nitrosocysteine (CSNO) can bind to the intracellular domain of voltage-gated potassium channels in vitro. CSNO binding inhibits these channels in the carotid body, leading to increased minute ventilation in vivo. However, only the l-isomer is active in vivo because it requires the l-amino acid transporter (LAT) for transmembrane transport. In rodents and dogs, the esterified D-CSNO precursor-d-cystine dimethyl ester (ATLX-0199)-overcomes opioid- and benzodiazepine-induced respiratory depression while maintaining analgesia. Although ATLX-0199 can enter cells independently of LAT because it is an ester, its stability in plasma is limited by the presence of esterases. Here, we hypothesized that the drug could be sequestered in erythrocytes to avoid de-esterification in circulation. We developed a liquid chromatography-mass spectrometry method for detecting ATLX-0199 and characterized a new metabolite, S-nitroso-d-cysteine monomethyl ester (DNOCE), which is also a D-CSNO precursor. We found that both ATLX-0199 and DNOCE readily enter erythrocytes and neurons and remain stable over 20 min; thus ATLX-0199 can enter cells where the ester is stable, but the thiol is reduced. Depending on hemoglobin conformation, the reduced ester can be S-nitrosylated and enter carotid body neurons, where it then increases minute ventilation. These data may help explain the paradox that ATLX-0199, a dimethyl ester, can avoid de-esterification in plasma and exert its effects at the level of the carotid body.
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    S‐Nitroso‐L‐cysteine and ventilatory drive: A pediatric perspective
    (Wiley, 2022) Hubbard, Dallin; Tutrow, Kaylee; Gaston, Benjamin; Pediatrics, School of Medicine
    Though endogenous S‐nitroso‐l‐cysteine (l‐CSNO) signaling at the level of the carotid body increases minute ventilation (v̇E), neither the background data nor the potential clinical relevance are well‐understood by pulmonologists in general, or by pediatric pulmonologists in particular. Here, we first review how regulation of the synthesis, activation, transmembrane transport, target interaction, and degradation of l‐CSNO can affect the ventilatory drive. In particular, we review l‐CSNO formation by hemoglobin R to T conformational change and by nitric oxide (NO) synthases (NOS), and the downstream effects on v̇E through interaction with voltage‐gated K+ (Kv) channel proteins and other targets in the peripheral and central nervous systems. We will review how these effects are independent of—and, in fact may be opposite to—those of NO. Next, we will review evidence that specific elements of this pathway may underlie disorders of respiratory control in childhood. Finally, we will review the potential clinical implications of this pathway in the development of respiratory stimulants, with a particular focus on potential pediatric applications.