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GAL-021 and GAL-160 are Efficacious in Rat Models of Obstructive and Central Sleep Apnea and Inhibit BKCa in Isolated Rat Carotid Body Glomus Cells

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Arterial Chemoreceptors in Physiology and Pathophysiology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 860))

Abstract

GAL-021 and GAL-160 are alkylamino triazine analogues, which stimulate ventilation in rodents, non-human primates and (for GAL-021) in humans. To probe the site and mechanism of action of GAL-021 and GAL-160 we utilized spirometry in urethane anesthetized rats subjected to acute bilateral carotid sinus nerve transection (CSNTX) or sham surgery. In addition, using patch clamp electrophysiology we evaluated ionic currents in carotid body glomus cells isolated from neonatal rats. Acute CSNTX markedly attenuated and in some instances abolished the ventilatory stimulant effects of GAL-021 and GAL-160 (0.3 mg/kg IV), suggesting the carotid body is a/the major locus of action. Electrophysiology studies, in isolated Type I cells, established that GAL-021 (30 μM) and GAL-160 (30 μM) inhibited the BKCa current without affecting the delayed rectifier K+, leak K+ or inward Ca2+ currents. At a higher concentration of GAL-160 (100 μM), inhibition of the delayed rectifier K+ current and leak K+ current were observed. These data are consistent with the concept that GAL-021 and GAL-160 influence breathing control by acting as peripheral chemoreceptor modulators predominantly by inhibiting BKCa mediated currents in glomus cells of the carotid body.

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Acknowledgements

This work was supported by Galleon Pharmaceuticals, Inc.

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Authors and Affiliations

  1. School of Pharmacy, University of Reading, Reading, RG6 6UB, UK

    Mark L. Dallas

  2. Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK

    Chris Peers

  3. Galleon Pharmaceuticals Inc., Horsham, PA, 19044, USA

    Francis J. Golder, Santhosh Baby, Ryan Gruber & D. Euan MacIntyre

Authors
  1. Mark L. Dallas
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  2. Chris Peers
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  3. Francis J. Golder
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  4. Santhosh Baby
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  5. Ryan Gruber
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  6. D. Euan MacIntyre
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Corresponding author

Correspondence to D. Euan MacIntyre .

Editor information

Editors and Affiliations

  1. Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Faculty of Medicine and Health, Leeds, United Kingdom

    Chris Peers

  2. College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

    Prem Kumar

  3. Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio, USA

    Christopher Wyatt

  4. Department of Pediatrics, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

    Estelle Gauda

  5. Department of Biology, McMaster University, Hamilton, Ontario, Canada

    Colin A. Nurse

  6. Institute for Integrative Physiology and Center for Systems Biology of O(2) Sensing Biological Sciences Division, University of Chicago, Chicago, Illinois, USA

    Nanduri Prabhakar

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Dallas, M.L., Peers, C., Golder, F.J., Baby, S., Gruber, R., MacIntyre, D.E. (2015). GAL-021 and GAL-160 are Efficacious in Rat Models of Obstructive and Central Sleep Apnea and Inhibit BKCa in Isolated Rat Carotid Body Glomus Cells. In: Peers, C., Kumar, P., Wyatt, C., Gauda, E., Nurse, C., Prabhakar, N. (eds) Arterial Chemoreceptors in Physiology and Pathophysiology. Advances in Experimental Medicine and Biology, vol 860. Springer, Cham. https://doi.org/10.1007/978-3-319-18440-1_41

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