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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

  • Mark L. Dallas
  • Chris Peers
  • Francis J. Golder
  • Santhosh Baby
  • Ryan Gruber
  • D. Euan MacIntyreEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (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.

Keywords

GAL-021 GAL-160 BKCa channel Carotid body Carotid sinus nerve Peripheral chemoreceptor modulators 

Notes

Acknowledgements

This work was supported by Galleon Pharmaceuticals, Inc.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Mark L. Dallas
    • 1
  • Chris Peers
    • 2
  • Francis J. Golder
    • 3
  • Santhosh Baby
    • 3
  • Ryan Gruber
    • 3
  • D. Euan MacIntyre
    • 3
    Email author
  1. 1.School of PharmacyUniversity of ReadingReadingUK
  2. 2.Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and HealthUniversity of LeedsLeedsUK
  3. 3.Galleon Pharmaceuticals Inc.HorshamUSA

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