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

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 BK Ca current without affecting the delayed rectifi er K+ , leak K+ or inward Ca 2+ 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 infl uence breathing control by acting as peripheral chemoreceptor modulators predominantly by inhibiting BKCa mediated currents in glomus cells of the carotid body.