Abstract | BACKGROUND: The authors describe the preclinical pharmacological properties of GAL-021, a novel peripheral chemoreceptor modulator. METHODS: The ventilatory effects of GAL-021 were characterized using tracheal pneumotachometry (n = 4 to 6), plethysmography (n = 5 to 6), arterial blood gas analyses (n = 6 to 11), and nasal capnography (n = 3 to 4) in naive animals and those subjected to morphine-induced respiratory depression. Morphine analgesia in rats was evaluated by tail-flick test (n = 6). Carotid body involvement in GAL-021 ventilatory effects was assessed by comparing responses in intact and carotid sinus nerve-transected rats. Hemodynamic effects of GAL-021 were evaluated in urethane-anesthetized rats (n = 7). The pharmacological profile of GAL-021 in vitro was investigated using radioligand binding, enzyme inhibition, and cellular electrophysiology assays. RESULTS:
GAL-021 given intravenously stimulated ventilation and/or attenuated opiate-induced respiratory depression in rats, mice, and nonhuman primates, without decreasing morphine analgesia in rats. GAL-021 did not alter mean arterial pressure but produced a modest increase in heart rate. Ventilatory stimulation in rats was attenuated by carotid sinus nerve transection. GAL-021 inhibited KCa1.1 in GH3 cells, and the evoked ventilatory stimulation was attenuated in Slo1 mice lacking the pore-forming α-subunit of the KCa1.1 channel. CONCLUSIONS:
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Authors | Francis J Golder, Scott Dax, Santhosh M Baby, Ryan Gruber, Toshinori Hoshi, Courtney Ideo, Andrew Kennedy, Sean Peng, Veljko Puskovic, David Ritchie, Richard Woodward, Robert L Wardle, Michael R Van Scott, James C Mannion, D Euan MacIntyre |
Journal | Anesthesiology
(Anesthesiology)
Vol. 123
Issue 5
Pg. 1093-104
(Nov 2015)
ISSN: 1528-1175 [Electronic] United States |
PMID | 26352381
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Analgesics, Opioid
- Kcnma1 protein, mouse
- Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
- Triazines
- GAL021
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Topics |
- Analgesics, Opioid
(toxicity)
- Animals
- Carotid Body
(drug effects, physiology)
- Female
- Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
(antagonists & inhibitors, physiology)
- Macaca fascicularis
- Male
- Mice
- Mice, Transgenic
- Rats
- Rats, Sprague-Dawley
- Respiration
(drug effects)
- Respiratory Insufficiency
(chemically induced, physiopathology, prevention & control)
- Respiratory Mechanics
(drug effects, physiology)
- Triazines
(pharmacology, therapeutic use)
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