The Ventilatory Stimulant Doxapram Inhibits TASK Tandem Pore (K2P) Potassium Channel Function but Does Not Affect Minimum Alveolar Anesthetic Concentration

Cotten, Joseph F.; Keshavaprasad, Bharat; Laster, Michael J.; Eger, Edmond I.; Yost, C. Spencer

doi:10.1213/01.ane.0000194289.34345.63

Cited by 73 publications

(89 citation statements)

References 25 publications

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“…Based on this information, our dose for in vivo studies was well below this limit. DXP has been shown to work through inhibition of TASK-1/TASK-3 heterodimeric potassium channels (70), which, in general, provide a background "leak" potassium conductance important in determining the resting membrane potential and the excitability of host cells (70)(71)(72). This inhibition of potassium channels is predicted to stimulate catecholamine release, which, in turn, results in the stimulation of peripheral carotid chemoreceptors.…”

Section: Discussionmentioning

confidence: 99%

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Andersson

Fitts

Kirtley

et al. 2016

Antimicrob Agents Chemother

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h Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

Andersson

Fitts

Kirtley

et al. 2016

Antimicrob Agents Chemother

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“…To our knowledge, the effects of almitrine on leak K + currents or TASK channels have not been tested. BKCa current in rat glomus cells is also inhibited by doxapram (IC50 5µM) (Peers, 1991), which also inhibits current through cloned rat TASK channels expressed in oocytes with IC50 400nM for TASK-1 and IC50 47µM for TASK-3 (Cotten et al, 2006).…”

Section: Xx5 Discussionmentioning

confidence: 99%

“…Leak K + currents, carried by TASK-channels are implicated in carotid body activation by physiological stimuli, such as hypoxia , Kim et al 2012, as well as by doxapram (Cotten et al, 2006).…”

Section: Xx45 Gal-021 and Gal-160 Do Not Inhibit Leak K + Currents Imentioning

confidence: 99%

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

Dallas

Peers

Golder³

et al. 2015

Advances in Experimental Medicine and Biology

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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 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 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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“…Cotten et al recently established that doxapram has potent direct inhibitory effects on cloned TASK-1 and TASK-3 channels (12). Doxapram inhibited TASK-1 (half-maximal effective concentration [EC 50 ], 410 nM), TASK-3 (EC 50 , 37 ìM), and TASK-1/TASK-3 heterodimeric channel function (EC 50 , 9 ìM).…”

Section: Role For K 2p Channels In Doxapram Actionmentioning

confidence: 99%

A New Look at the Respiratory Stimulant Doxapram

2006

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A number of life-threatening clinical disorders may be amenable to treatment with a drug that can stimulate respiratory drive. These include acute respiratory failure secondary to chronic obstructive pulmonary disease, post-anesthetic respiratory depression, and apnea of prematurity. Doxapram has been available for over forty years for the treatment of these conditions and it has a low side effect profile compared to other available agents. Generally though, the use of doxapram has been limited to these clinical niches involving patients in the intensive care, post-anesthesia care and neonatal intensive care units. Recent basic science studies have made considerable progress in understanding the molecular mechanism of doxapram's respiratory stimulant action. Although it is unlikely that doxapram will undergo a clinical renaissance based on this new understanding, it represents a significant advance in our knowledge of the control of breathing.

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The Ventilatory Stimulant Doxapram Inhibits TASK Tandem Pore (K2P) Potassium Channel Function but Does Not Affect Minimum Alveolar Anesthetic Concentration

Cited by 73 publications

References 25 publications

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

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

A New Look at the Respiratory Stimulant Doxapram

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