Hemodynamic Responses to Doxapram in Normovolemic and Hypovolemic Dogs

Kim, S. I.; Winnie, Alon P.; Collins, Vincent J.; Shoemaker, W. C.

doi:10.1213/00000539-197150050-00003

Cited by 18 publications

(4 citation statements)

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“…[24][25][26] It was also observed in these studies that some of the known side-effects of this drug, were restricted to the distomer, raising hope for an improved ventilatory stimulant, with few side effects. Disappointingly, the known pressor effects of doxapram in human and dogs 47,48 were still evident with GAL-054. In conscious rats and in healthy human volunteers of a Phase 1 clinical trial.…”

Section: Discussionmentioning

confidence: 99%

Effects of the ventilatory stimulant, doxapram on human TASK‐3 (KCNK9, K2P9.1) channels and TASK‐1 (KCNK3, K2P3.1) channels

Cunningham

MacIntyre²,

Mathie

et al. 2019

Acta Physiologica

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Aims:The mode of action by which doxapram acts as a respiratory stimulant in humans is controversial. Studies in rodent models, have shown that doxapram is a more potent and selective inhibitor of TASK-1 and TASK-1/TASK-3 heterodimer channels, than TASK-3. Here we investigate the direct effect of doxapram and chirally separated, individual positive and negative enantiomers of the compound, on both human and mouse, homodimeric and heterodimeric variants of TASK-1 and TASK-3. Methods: Whole-cell patch clamp electrophysiology on tsA201 cells was used to assess the potency of doxapram on cloned human or mouse TASK-1, TASK-3 and TASK-2 channels. Mutations of amino acids in the pore-lining region of TASK-3 channels were introduced using site-directed mutagenesis. Results: Doxapram was an equipotent inhibitor of human TASK-1 and TASK-3 channels, compared with mouse channel variants, where it was more selective for TASK-1 and heterodimers of TASK-1 and TASK-3. The effect of doxapram could be attenuated by either the removal of the C-terminus of human TASK-3 channels or mutations of particular hydrophobic residues in the pore-lining region. These mutations, however, did not alter the effect of a known extracellular inhibitor of TASK-3, zinc. The positive enantiomer of doxapram, GAL-054, was a more potent antagonist of TASK channels, than doxapram, whereas the negative enantiomer, GAL-053, had little inhibitory effect. Conclusion: These data show that in contrast to rodent channels, doxapram is a potent inhibitor of both TASK-1 and TASK-3 human channels, providing further understanding of the pharmacological profile of doxapram in humans and informing the development of new therapeutic agents. K E Y W O R D Sdoxapram, enantiomers, heterodimers, K2P channels, respiratory stimulant, TASK-1 channels, TASK-3 channels This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

Effects of the ventilatory stimulant, doxapram on human TASK‐3 (KCNK9, K2P9.1) channels and TASK‐1 (KCNK3, K2P3.1) channels

Cunningham

MacIntyre²,

Mathie

et al. 2019

Acta Physiologica

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“…The cardiac effects of doxapram in humans are mild, perhaps less so than in dogs, which may reflect species differences. A mild pressor effect, more marked in hypovolemic than in normovolemic states (26) is probably due to release of catecholamines. Critically ill patient in the intensive care unit (ICU) demonstrated a 25% increase in cardiac output with doxapram, an effect best explained by an increase in cardiac contractility (26).…”

Section: Cardiac Effectsmentioning

confidence: 96%

“…A mild pressor effect, more marked in hypovolemic than in normovolemic states (26) is probably due to release of catecholamines. Critically ill patient in the intensive care unit (ICU) demonstrated a 25% increase in cardiac output with doxapram, an effect best explained by an increase in cardiac contractility (26). A latter study found no change in blood pressure or hemodynamics in patients given doxapram following thoracic surgery (29).…”

Section: Cardiac Effectsmentioning

confidence: 96%

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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“…In dogs, an acute increase in systemic blood pressure (10-20 mmHg) was reported after doxapram treatment, accompanied by an increase (~25 %) in cardiac output 24,40 . A clinical study in patients, receiving doxapram following thoracic surgery found no change in blood pressure or hemodynamics 41 .…”

Section: Antiarrhythmic Potential Of Doxaprammentioning

confidence: 99%

Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy

Wiedmann

Beyersdorf

Zhou

et al. 2021

Cardiovascular Research

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Aims TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In the present study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF. Methods and Results Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 d of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 d of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram. Conclusions Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients. Translational perspective Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.

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Hemodynamic Responses to Doxapram in Normovolemic and Hypovolemic Dogs

Cited by 18 publications

References 0 publications

Effects of the ventilatory stimulant, doxapram on human TASK‐3 (KCNK9, K2P9.1) channels and TASK‐1 (KCNK3, K2P3.1) channels

Effects of the ventilatory stimulant, doxapram on human TASK‐3 (KCNK9, K2P9.1) channels and TASK‐1 (KCNK3, K2P3.1) channels

A New Look at the Respiratory Stimulant Doxapram

Treatment of atrial fibrillation with doxapram: TASK-1 potassium channel inhibition as a novel pharmacological strategy

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