Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve
As part of a drug discovery effort to identify potent inhibitors of NaV1.7 for the treatment of pain, we observed that inhibitors produced unexpected cardiovascular and respiratory effects in vivo. Specifically, inhibitors administered to rodents produced changes in cardiovascular parameters and res...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Channels |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19336950.2022.2122309 |
| _version_ | 1811339368956166144 |
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| author | Rebecca M. Klein Mark E. Layton Hillary Regan Christopher P. Regan Yuxing Li Tracey Filzen Matt Cato Michelle K. Clements Jixin Wang Raul Sanoja Thomas J. Greshock Anthony J. Roecker Joseph E. Pero Ron Kim Christopher Burgey Christopher T. John Ying-Hong Wang Neetesh Bhandari Arie Struyk Richard L. Kraus Darrell A. Henze Andrea K. Houghton |
| author_facet | Rebecca M. Klein Mark E. Layton Hillary Regan Christopher P. Regan Yuxing Li Tracey Filzen Matt Cato Michelle K. Clements Jixin Wang Raul Sanoja Thomas J. Greshock Anthony J. Roecker Joseph E. Pero Ron Kim Christopher Burgey Christopher T. John Ying-Hong Wang Neetesh Bhandari Arie Struyk Richard L. Kraus Darrell A. Henze Andrea K. Houghton |
| author_sort | Rebecca M. Klein |
| collection | DOAJ |
| description | As part of a drug discovery effort to identify potent inhibitors of NaV1.7 for the treatment of pain, we observed that inhibitors produced unexpected cardiovascular and respiratory effects in vivo. Specifically, inhibitors administered to rodents produced changes in cardiovascular parameters and respiratory cessation. We sought to determine the mechanism of the in vivo adverse effects by studying the selectivity of the compounds on NaV1.5, NaV1.4, and NaV1.6 in in vitro and ex vivo assays. Inhibitors lacking sufficient NaV1.7 selectivity over NaV1.6 were associated with respiratory cessation after in vivo administration to rodents. Effects on respiratory rate in rats were consistent with effects in an ex vivo hemisected rat diaphragm model and in vitro NaV1.6 potency. Furthermore, direct blockade of the phrenic nerve signaling was observed at exposures known to cause respiratory cessation in rats. Collectively, these results support a significant role for NaV1.6 in phrenic nerve signaling and respiratory function. |
| first_indexed | 2024-04-13T18:25:34Z |
| format | Article |
| id | doaj.art-55057518620746559c951066d12dfcf1 |
| institution | Directory Open Access Journal |
| issn | 1933-6950 1933-6969 |
| language | English |
| last_indexed | 2024-04-13T18:25:34Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Channels |
| spelling | doaj.art-55057518620746559c951066d12dfcf12022-12-22T02:35:16ZengTaylor & Francis GroupChannels1933-69501933-69692022-12-0116123024310.1080/19336950.2022.2122309Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerveRebecca M. Klein0Mark E. LaytonHillary ReganChristopher P. ReganYuxing LiTracey FilzenMatt CatoMichelle K. ClementsJixin WangRaul SanojaThomas J. GreshockAnthony J. RoeckerJoseph E. PeroRon KimChristopher BurgeyChristopher T. JohnYing-Hong WangNeetesh BhandariArie StruykRichard L. KrausDarrell A. HenzeAndrea K. HoughtonMerck Research Laboratories, Merck & Co., Rahway, NJ, USAAs part of a drug discovery effort to identify potent inhibitors of NaV1.7 for the treatment of pain, we observed that inhibitors produced unexpected cardiovascular and respiratory effects in vivo. Specifically, inhibitors administered to rodents produced changes in cardiovascular parameters and respiratory cessation. We sought to determine the mechanism of the in vivo adverse effects by studying the selectivity of the compounds on NaV1.5, NaV1.4, and NaV1.6 in in vitro and ex vivo assays. Inhibitors lacking sufficient NaV1.7 selectivity over NaV1.6 were associated with respiratory cessation after in vivo administration to rodents. Effects on respiratory rate in rats were consistent with effects in an ex vivo hemisected rat diaphragm model and in vitro NaV1.6 potency. Furthermore, direct blockade of the phrenic nerve signaling was observed at exposures known to cause respiratory cessation in rats. Collectively, these results support a significant role for NaV1.6 in phrenic nerve signaling and respiratory function.https://www.tandfonline.com/doi/10.1080/19336950.2022.2122309Sodium channel inhibitorrespirationselectivityphrenic nerve |
| spellingShingle | Rebecca M. Klein Mark E. Layton Hillary Regan Christopher P. Regan Yuxing Li Tracey Filzen Matt Cato Michelle K. Clements Jixin Wang Raul Sanoja Thomas J. Greshock Anthony J. Roecker Joseph E. Pero Ron Kim Christopher Burgey Christopher T. John Ying-Hong Wang Neetesh Bhandari Arie Struyk Richard L. Kraus Darrell A. Henze Andrea K. Houghton Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve Channels Sodium channel inhibitor respiration selectivity phrenic nerve |
| title | Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve |
| title_full | Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve |
| title_fullStr | Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve |
| title_full_unstemmed | Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve |
| title_short | Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve |
| title_sort | association of respiratory failure with inhibition of nav1 6 in the phrenic nerve |
| topic | Sodium channel inhibitor respiration selectivity phrenic nerve |
| url | https://www.tandfonline.com/doi/10.1080/19336950.2022.2122309 |
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