Association of respiratory failure with inhibition of NaV1.6 in the phrenic nerve.
Channels (Austin)
; 16(1): 230-243, 2022 12.
Article
em En
| MEDLINE
| ID: mdl-36239534
ABSTRACT
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Insuficiência Respiratória
/
Canal de Sódio Disparado por Voltagem NAV1.7
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article