Na+/H+ exchanger-1 inhibitors reduce neuronal excitability and alter na+ channel inactivation properties in rat primary sensory neurons.
Toxicol Sci
; 103(2): 346-53, 2008 Jun.
Article
em En
| MEDLINE
| ID: mdl-18319243
ABSTRACT
Inhibitors of the Na+/H+ exchanger isoform 1 (NHE-1) have been associated with peripheral neuropathy in rats and dogs. Recent studies suggest that NHE-1 plays an important role in mediating neuronal excitability. To investigate potential NHE-1-mediated mechanisms contributing to neuronal toxicity, we studied the effects of NHE-1 inhibitors on nerve and dorsal root ganglion (DRG) neurons isolated from the adult rat. Compound action potentials (CAPs) were recorded from electrically stimulated sections of isolated sciatic nerve/DRG/root preparations. Whole-cell patch-clamp technique was used to record fast and slow voltage-dependent Na+ currents from dissociated DRG neurons (29-41 microm). Exposures to 1 and 10 microM of a selective NHE-1 inhibitor reduced the amplitude of the CAP recorded from the dorsal root by 33% and 58%, respectively (p < 0.05). The compound had no effect on CAPs recorded from the ventral root. Perfusion of dissociated DRG neurons with NHE-1 inhibitors at 10 and 100 microM shifted voltage-dependent inactivation curves of fast Na+ current by as much as 11 mV (p < 0.001) in the hyperpolarizing direction. No shift was observed in slow Na+ currents. No statistically significant drug effects were observed on voltage-dependent activation or recovery from inactivation of either fast or slow Na+ currents. These results suggest that NHE-1 inhibitors may reduce peripheral neuronal excitability by shifting fast Na+ channels into the inactivated state under physiological conditions. Such effects may underlie peripheral neuropathies reported in rats and dogs with NHE-1 inhibitors.
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Assunto principal:
Pirazóis
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Canais de Sódio
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Trocadores de Sódio-Hidrogênio
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Bloqueadores dos Canais de Sódio
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Gânglios Espinais
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Guanidinas
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Neurônios Aferentes
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article