ToxSci Advance Access published online on March 3, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn045
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Na+/H+ Exchanger-1 Inhibitors Reduce Neuronal Excitability and Alter Na+ Channel Inactivation Properties in Rat Primary Sensory Neurons
Department of Investigative Toxicology, Drug Safety Research & Development, Pfizer Global R & D, Groton, Connecticut 06340, USA
Address for Correspondence: Chris J. Somps, PhD, Investigative Toxicology, Drug Safety Research & Development Groton, MS 8274-1328, PGRD, Eastern Point Road, Groton, CT, 06340, Tel: (860) 715-2841, Fax: (860) 715-3577, E-mail: christopher.j.somps{at}pfizer.com
Received December 21, 2007; revision received February 22, 2008; accepted February 22, 2008
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Abstract |
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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 (CAP) 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 µm). Exposures to 1 and 10 µM 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 µM 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.
Key Words: patch clamp; dorsal root ganglion; dorsal root; NHE-1 inhibitor; sodium current; Zoniporide.