Advance Access publication March 3, 2008 Naþ/Hþ Exchanger-1 Inhibitors Reduce Neuronal Excitability and Alter Naþ Channel Inactivation Properties in Rat Primary Sensory Neurons

Inhibitors of the Na1/H1 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 Na1 currents from dissociated DRG neurons (29–41 mm). Expo-sures to 1 and 10mM 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 100mM shifted voltage-dependent inactivation curves of fast Na1 current by as much as 11 mV (p < 0.001) in the hyperpolarizing direction. No shift was observed in slow Na1 currents. No statistically significant drug effects were observed on voltage-dependent activation or recovery from inactivation of either fast or slow Na1 currents. These results suggest that NHE-1 inhibitors may reduce peripheral neuronal excitability by shifting fast Na1 channels into the inactivated state under physiological conditions. Such effects may underlie periph-eral 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. Pharmacological inhibition of the Naþ/Hþ exchanger iso-form 1, referred to as NHE-1, has been extensively demonstrated to protect the heart from ischemia-reperfusio