Niflumic acid reduces the hyperpolarization-activated current (Ih) in rod photoreceptor cells

We examined the effects of niflumic acid (NFA), a chloride channel blocker, on the hyperpolarization-activated current (I_h) in newt rod photoreceptors. At 100 μM, NFA delayed the activation of I_h induced by hyperpolarizing voltage pulses to −83 mV from a holding potential of −43 mV, and reduced the steady-state current. However, reduction by NFA was weakened when I_h was activated by hyperpolarizing steps to −123 mV, suggesting that these effects were voltage-dependent. The suppressive effects of NFA on I_h were accompanied by a negative shift in activation voltage. NFA also delayed the relaxation of I_h tail currents, showing that this drug also inhibited deactivation of the current. The reversal potential and the fully activated conductance were not affected. These observations suggest that NFA reduces I_h by modifying the gating kinetics of the underlying channels. The suppressive actions of NFA remained when intracellular Ca²⁺ was strongly chelated, and the failure of suppression by NFA in inside-out patches suggests that the agent may act on the I_h channel from the extracellular side. These results, obtained in rod photoreceptors, are consistent with similar effects of NFA on I_f in cardiac myocytes, suggesting that both currents share similar pharmacological properties.