Reply to Meriney and Lacomis: Comment on direct aminopyridine effects on voltage-gated Ca²⁺ channels

Meriney and Lacomis (1) contended that the therapeutic actions of aminopyridines are mediated by voltage-gated K⁺ channels (Kv), but not voltage-gated Ca²⁺ channels (Cav). We originally showed that aminopyridines, including 4-aminopyridine (4-AP) and 3,4-diaminopyridine, directly stimulate Cav independent of their effects on blocking Kv (2). We subsequently found that 4-AP at 100 μm selectively stimulates L-type, but not N- or P/Q-type, channels (3). Furthermore, 4-AP's potentiating effect on neuromuscular transmission is abolished by an L-type channel blocker. These findings indicate that 4-AP-induced enhancement of neuromuscular transmission occurs predominantly through its direct stimulating effect on Cav. Our interpretation is also supported by several reports that 4-AP is effective in treating patients who have overdosed on L-type channel blockers.

We agree that lower micromolar concentrations of 4-AP are more clinically relevant and that our findings did not fully address the concentration discrepancy. It should be noted that clinically relevant doses/concentrations of 4-AP increase nerve conduction and synaptic transmission only in animals with axonal injury, not in uninjured animals (4, 5). Because normal tissues/neurons were used in our studies, 4-AP at lower micromolar concentrations may stimulate L-type Cav at nerve terminals under disease conditions.

Importantly, blocking Kv with 4-AP requires a minimum concentration of 100–1000 μm (2, 6), and many selective Kv blockers have little effect on enhancing synaptic and neuromuscular transmission (2). Meriney and Lacomis offered no evidence that 4-AP can block Kv at low micromolar concentrations. Thus, the potential contribution of Cav to the therapeutic action of aminopyridines should not be dismissed.